The Economic Impact and

Functional Applications of
Human Genetics and Genomics
Commissioned by the American Society of Human Genetics
Produced by TEConomy Partners, LLC.
Report Authors: Simon Tripp and Martin Grueber

May 2021
TEConomy Partners, LLC (TEConomy) endeavors at all times to produce work of the highest quality, consistent with our contract
commitments. However, because of the research and/or experimental nature of this work, the client undertakes the sole
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Acknowledgements
ASHG and the project authors wish to thank the following organizations for their generous support of this study.

Invitae Corporation, San Francisco, CA

Regeneron Pharmaceuticals, Inc., Tarrytown, NY

The project authors express their sincere appreciation to the following indi-
viduals who provided their advice and input to this project.

ASHG Government and Public Advocacy Committee

Lynn B. Jorde, PhD
ASHG Government and Public Advocacy Committee (GPAC) Chair, President (2011)
Professor and Chair of Human Genetics
George and Dolores Eccles Institute of Human Genetics
University of Utah School of Medicine

Katrina Goddard, PhD

ASHG GPAC Incoming Chair, Board of Directors (2018-2020)
Distinguished Investigator, Associate Director, Science Programs
Kaiser Permanente Northwest

Melinda Aldrich, PhD, MPH

Associate Professor, Department of Medicine, Division of Genetic Medicine
Vanderbilt University Medical Center

Wendy Chung, MD, PhD

Professor of Pediatrics in Medicine and
Director, Clinical Cancer Genetics
Columbia University

Mira Irons, MD
Chief Health and Science Officer
American Medical Association

Peng Jin, PhD

Professor and Chair, Department of Human Genetics
Emory University

Allison McCague, PhD

Science Policy Analyst, Policy and Program Analysis Branch
National Human Genome Research Institute
Rebecca Meyer-Schuman, MS
Human Genetics Ph.D. Candidate, Antonellis Lab
University of Michigan

Charles Schwartz, PhD

Senior Research Scientist Emeritus
Greenwood Genetic Center

Wendy Uhlmann, MS, CGC

Clinical Professor of Internal Medicine and Clinical Professor of Human Genetics
Genetic Counselor and Clinic Coordinator, Medical Genetics Clinic
University of Michigan

David Wheeler, PhD

Director of Precision Genomics
Department of Computational Biology
St Jude Children’s Research Hospital

Advisors
Lawrence Brody, PhD
Director, Division of Genomics and Society
National Human Genome Research Institute

Eric D. Green, MD, PhD

Director
National Human Genome Research Institute

Cristina Kapustij, MS
Chief, Policy and Program Analysis Branch
National Human Genome Research Institute

Cynthia Casson Morton, PhD

ASHG President (2014)
Professor of Obstetrics, Gynecology and Reproductive Biology and Professor of Pathology
Harvard Medical School
Chair, Obstetrics and Gynecology, and Director of Cytogenetics
Brigham and Women’s Hospital

Heather C. Mefford, MD, PhD

ASHG Program Committee Chair (2018), Board of Directors (2021)
Associate Professor
Genetics, Epilepsy Program—Center for Integrative Brain Research
University of Washington and Seattle Children’s

Kiran Musunuru, MD, PhD, MPH, ML

ASHG Program Committee Chair (2019), Board of Directors (2021)
Professor of Medicine
Director, Genetic and Epigenetic Origins of Disease Program, Cardiovascular Institute
Perelman School of Medicine at the University of Pennsylvania

David L. Nelson, PhD

ASHG President (2018)
Professor
Molecular and Human Genetics
Baylor College of Medicine

Telephone and Email Interview Participants

Todd R. Golub, MD
Director, Founding Core Institute Member, Broad Institute of MIT and Harvard, and
Founding Core Member and Director of the Gerstner Center for Cancer Diagnostics, Broad Institute

Leroy Hood, MD, PhD

Senior Vice President and Chief Science Officer
Providence St. Joseph Health, and
Chief Strategy Officer and Professor, Institute for Systems Biology

Kathryn A. Phillips, PhD

Professor of Health Economics and Health Services Research, and
Founding Director, UCSF Center for Translational and Policy Research on Personalized Medicine
University of California, San Francisco

Philip Reilly, MD, JD

Venture Partner, Third Rock Ventures

David Veenstra, PharmD, PhD

Professor and Associate Director, Comparative Health Outcomes, Policy & Economics (CHOICE) Institute
School of Pharmacy, University of Washington

Carrie D. Wolinetz, PhD

Associate Director for Science Policy
National Institutes of Health

American Society of Human Genetics Staff

Mona Miller, MPP
Chief Executive Officer

Derek Scholes, PhD

Senior Director, Policy and Advocacy

Lyly G. Luhachack, PhD

Policy and Advocacy Specialist
Contents

Executive Summary.......................................................................................................................................................ES-1
I. Introduction......................................................................................................................................................................... 1
A. Science as a Driver of Economic and Social Advancement.................................................................................. 1
B. Funding and Supporting American Science................................................................................................................. 2
C. Human Life Sciences..................................................................................................................................................................... 2
D. The Genome—Coding Life........................................................................................................................................................ 3
E. Human Genetics and Genomics—Applications and Impacts............................................................................ 5
F. Purpose of the Study..................................................................................................................................................................... 7
G. Limitations of the Study ............................................................................................................................................................ 9
II. The Economic Impact of Human Genetics and Genomics............................................................................ 11
A. Measuring Human Genetics and Genomics Economic Impacts......................................................................11
B. Drivers of Economic Impacts: Methodology and Assumptions.......................................................................13
C. Economic Impact Analysis of Human Genetics and Genomics in the U.S............................................... 19
D. Healthcare Costs for Genetic Diseases........................................................................................................................... 20
III. The Functional Impacts of Human Genetics and Genomics..................................................................... 23
A. The Structure of Functional Impacts (Application Domains of Human Genomics)..........................23
B. Fundamental Knowledge Advancement..................................................................................................................... 24
C. Functional Applications for Human Health..................................................................................................................26
D. Summary........................................................................................................................................................................................... 65
IV. Into the Future.............................................................................................................................................................. 67
A. Ongoing Fundamental Discovery..................................................................................................................................... 68
B. Expanding the Clinical Application of Genomics.................................................................................................... 70
C. Educating and Updating Providers................................................................................................................................... 71
D. Ethical Considerations............................................................................................................................................................... 71
E. Conclusion..........................................................................................................................................................................................72
Glossary of Terms............................................................................................................................................................... 75
Appendix—Additional Economic Impact Information....................................................................................... 77
Executive Summary
Modern life sciences and associated advancements
in biopharmaceuticals, diagnostics, medical devices,
and healthcare services have enabled unprecedented
improvements in human health and longevity.

The Economic Impact

Perhaps nowhere has life science research advanced
of the Human Genetics
more in the modern age than through insights provid-
ed by genetics and genomics. This field is both funda-
and Genomics Sector
mental in biological research—elucidating the basic The U.S. economy has advanced on the back of sci-
code of life, DNA, upon which our form and function entific progress—progress that has enabled national
depend—and in enabling applied and translational leadership in diverse industries such as aerospace,
discoveries across most diseases and health disorders. energy, agriculture, transportation, advanced ma-
terials, information technology, and biotechnology.
This report examines and describes the positive im- Continuing to strengthen the competitiveness of
pacts that are derived from modern human genetics the U.S. economy requires ongoing expansion of the
and genomics science and its associated commercial national capacity for innovation and the scientific and
and clinical applications on the nation’s economy, technological research and development (R&D) upon
society, and the health and well-being of individuals. which innovation depends. Particularly important is
leveraging science and innovation to give rise to new,
Twenty years after the completion of the Human fast-growing, advanced industries that spark econom-
Genome Project, there has been widespread expan- ic growth and improved standards of living. Born out
sion and application of human genetics and genomics of federal investment in the Human Genome Project,
technologies. Technologies for sequencing and for the U.S. achieved early leadership in the genetics and
genome analysis have advanced quite spectacularly— genomics industry—leadership that has resulted in the
to the extent that genome sequencing is now both growth of an important and dynamic economic sector.
fast and affordable. The technologies of genetics
and genomics, and the research advancements they Substantial U.S. economic activity, supporting a
have enabled scientists to make, have now brought large volume of high-paying jobs across the nation,
human genetics and genomics to a visible inflection is generated from the performance of genetic and
point—a point in time where scientific discoveries are genomic research, the development and manufactur-
rapidly translating into clinical insights and signifi- ing of commercial genomic technologies, the broad
cant human health and well-being advancements. range of diagnostics products and therapeutics on the

ES-1
Figure ES-1: The Economic Impact of the Human Genetics
and Genomics Sector in the United States

DIRECT EFFECT INDIRECT EFFECT INDUCED EFFECT

Total Economic
Human Genetics & Human Genetics &
Impacts of
Genomics Focused Purchase of Secondary Genomic Supported
Research Expenditures, Inputs & Services from U.S. Employees Spending
Human Genetics
Services, and Corporate Suppliers and Vendors Disposable Income & Genomics
Operations in the U.S. in the U.S. Economy

$3.3B
FEDERAL RESEARCH
Federal research funding, using a conservative definition of what constitutes human genetics
and genomics research, reached $3.3 billion in 2019, with most of this coming from NIH.

152,000
89,464 core private sector industry jobs and an estimated 62,710 additional extended
industry jobs (related employment share from major pharmaceutical and medical
INDUSTRY JOBS testing/diagnostics companies).

850,000
With a direct employment estimate of nearly 166,000 academic and industry jobs,
human genetics and genomics supports more than 850,000 total jobs. Each direct
TOTAL SUPPORTED JOBS human genetics and genomics job supports 4.12 additional jobs in the U.S. economy.

The direct economic activity generated by the human genetics and genomics industry

$ $265B
TOTAL ECONOMIC IMPACT
exceeds $108 billion in 2019 and ultimately supports a total of more than $265 billion across
the U.S. economy. Every $1.00 of direct human genetics and genomics activity generates
an additional $1.45 in the U.S. economy.

$5.2B
The federal tax revenues of $5.2 billion generated by the direct operations of the human
genetics and genomics domain alone surpasses the single year federal investment in human
DIRECT FEDERAL TAX REVENUES genetics and genomics of approximately $3.3 billion across all federal agencies.

In the simplest of terms, from a federal investment and revenue perspective, the overall

4.75:1.00
FEDERAL RETURN ON INVESTMENT
economic impacts of U.S. human genetics and genomics generates a return on investment
(ROI) of more than 4.75 to 1.00 ($3.3 billion in federal investment in human genetics and
genomics – while the whole domain generates $15.5 billion in federal tax revenues).

Source: TEConomy Partners, LLC.

market that are derived from genomics knowledge well-being. Figure ES-1 summarizes some of the
and have pharmacogenomic associations, and the topline findings from the economic impact analysis.
associated healthcare services that are delivered.
The economic impact of the human genetics and The sector also supports high wage jobs. Because it
genomics sector on the U.S. economy is assessed requires a well-educated and technically skilled work-
using the standard regional economics methodology force, direct jobs in the genetics and genomics sector
of input-output analysis. The results demonstrate pay more than $130,000 in annual total compensation
the growth of a powerful economic sector across (income and benefits) per worker, while the total jobs
the nation— a sector that has grown five-fold in supported by human genetics and genomics eco-
its annual economic impact since 2010. Even more nomic activity (direct + induced) average greater than
importantly, it is a sector that also generates robust $81,000 in compensation per employee.
functional impacts in terms of human health and

ES-2
The Functional Impacts of
treatment) and is increasingly front-and-center in
Human Genetics and Genomics neurological, psychiatric, gastrointestinal, immunolog-
The speed and affordability of gene sequencing ic, rheumatologic, dermatologic, pain management,
and advanced genomic data analytics have helped and other application areas of clinical medicine. It is
produce deep biomedical insights and innovations, also fundamental to advancements being made in
which are being combined with advancements in the diagnosis and treatment of a wide range of rare
biopharmaceuticals, diagnostics, and other medical diseases and disorders—helping to end the diagnostic
technologies that leverage genomic information. An odysseys of millions of patients afflicted with rare
evident tipping point has been achieved where the diseases that have been difficult to diagnose and
utility of genomics and wide-spread use of sequencing sparsely served in terms of available treatments.
is clearly advantageous for significantly enhancing
human health outcomes. As this report highlights, In reviewing the functional applications of human
the functional application of human genetics and genetics and genomics, the authors find that
genomics to clinical healthcare is now a daily reality the positive impacts being generated are highly
in some medical fields (e.g., cancer diagnosis and diverse—generated within eight major domains

Figure ES-2: Functional Biomedical Impact Domains

(Applications) of Human Genetics and Genomics

Examining the impact Analyzing sequencing

of human interactions data from large and
with the environment diverse populations to
on the human genome, provide deep insights
gene regulation, muta- into disease biology and
tion, and disease identify characteristics
etiology. associated with health.

Environmental Genomics Minable Big Data

and Metagenomics (Discovery Science)
Examining the human Genetic and genomic
genome’s impact testing to identify
upon hosted microbial 8 1 carrier status, and
populations, and identify predisposition
microbe impacts upon Biomedical for genetic disease via
Human-Microbe Identifying Predisposition
the human genome 7 Application
Biomedical 2 prenatal, newborn and
and gene expression Interaction to Diseases and Disorders adult screening.
Domains of
Application
Human of
Domains
Genetics
Human Genetics
Modifying the genes Gene Editing and and
Genomics Diagnosing Diseases Using biomarkers
associated with a 6 3 and gene signatures
disease or disorder
and Gene Therapy Genomics and Disorders
to diagnose the
to treat or cure the presence of diseases
5 4
disease or disorders that are
associated with
Pharmacogenomics Rational Drug specific genes or
(Personalized Medicine) Development gene products.

Using sequencing data Using genetic

to enable the information and gene
prescription of drugs associated biomarkers
best suited to the to inform molecular
patient’s genotype targeting in drug design.
(increasing efficacy and
reducing adverse events)

Source: TEConomy Partners, LLC.

ES-3
of activities impacting human health. These are to inform family planning and associated decisions);
summarized and briefly described in Figure ES-2. 2) pre-natal and post-natal testing, which focuses on
testing for genetic predisposition to disease in the
The eight domains identified in Figure ES-2 are fetus or in newborns; and, 3) child and adult testing.
already having profound impacts in advancing
clinical health sciences and health outcomes. Information provided by predisposition screening
Each of these areas is profiled briefly below and enables patients and their physicians to make in-
detailed further in the full body of the report. formed healthcare decisions, plan follow-up health
monitoring strategies, and identify strategies for
1. Minable Big Data (Discovery Science) care using evidence-based clinical best practices.
Advancements in high-speed gene sequencing
technologies have facilitated the assembly of exabytes1 3. Diagnosing Disease,
of genomic information that can be analyzed (assisted Rare Diseases, and Disorders
by highly advanced and automated analytical systems) Whole genome and whole exome sequencing are
for unique insights into genome structure and func- increasingly being used in clinical practice to facilitate
tion and the association of gene variants with human the diagnosis of diseases or health disorders. In addi-
diseases and health disorders. It is anticipated that by tion to the many common chronic diseases (such as
2025 more than 60 million patients will have had their heart disease, diabetes, cancer, etc.), approximately
genome sequenced in a healthcare context. Access to 2
7,000 rare diseases have been recognized3 and have
extremely large volumes of sequenced individuals pro- historically been a significant challenge to diagnose.
vides a rich platform for important scientific discovery Rare diseases, by their inherent nature of being rare,
and for advancing the identification and classification present diagnostic challenges because so few physi-
of genomic variant pathogenicity (variants associated cians have encountered them. Often, these diseases
with causation of disease). Both science and techno- may present symptoms seen in other, more common
logical capabilities are now at the point where the diseases, resulting in an understandable misdiagnosis
analysis of genomic and phenomic big data provides and inappropriate treatment strategies being adopt-
a powerful pathway forward for biomedical discovery ed. Patients, and their families, may embark on long
and clinical applications to improve human health. “diagnostic odysseys”, seeing dozens of practitioners,
undergoing multiple tests and procedures, enduring
2. Identifying Predisposition fruitless attempts at treatment over many years
to Diseases and Disorders without ever getting a definitive, accurate diagnosis.
One of the primary research and clinical applications Genetic and genomic testing provides a pathway
of human genetics and genomics is identification of to solving this dilemma in multiple diseases and
the potential predisposition for individuals to develop disorders impacting many thousands of patients.
specific diseases or health disorders. Modern genetic
screening for such predispositions divides into three Collectively, rare diseases have a significant population
key categories: 1) carrier screening, which tests a impact, with approximately 1 in 10 individuals having
prospective parent for the presence of gene variants a rare disease (estimated at between 25-30 million pa-
that have been shown to be associated with risk of tients in the U.S. and 350 million worldwide).4 Modern
passing down a hereditary disorder (thereby helping genetic and genomic diagnostic tools, informed by

1 An exabyte = 10006 bytes (1,000,000,000,000,000,000 bytes).

2 Birney, Ewan. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics Magazine, vol. 6, no. 2, March-
April 2019.
3 National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center. “FAQs About Rare Diseases.” https://
rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases. Accessed 12 May 2021.
4 Ibid.

ES-4
The ability to tailor a drug regimen to a specific genetic code that is
truly personalized to that specific DNA double helix has been a dream of
researchers, physicians, and patients alike. Advances in precision medicine,
specifically around the genome…are making this dream a reality.”
Kristen Ciriello Pothier. Personalizing Precision Medicine. A Global Voyage from Vision to Reality. John Wiley & Sons, Inc., 2017.

scientific advancements in identifying gene variants they are more likely to demonstrate efficacy in
associated with specific diseases, are providing clear their trials by virtue of being rationally targeted.
diagnostic benefits. By deploying genetic and ge-
nomic testing, up to and including whole genome It is also notable that progress in genetics and
sequencing, diagnostic odysseys may be ended for genomics has enabled pharmaceutical research
many patients—not only providing a pathway to to increasingly address rare diseases—helping to
appropriate treatment but also reducing significant rebalance biopharmaceutical research in terms of
waste in the healthcare system and the associated work on chronic diseases versus rare diseases.
costs of incorrect diagnosis. Even if no treatment is
available, peace of mind can result through simply 5. Precision Medicine and Targeted
having an “answer” and being able to end the costly Therapeutics (Pharmacogenetics)
hunt for diagnosis. It has been noted that “this is Having an ability to sequence a patient’s whole
clearly the most powerful diagnostic tool ever devel- genome rapidly and cost-effectively has opened
oped for the millions of children with rare diseases.”5 the door to a new paradigm in healthcare termed
“precision medicine” whereby an individual’s genetic
4. Rational Drug Development profile is used to guide decisions made in regard to
Rational drug development uses genetic and genomic the prevention, diagnosis, and treatment of disease.
information to advance the development of new The discipline of “pharmacogenetics” (also “pharma-
biopharmaceuticals to treat diseases. Biomarkers cogenomics”) has developed as a field of research
(genes or gene products) are providing molecular and, increasingly, clinical practice, that addresses the
targets for purposefully designed drugs that are engi- genetically determined variation in how individuals re-
neered to bind to targets. The application of genetics spond to specific drugs in terms of differences in dose
and genomics to drug development has resulted in requirement, efficacy, and the risk of adverse drug
multiple clinical successes, with specific examples reactions (ADRs). It is increasingly being employed to
highlighted in this report. Biopharmaceutical com- help physicians select the “right drug and the right
panies are now able to use genetic and genomic dose” for a patient based on their genome (assuming
information to target the trials of their pharma- there is statistically significant clinical information
ceutical and biologic molecules to patients who linking a drug to specific gene variants in terms of effi-
have been preselected through the presence of cacy and side effects). Currently, pharmacogenetics is
biomarkers (often genetic). This has the potential to improving health outcomes along three primary paths:
advance more drugs successfully to market since

5 Kingsmore, Stephen. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics Magazine, vol. 6, no. 2,
March-April 2019.

ES-5
• Selection of the therapeutic (among multiple disease through what is termed gene editing or gene
choices) that is likely to prove most efficacious therapy. Ultimately, gene editing and gene therapy
based on the patient’s genome and a drug’s represent new pathways to the treatment and curing
proven efficacy for their specific genotype. of diseases, but these approaches are still in the early
• Ruling-out a therapeutic (among multiple stages of clinical application.6 Part of the caution in
choices) based on the patient’s genome and clinical application arises from a need for further study
a drug’s potential for unacceptable adverse of the potential for off-target gene edits (mutagenesis)
side effects given their specific genotype. to occur in non-targeted genes and for unintended
• Development of an optimized drug dosage for a mosaicism to occur. Despite these challenges, there
patient based on their genotype’s influence on are several important gene therapies that have suc-
the rate at which they will metabolize the drug. cessfully advanced through clinical trials, helping to
treat a series of previously untreatable rare diseases.
Cancer is perhaps the most well-recognized cluster
It is a promising field for ongoing advancement.
of disease for which genetic tests may impact drug
selection and dosing; however, analysis of U.S. Food 7. Human-Microbe Interactions
and Drug Administration (FDA) data shows that Each of us is host to communities of trillions of
pharmacogenetic associations are also in place for microbes. Microbes serve important functions for
multiple chronic diseases and conditions, covering humans, for example aiding our digestion and the
applications in major categories such as cardio- breakdown of micronutrients, defending us from
vascular disease, gastroenterological diseases and pathogenetic microbes, and priming our immune
disorders, infectious diseases, neurological diseases system. Recent research has shown that we have a
and disorders, psychiatric conditions, and rheuma- symbiotic two-way genetic interaction with microbes,
tologic diseases. Pharmacogenetic associations with microbes impacting our genes and gene expres-
now span a range from relatively rare diseases, such sion, and human genotype impacting the make-up of
as Tourette’s syndrome and Tardive dyskinesia, to the microbial communities we host.
common conditions, such as hypercholesterolemia
and depression. There are more than 100 drugs for While microbes play an important positive role in
which the associations are now listed by the FDA. our health, many microbes are pathogenic, being
the causative agents for human infectious diseases.
6. Gene Editing and Gene Therapy Research is finding that individual genomes can
As noted above, genetic and genomic advancements be associated with resistance or susceptibility to
are elucidating gene variant associations with the certain infectious diseases, and the recent COVID-19
predisposition for disease, providing enhanced diag- pandemic, coinciding with the current significant
nosis of diseases, and providing increasingly effective volumes of patients for which genome sequences
pathways for therapeutics and disease treatment. are available, has enabled significant clinical study of
Another developing approach is to use the expanding genome effects on viral susceptibility and resistance.
knowledge of gene variants associated with disease
to provide targets for potential modification of a
patient’s genes themselves—modification that has
the goal of treating, and potentially curing, the target

6 It should be noted that the discussion of gene editing and gene therapy pertains to modifying non-hereditable (somatic) genes—changes
to an individual’s genes that will only affect the individual being treated but not the genes of future generations. There is ongoing discussion
and public debate about the potential use of gene editing to make heritable genetic changes (changes to the germline). Such genome edits
would result in changes to an individual’s DNA being passed to their progeny and subsequent generations. At the present time, the general
consensus of leading organizations in medical genetics, genetics research, and genetic counseling is that genome editing which culminates
in human pregnancy should not be undertaken, and that further research is required into the scientific, clinical, and ethical implications of
germline editing.

ES-6
8. Metagenomics and
Environmental Genomics
Genomics in the There exists a vast network of interactions between
COVID-19 Pandemic individual genomes and other biological and environ-
mental systems. Each of us walks a slightly different
Genomics rapidly assumed crucial roles in
COVID-19 research and clinical care in areas such path through life, experiencing different influences
as: (1) the deployment of DNA and RNA sequenc- upon our physiology in terms of the food we eat, the
ing technologies for diagnostics, tracking of viral
isolates, and environmental monitoring; (2) the amount of sun we expose ourselves to, the environ-
use of synthetic nucleic acid technologies for ments we experience in our jobs, the pathogens that
studying SAR- CoV-2 virulence and facilitating vac-
cine development; (3) examination of how human we by chance encounter, etc. Any and all of these and
genomic variation influences infectivity, disease more may be subtly changing (mutating) letters in our
severity, vaccine efficacy, and treatment response;
(4) the adherence to principles and values relat-
genome or periodically influencing gene regulation
ed to open science, data sharing, and consortia or expression. Metagenomics is the field of genomics
based collaborations; and (5) the provision of
that investigates these interactions and their effects.
genomic data science tools to study COVID-19
pathophysiology. The growing adoption of ge-
nomic approaches and technologies into myriad Obviously, the human genome is highly complex. Add
aspects of the global response to the COVID-19
pandemic serves as another important and highly to that all the genomes in the environment with which
visible example of the integral and vital nature of one may come into contact, and the enormity of the
genomics in modern research and medicine.
subject comes into focus. Large-scale sequencing
Eric D. Green, et al. “Perspective: Strategic Vision for programs are, however, providing a rich resource of
Improving Human Health at the Forefront of Genomics.”
Nature, vol. 586, no. 29, October 2020. data for scientists to mine in metagenomic studies.

ES-7
Conclusion
The fields of human genetics and genomics are beyond their initial expectations, with many
having profound positive impacts not only in terms more anticipated in the next decade.7
of biomedical discovery, but also in terms of the
While generating these positive functional impacts
clinical practice of medicine—working to improve
is the raison d’etre for pursuing the advancement of
the lives for millions of patients and demonstrating
human genetics and genomics, it has also had the very
great promise for future highly positive contribu-
positive spillover effect of building a powerful science-
tions to human health and well-being worldwide.
and technology-based economic sector for the U.S.—a
sector that supports over 850,000 jobs across the nation
As the eight functional domains for human health
and generates a $265 billion economic impact in terms
application of genetics and genomics illustrate,
of U.S. economic output. The continued innovation in
this field of science (and the expanding industry
human genetics and genomics is expanding the stock
associated with it) generates a profound impact
of knowledge upon which our continued advancement
on biomedical research and the practice of clinical
depends and shows great promise to continue to do
healthcare. In addition to applications in human
so long into the future. The field represents a particu-
medicine and wellness, there are also several
larly strong example of how investing in fundamental
non-medical human applications of genetics and
and applied science generates robust economic,
genomics, including forensic science, anthropology
social, and individual benefits for humankind.
and genealogy, evolutionary biology, and paternity
testing. These are also highlighted in the report.

It is readily evident that, as fundamental genomic

knowledge has expanded, the enhanced understand-
ing of genetic mechanisms generated, in concert with
access to rich whole exome and genome datasets
(and associated reference compendia of human gene
variants), has opened the door to a new era of discov-
ery and progress in medicine. The impacts of these
advancements are now increasingly reverberating
across medicine, a fact highlighted by Eric Green, the
Director of the National Human Genome Research
Institute (NHGRI), and colleagues who note that:”

With insights about the structure and function

of the human genome, and ever improving
laboratory and computational technologies,
genomics has become increasingly woven
into the fabric of biomedical research, medical
practice, and society. The scope, scale, and
pace of genomic advances so far were nearly
unimaginable when the human genome
project began; Even today, opportunities

7 Green, Eric D., et al. “Perspective: Strategic Vision for Improving Human Health at the Forefront of Genomics.” Nature, vol. 586, 29 Oct. 2020.

ES-8
I. Introduction
From Fundamental
to Applied Research
Public/Private and Market/
Non-Market Returns
A. Science as a Driver of Economic Scientific research may produce both private and so-
and Social Advancement cial returns. Research that leads to improved knowl-
edge, national security, public health, enhanced food
Scientific research is of high importance not only be- security, etc. provides social (public) returns. Research
generating a patented technology or improving the
cause it reveals fundamental truths but also because it productivity of a production process provides private
increases the stock of human knowledge upon which returns to those inventing and using the research-
based tool or knowledge for commerce. Often, re-
economic, societal, and technological progress de- search leads to both forms of return at the same time.
pends. The U.S. economy, in particular, has advanced For example, the development of a vaccine for an
infectious disease provides private monetary returns
on the back of scientific progress that has enabled to the vaccine developer and social returns through
national leadership in diverse industries such as aero- enhanced public health. Both types of returns mo-
tivate investment in research. Research finds that
space, energy, agriculture, transportation, materials,
the rate of social return on R&D exceeds the rate of
digital technology, communications, and healthcare. private return (although both are strong). Despite the
large U.S. national investment in research, analysis
shows that optimal investment in research would be
In the past two decades, scientific advancements more than four times actual investment.
have seen new industries advanced, typically with the
The robust levels of social return on research un-
U.S. being an early innovator in commercial applica- derpin the core rationale for public investment in
tions of both science and associated technologies. research. Indeed, without public support for research,
a wide-ranging and important suite of research topics
Developments in physics, chemistry, biology, and would go unaddressed. Because so much important
mathematical and computational sciences have paved research is non-market (focused on phenomena or
subject matter without an immediate line-of-sight to
the way for new industries in nanotechnology and a market application) or focused on the generation of
advanced materials, renewable energy, AI-powered social returns (benefiting society overall, but perhaps
not able to realize private returns to investment),
autonomous systems, biotechnology, and genetic the public sector plays a critically important fund-
engineering. There has also been an observable trend ing function in the R&D ecosystem. Further, private
sector investment in basic science is relatively scarce
of “convergence,” whereby multiple science and
because of the speculative nature of early fundamen-
technological disciplines combine to advance new tal research, the long time-horizons involved in the
opportunities. Advancements in computational and performance of basic inquiry, the risk of experiment
failures, and, most importantly, the lack of immediate
digital analytics converging with large-scale data from line-of-sight to market.
other sciences have helped accelerate this trend.
What is critically important to understand is that the
U.S. economy, and the innovations and technologies
What has become clear is that continuing to strength- upon which it depends, is built upon a bedrock of
fundamental scientific advancements and an overly-
en the competitiveness of the U.S. economy requires ing strata of applied and translational discoveries that
ongoing expansion of national innovation capacity leverage fundamental knowledge.
and the scientific and technological research and
development (R&D) upon which that innovation

1
depends. This requires funding for research and the supporting basic through applied research while
institutions that perform research, together with private (commercial) funding focuses primarily on
funding for the education of the scientists, technol- powering applied and translational research that
ogists, engineers, mathematicians, and other skilled advances innovations into commercial application. In
intellectual talent that innovates and produces the total, the U.S. R&D enterprise spent $596.6 billion in
products and services that result from innovation. 2019, representing 2.84% of GDP.8 However, the extent
to which the economy is driven by and built upon the
innovative output of R&D makes the impact of R&D
B. Funding and Supporting
on overall GDP many times larger and a dominant
American Science factor in U.S. economic success. The economic future
The federal government has been and continues of the U.S. hinges upon research and development.
to be an essential component of the U.S. research
ecosystem, funding research performed at univer-
C. Human Life Sciences
sities, independent research institutions, and other
organizations and conducting research within na- Scientific research produces many benefits and
tional institutes and laboratories. Federal funding for returns for society, but perhaps none are as important
research has been especially important in supporting as the preservation and extension of human life itself.
fundamental science, which in turn represents the Modern life sciences and associated advancements
platform upon which applied research may advance. in biopharmaceuticals, diagnostics, medical devices,
Federal funding also plays an important role in trans- and healthcare services have enabled unprecedented
lating research into early-stage commercialization, improvements in human health and longevity. Today,
through translational research funding and dedicated the average life expectancy for a newborn female
early-stage venture support through the federal and male in the U.S. is 81.4 years and 76.3 years,
Small Business Innovation Research (SBIR) and Small respectively.9 In 1950, those same metrics were 71.1
Business Technology Transfer (STTR) programs. and 65.6 years.10 Average lifespans have expanded
by more than a decade in less than two generations
Support for scientific research in the U.S. comes from through advancements in health, hygiene, and safety.
both public and private sources. As noted in the prior
sidebar textbox, public resources focus primarily on

“
Today, a powerful argument can be made for substantially
increased investment in research in the United States. Equally
great is the need to train the next generation of scientists and
citizens for what will be a very different world.”
National Academy of Sciences. 2021. “The Endless Frontier. The Next 75 Years in Science.”

8 “2020 Global R&D Funding Forecast”, R&D World, February 2020, WTWH Media, LLC.
9 Kochanek, Kenneth D., et al. “Mortality in the United States, 2019.” NCHS Data Brief, No. 395, Dec. 2020.
10 Ibid.

2
Investing in People
and Inf rastructure
Science relies on an educated base of sci-
entists who make discoveries and is also
advanced through the development of new
tools and technologies that power experi-
ments and enable new insights into biolog-
ical processes. For example, advancements
in ultra-high resolution imaging technology,
functional imaging of real-time processes,
analytical chemistry instruments, computa-
tional systems, and gene sequencing equip-
ment have facilitated leaps forward in funda-
mental and applied scientific insights.

The impact and importance of human life science Perhaps nowhere has life science research advanced
advancement have come sharply into focus during the more in the modern age than through insights
COVID-19 pandemic, where R&D-based innovation of provided by genetics and genomics. This field is both
diagnostic tests, advanced therapeutics, and the rapid fundamental in biological research—elucidating the
development of vaccines has proven crucial in forg- basic code of life, DNA, upon which our form and func-
ing a path for a return to normal life and commerce. tion depend—and in enabling applied and translational
As noted in a recent report: “the COVID-19 crisis has discoveries across most diseases and health disorders.
vividly illustrated the critical importance of life science
research and innovation systems and the ecosystems
D. The Genome—Coding Life
that support the advancement of innovations through
commercial deployment to address health needs.” 11 Humans are complex. That is true on many levels,
and it is certainly true in terms of our biology. The
Scientific advancements in biology and medicine more biologists learn of our biological structure
contribute to our daily lives and are also unveiling the and function, the more complex and intricate
incredibly complex physical mechanisms and human/ the machinery of our biology is revealed to be.
environment interactions that govern our develop-
ment and health. The Russian doll analogy appears We each comprise approximately 30 trillion indi-
to hold, with the life sciences uncovering level upon vidual cells and over 200 different cell types. Our
level of complexity and interrelationships in biological development and ongoing biological function are
structures, mechanisms of influence, and associated orchestrated by our DNA (deoxyribonucleic acid), a
health outcomes. While unveiled complexity may linear molecule arranged in a double helix (a spiraling
confound easy solutions to questions and problems, ladder) comprising linked base pairs of the nucleo-
it also provides an expanding universe of potential for tides adenine (A) and cytosine (T), and guanine (G)
discoveries, applications, and functional possibilities. and thymine (T). Our DNA contains six billion base
pairs of these nucleotides, the sum of which is called

11 Tripp, Simon, et al. Response and Resilience: Lessons Learned from Global Life Sciences Ecosystems in the COVID-19 Pandemic. TEConomy
Partners, LLC for Pfizer, Inc., Jan. 2021.

3
our “genome,” which is effectively the governing After the publishing of the draft human genome by
instruction set and a regulatory “code” for our bodies. the Human Genome Project and Celera, an inter-
national team of 442 scientists from 32 institutions
The six billion base pairs of our genome are organized embarked on a large-scale team research project
into 46 chromosomes (23 inherited from our mother called ENCODE (the ENCyclopedia of DNA Elements),
and 23 from our father). A chromosome consists of which used leading edge approaches to measure
a long section of DNA containing up to 500 million biochemical activity across the entire human genome,
base pairs of DNA with thousands of genes. An not just protein coding genes. ENCODE revealed that
individual “gene” is defined as a grouping of base the non-protein coding regions are far from being
pairs that together perform a function, encoding the “junk” and primarily contain DNA with an active
synthesis of a gene product (either RNA or a protein). biochemistry, even if the preliminary findings did not
We each have approximately 20,000 protein-coding elucidate the function of that activity. The results
genes, which comprise circa 2% of our genome. indicate a far more complex and multifaceted func-
tionality to our genome than previously thought.12

Complicating matters further is that while the genome

We also are each host to trillions of codes for our fundamental life processes it is not
microorganisms found in our gut and deterministic. Other factors also influence our biology
other parts of our anatomy, many of and health, including a multitude of interactions
which play an important symbiotic role
with external environmental factors and stimuli,
for us in digestion and immune system
such as the foods we consume and the microbial
function. Each of these microorganisms
communities that inhabit us over our life journey.
has its own DNA. Collectively, all of
those microorganisms and their DNA
comprise our “microbiome.” Research in We are all the same species, homo sapiens, but we
epigenetics has found that microbiome are all different. None of us have exactly the same
structure can influence and impact genome sequence nor the same environmental
human gene expression and regulation. interactions. A large number of the diseases and
health disorders we will face across our lifespan will
be similarly diverse and complex, many being found
to be associated with multiple genes and gene
As genetics and genomics developed as scientific variants in combination with wide-ranging external
disciplines, for a long time the standard hypothesis factors—for example, prior infection with pathogens
was that the part of our genome that “mattered” is or differential exposure to mutagenic factors such as
the 2% comprising our protein-coding genes, because chemicals or radiation (causing genotoxic injury).
proteins are the functional biomolecules performing
the vast majority of biological activities. It was com- Numerous diseases and health disorders result
mon to consider the 98% majority of our DNA as “junk from single gene changes (known as monogenic
DNA”, legacy base pairs accumulated over the huge or Mendelian diseases), where a variant within a
span of time in our evolution, but no longer relevant or single gene may code the wrong protein or a dys-
“functional” to our development and predominant bio- functional gene product. However, many diseases
logical functioning. We now know that is not the case. with genetic engagement involve multiple genes
and interactions between various genes and ad-
ditional factors. Many diseases, including most of

12 Parrington, John. The Deeper Genome: Why There Is More to the Human Genome than Meets the Eye. Oxford University Press, 2015.

4
our large-scale chronic diseases, turn out to be a genes and gene variants that stand out differently in
complex soup of genetic, epigenetic, and envi- people with a disease or condition of interest. These
ronmental factors interfacing with one another. identified genes and variants can then be studied
to identify their gene products and the biochem-
As individuals, our incredible complexity, and the istry involved in their regulation and expression.
biologically influential environmental factors we
each uniquely encounter across our lives, explain
why the development of diagnostics and drugs
E. Human Genetics and
is such an intense, difficult, and expensive chal- Genomics—Applications
lenge. Finding generic solutions to individually and Impacts
variable disease causations and expressions is no The applications and impacts of genetics and ge-
small task. It is further complicated by the fact nomics in human biology and medicine have grown
that genetic, and other factors, can influence how in parallel with advancements in gene sequencing
we each respond to and metabolize a drug. technologies and digital analytics platforms for de-
riving meaning within the resulting large sequence
Biomarkers are one of the pathways by which the datasets. The Human Genome Project cost approx-
complexity problem is resolved. At the highest level, a imately $2.7 billion resulting in publishing of the
“biomarker” is a measurable substance in an organism reference genome.14 The Human Genome Project
whose presence is indicative of some phenomenon and subsequent genomics initiatives sparked the
such as disease, infection, or environmental exposure. advancement of commercial sequencing instruments
When a biomarker is discovered related to a disease, and processes that have dramatically increased the
it provides a target for further research, a potential speed of sequencing and decreased the price of
measure to be used in achieving diagnosis, and, if each sequence. In March 2021, Nebula Genetics was
found to be “druggable,” a target for a therapeutic. providing whole genome sequencing (WGS)15 with
In 1998, the National Institutes of Health Biomarkers 30x resolution (meaning that each position is read
Definitions Working Group defined a biomarker 30 times to enhance accuracy) for less than $300, a
as “a characteristic that is objectively measured nearly 10,000 fold decrease in price versus the first
and evaluated as an indicator of normal biological sequenced human genomes.16 NHGRI tracks costs
processes, pathogenic processes, or pharmacologic associated with DNA sequencing performed at the
responses to a therapeutic intervention.” 13 Genetics sequencing centers funded by the Institute, and the
and genomics advancements, including technolog- most recent NHGRI data (August 2020) place the cost
ical advancements such as genome sequencing, per genome at $689.17 The pace of advancement in
have provided an important modern pathway for gene sequencing has exceeded even the much-vaunt-
identifying genetic biomarkers, including diagnostic ed pace of Moore’s Law in computer processors.
and therapeutic targets. As extensive collections of
whole-genome or partial genome sequences build,
scientists can mine these sequences to identify

13 Strimbu, Kyle, and Jorge A Tavel. “What are Biomarkers?” Current Opinion in HIV and AIDS vol. 5,6 (2010): 463-6. doi:10.1097/
COH.0b013e32833ed177
14 National Human Genome Research Institute. “The Cost of Sequencing a Human Genome.” www.genome.gov/about-genomics/fact-sheets/
Sequencing-Human-Genome-cost. Accessed 12 May 2021.
15 Whole Genome Sequencing (WGS) is a term used to describe sequencing that at present does not provide full coverage of the entire
genome, where repeat sections in the genome still remain a challenge to resolve. As defined by the National Cancer Institute, whole genome
sequencing is a laboratory process that is used to determine nearly all of the approximately 3 billion nucleotides of an individual’s complete
DNA sequence, including non-coding sequence.
16 Nebula Genomics. “Did You Know that most DNA Tests Decode Only 0.02% of Your DNA?” www.nebula.org/whole-genome-sequencing-dna-
test/. Accessed 12 May 2021.
17 National Human Genome Research Institute. “DNA Sequencing Costs: Data.” www.genome.gov/about-genomics/fact-sheets/DNA-
Sequencing-Costs-Data. Accessed 30 April 2021.

5
Genomics in the also fundamental to advancements being made in
Mainstream of Human the diagnosis and treatment of a wide range of rare
Biological Research diseases and disorders—helping to end the diagnostic
odysseys of millions of patients afflicted with rare
The movement of genetics and genomics from a
niche in biomedical science into the mainstream diseases that have been difficult to diagnose and
underpinning research across most biomedical sparsely served in terms of available treatments.
disciplines is evident in the expansion of genetics
and genomics content across the research sphere
funded by the National Institutes of Health (NIH). TEConomy has divided this study of the impacts of

In 1990, greater than 95% of human genomics

human genetics and genomics into two macro classes
research funding flowed, in a concentrated way, of impacts: economic impacts (examining the impact
through the National Human Genome Research
of human genetics and genomics on the U.S. econo-
Institute (NHGRI) at NIH. By 2020, the vast majority
of human genomics research funding is provided my) and the functional (application) impact domains
through twenty other individual NIH institutes, in which genetics and genomics are affecting human
indicative of the relevance of genomics across al-
most every domain of medical science and human health and the clinical practice of medicine.
life science research.

1. Economic Impacts
The performance of research, the development and
manufacturing of commercial genomics technology
platforms, the multitude of diagnostics products
and therapeutics on the market that is derived from
The current speed and price of sequencing a hu- genomics knowledge, and the associated healthcare
man’s genome has led to the sequencing of patients services provided generate economic activity and
increasingly becoming a clinical reality in modern support a large volume of jobs across the nation—
healthcare systems. Barriers are less a factor of se- these are economic impacts, that positively ripple
quencing cost, and instead relate more to building through the U.S. economy. Other economic impacts
the capacity needed to analyze the huge volume are associated with lives saved, lives improved, and
of data generated, to interpret the meaning of that impacts on people who would otherwise have to be
genetic code for the individual patient, and counsel caregivers to loved ones. It is also the case that the
the patient as to implications for their health. application of genetics and genomics to individual
healthcare needs costs money, and there is con-
A developmental tipping point has been achieved in siderable complexity in assessing the comparative
which the utility of genomics and wide-spread use of costs and benefits of one therapy versus another, or
sequencing is clearly advantageous for significantly whole-genome sequencing (and what it may eluci-
enhancing human health outcomes. As discussed date) versus other diagnostic tools and technologies.
below, and in further detail within Chapter III, the Because genetics and genomics are such a rapidly
functional application of human genetics and ge- advancing field of application and technology in
nomics to clinical healthcare is now a daily reality healthcare, cost/benefit equations are continually
in some medical fields (e.g., cancer diagnosis and changing. No health insurer was going to pay $3 billion
treatment) and is increasingly front-and-center in to sequence a whole genome for a patient, but $689
neurological, psychiatric, gastrointestinal, immunolog- (less than the average cost of a single MRI)18 to gener-
ic, rheumatologic, dermatologic, pain management, ate a dataset with lifelong, and increasingly expanding
and other application areas of clinical medicine. It is utility for the patient opens up a whole new ballgame.

18 Note: the average cost of an MRI in the U.S. is $1,325. Source: Vanvuren, Christina. “What Can Affect the Cost of an MRI?” New Choice Health,
Inc., www.newchoicehealth.com/mri/cost. Accessed 12 May 2021.

6
Figure 1: Current Functional Impact Domains (Applications)
of Human Genetics and Genomics

Carrier Screening
Minable Big Data (Discovery Science)
Pre-Natal Screening
Predisposition to Diseases and Disorders
Newborn Screening

Rational Drug Development Child and Adult Testing

Diagnosing Diseases and Disorders

Medical

Resolving Mystery Diseases

Gene Editing and Gene Therapy
Single Gene (Mendelian) Diseases & Disorders

Human-Microbe Interaction Polygenic Diseases & Disorders

FUNCTIONAL
IMPACT DOMAINS
(APPLICATIONS) OF Pharmacogenomics (Personalized Medicine)
HUMAN GENETICS
AND GENOMICS Targeting to Increase Effectiveness
Environmental Genomics, Metagenomics, & OneHealth
Reducing Adverse Events

Forensic Science
Non-Medical

Evolutionary Biology and Anthropology

Paternity Testing

Source: TEConomy Partners, LLC.

2. Functional Applications forms the foundation for discussion of functional im-

The functional impacts of human genetics and ge-
pacts of human genetics and genomics contained in
nomics are the impacts resulting from discoveries
Chapter III. The study also briefly describes non-med-
via the advancement of research and the clinical
ical applications of human genetics and genomics.
applications of genomics to benefit human health.
The decoding of the human genome was a signature
inflection point for science and has been widely F. Purpose of the Study
acknowledged as a towering achievement for life sci- This study seeks to provide an accessible reporting of
ences. What it sparked, however, has been an ongoing the positive impacts for the economy, society, and in-
expanding universe of advancement in genetics and dividual health that are derived from modern human
genomics and incredibly wide-ranging elucidation genetics and genomics science and the associated
of biological processes, systems, and outcomes with commercial and clinical application of advancements.
genetic connectivity that is now fundamental to
advancing human health and clinical medicine. In 2011, the authors of this report (while at Battelle
Memorial Institute) conducted a detailed impact
In reviewing applications of human genetics and ge- analysis of the Human Genome Project. The result-
nomics, functional impacts are generated within eight ing Battelle report19 highlighted the growth of an
major domains of activities impacting human health. emerging industry in the application of genomics
These are illustrated in Figure 1, and this structure that was born from the scientific and technological

19 Tripp, Simon, and Martin Grueber. Economic Impact of the Human Genome Project. Battelle Memorial Institute, May 2011.

7
momentum driven by the Human Genome Project the sequencing data. Research discoveries in hu-
and Celera’s work to sequence a reference human man genetics and genomics have compounded,
genome. It also highlighted some of the early appli- building upon one another in a virtuous network of
cations occurring through genetics and genomics expanding information, knowledge, and application.
advancements in healthcare and other life science-re- Today, this expansion has brought human genetics
lated challenges and needs. The 2011 report played a and genomics to a rather visible inflection point.
role in highlighting not only the important scientific The speed and affordability of gene sequencing,
impacts of federal government investment in “big in combination with deep insights into genomics
science” and genomics in particular, but also demon- and -omic sciences more broadly, together with
strated the robust return on public investment that advancing biopharmaceutical, diagnostics, and
had occurred through economic growth in genom- other medical technologies that can leverage ge-
ics technologies and emerging applied genomics nomic information, have now made genomics a
application domains. The report continues to be part of the clinical practice of medicine across many
linked on the website of NHGRI at genome.gov. 20
medical specializations and medical conditions.

Now, 20 years after the publication of the draft se- This study seeks to provide a generalized overview
quence, there has been a significant and large-scale of human genetics and genomics achievements
expansion of the human genetics and genomics and scan the current status of human genetics and
universe. Technologies for sequencing and for genome genomics in answering human health questions
analysis have advanced significantly—to the extent and advancing clinical applications. The study also
that whole-genome sequencing is quite affordable seeks to highlight the economic contribution of the
(certainly in comparison to many common medical expanding genetics and genomics sector. The U.S.
procedures and tests) and an entire genome may be has been a pioneer in genomic sciences, leveraging
sequenced in less than one day. Advanced analytics
21
both public and private sector investment to build
and artificial intelligence systems are now available an advanced industry that provides economic ex-
that can simplify deriving actionable insights from pansion and opportunities for further growth while

20 Ibid.
21 Genomics England. “Sequencing a Genome.” www.genomicsengland.co.uk/understanding-genomics/genome-sequencing/#:~:text=One%20
human%20genome%20can%20be,pieces %2C%20around%20150%20letters%20long. Accessed 12 May 2021.

8
at the same time advancing human health and while for some enterprises or organizations genetics
well-being. This report characterizes those positive and genomics comprises the preponderance of their
impacts using quantitative analytics in conjunction business or institutional work (for example, gene
with a qualitative description of identified func- sequencer manufacturers, genetic testing companies,
tional impact domains and associated benefits. genetic counselors), for many active in the sector, it is
only part of their business or work (for example drug
It is anticipated that this report will be useful to public companies, large national diagnostic laboratories,
policymakers and those seeking an understanding of clinical care providers, etc.). Informed estimations have
the public and private, and monetary and non-mon- to be made of the portion of revenues, expenditures,
etary, returns to investments in science broadly, and employment at organizations that are related
and specific to genomics. It may also be useful for to the application of genetics and genomics. The
those seeking to gain a broad introduction into the fact that estimates must be used this way to build
multi-faceted ways genetics and genomics are being the overall dataset that drives the direct effect in the
used to improve human health and clinical health input-output models used is a limitation (discussed
outcomes—helping to illustrate the power of a rapidly further in Chapter II). The study has endeavored to
expanding biomedical field that is poised to advance err on the side of being conservative in developing
and transform many avenues of clinical medicine. It is portioning estimates, and thus the resulting mea-
also hoped that the reader will be encouraged by the sures of impact are likely low rather than high.
promise of genomic medicine and the evident hope it
provides for improved health outcomes for humanity. The examination of functional impacts is, in many
respects, an even greater challenge. Part of this is evi-
dent in the very large volume of academic and indus-
G. Limitations of the Study
try life science research studies in which genetics and
The economic analysis deployed in this study provides genomics are a component or focus. As a fast-moving
a one-year, point-in-time quantification of the nation’s field, there is ongoing evolution and expansion in
genetics and genomics sector. One of the challenges the applications of genomics in human healthcare,
in measuring genetics and genomics impacts in the and it is a significant challenge to do justice to such a
economy is that the U.S. industry classification sys- wide-ranging field. With thousands of diseases, many
tem does not contain a NAICS22 code that covers the hundreds of drugs, and a broad compendium of diag-
industry specifically. Instead, it is a partial component nostics tests having genetic associations, providing full
of many different industry sectors. Without having coverage of every application of genomics in health-
access to data through NAICS codes, establishing a care would be an extremely challenging task and out-
baseline measure of the genetics and genomics indus- of-date immediately upon completion, not to mention
try in aggregate within the U.S. economy requires the a rather daunting read. This is not attempted in this
development of a custom dataset (comprising data study, but rather the functional impact assessment
on individual establishments and companies engaged herein works to classify human genetics and genomics
in human genetics and genomics research, technol- advancements by broad application domain (disease
ogy development, and application) that effectively diagnostics, pharmacogenomics, gene therapy, etc.)
builds the data from the ground-up, establishment and then uses specific narrative examples of genetics
by establishment (rather than relying on generally and genomics in action within these domains (to-
available government summary sectoral statistics). gether with some measures indicative of scale where
readily available). As such, the functional impact
One of the principal challenges in developing estab- section of this report should be viewed as providing
lishment-level data in genetics and genomics is that

22 NAICS is an abbreviation for the North American Industrial Classification System.

9
an overview of the broad areas in which genetics of pain and discomfort from a medical condition, the
and genomics are providing benefits to human ending of a diagnostic odyssey of a patient with a
health, not a formal quantification of these impacts. mystery disease, or the lifelong experiences of a child
and their parent made possible through that child
This report is also limited in that it focuses on human being effectively treated for a rare genetic condition,
genetics and genomics only, and this certainly under- are principally humanitarian benefits. The other side
counts the wide economic and societal benefits that of the coin is that novel genetic tests, customized
accrue to advancements in genetics and genomics medicines, and highly specialized care can come at
more broadly. While the application of genomics to a significant cost to individuals and those who pay
medicine is certainly an important area of use, the for healthcare, and it is important to understand the
ubiquity of DNA as the basis for all life on Earth means economic implications of emerging clinical frontiers.
that genomics finds application in many more fields of
science and commerce. Both the science of genomics In this regard, we caution that because medical
and the tools and technologies of genomics find ap- genomics is an emerging field, there is relatively
plication in multiple additional endeavors, including: sparse literature on the monetary impacts and costs/
benefits associated with genomic medicine. It is
• Veterinary medicine
anticipated that genomic medicine may increase
• Agriculture (in applications such as
costs in many of its early applications, but these early
crop improvement, crop protection,
applications are part of a path that will lead to overall
animal science, and nutrition)
cost savings as medicines are targeted and used
• Industrial biotechnology (in applications
more effectively, chronic diseases better managed
using microbes with engineered genomes
(or perhaps cured), adverse reactions to medications
to produce biochemical products), and
curbed, and the costs of lifelong care potentially
• Environmental and ecological services (in
avoided by addressing genetic components in
applications using engineered microbes
diseases that may be attended to through gene
in industrial waste cleanup, wastewater
therapies and effective personalized therapeutics.
treatment, and other applications).

These additional areas of genetics and ge- Chapter II provides an assessment of the eco-
nomics application have significant impacts nomic impact of sectors engaged in human
that are not addressed in this report. genetics and genomics R&D, the provision of
genetics and genomics tools, technologies, and
This report is primarily intended to highlight the services, and associated economic activity.
current status of human genetics and genomics
impacts, but it does contain a chapter that briefly Chapter III provides discussion of the multifaceted
discusses the frontiers and potential future advance- functional impacts allocable to the key application do-
ments that may occur in the foreseeable future. The mains of human genetics and genomics in healthcare.
discussion in that chapter is, of course, speculative, This follows the structure shown previously in Figure 1,
and thus subject to the usual limitations involved and also briefly touches upon some of the non-med-
when looking towards an uncertain future. ical applications of human genetics and genomics.

Readers should consider the benefits of genomics Chapter IV looks to the future of human ge-
from both the economic and functional perspectives, netics and genomics and introduces some of
not just one or the other. Examining the field through the factors that need to be addressed to in-
the hard lens of economics must be tempered by the crease the positive impacts of the sector.
fact that much that matters in life may not be readily
broken down into dollars and cents. The alleviation

10
II. The Economic Impact of
Human Genetics and Genomics

A. Measuring Human Genetics and spent in the economy (the direct effect) is re-spent
on the purchase of additional inputs, goods, or ser-
Genomics Economic Impacts vices generating additional economic activity and
As described in the previous chapter, the develop- impacts. I-O analysis is the generally accepted “gold
ment of the economic (expenditure) impacts within standard” in economic impact measurement and
this study is focused on and limited to estimating examines the relationships among economic sectors
those impacts stemming from the use of genetics (e.g., institutions or industries) and final consumers.
and genomics for human biomedical purposes.
For the purposes of this study, the I-O analysis
1. Basics of Impact Modeling models the “ripple effect” that originates from the
The estimation of economic impact makes use of an expenditures made for human genetics and genom-
input-output (I-O) model to represent the interrela- ics research and direct company operations in the
tionships among economic actors and sectors. Within economy, flows through suppliers and vendors as
these models, the flow of commodities (or the value additional inputs are purchased, and through employ-
they represent) between industries, consumers, and ees, faculty, staff, and related supplier workers who
institutions in an economy are modeled through spend their wages in the U.S. economy (Figure 2).
a matrix representation allowing for the impact of
changes in employment, expenditures, or economic For modeling and estimating expenditure impacts,
output in one sector of the economy to be projected TEConomy used a 2019 professional IMPLAN I-O
onto other sectors of the economy. These transac- economic impact model of the U.S. Originally de-
tions continue under the premise that every dollar veloped in 1976 by the U.S. Forest Service, IMPLAN

Figure 2: Measuring Economic Impacts of Human Genetics and Genomics

DIRECT EFFECT INDIRECT EFFECT INDUCED EFFECT

Total Economic
Human Genetics & Human Genetics &
Impacts of
Genomics Focused Purchase of Secondary Genomic Supported
Research Expenditures, Inputs & Services from U.S. Employees Spending
Human Genetics
Services, and Corporate Suppliers and Vendors Disposable Income & Genomics
Operations in the U.S. in the U.S. Economy

Source: TEConomy Partners, LLC.

11
Table 1: Impact Measures Included in the Analysis

Impact Measure Definition

Also known as production, sales, or business volume, is the total value of goods
Output and services produced in the economy. For public/non-profit entities, such as
universities, expenditures are often the truest measure of this economic activity.

The total number of jobs created; Includes the direct jobs paid for through salary
Employment and benefit expenditures and indirect/induced jobs generated through purchase
expenditures.

Also known as total compensation, is the total amount of income, including

Labor Income salaries, wages and benefits, received by employees, proprietors, and other
supplier workers in the economy;

The difference between an industry’s total output and the cost of its intermediate
Value Added
inputs; sometimes referred to as the industry’s “Contribution to GDP”.

Federal and State/Local

Includes the estimated revenues to federal and state/local governments from all
Government Tax
sources as a result of the impacts estimated.
Revenues

is now the most widely used economic impact and induced impacts (also known as the multiplier
modeling data and analysis tool in the nation.23 effects) for employment, personal income, value add-
ed, output, and federal and state/local tax revenues.
IMPLAN models are built upon underlying federal
information including the U.S. Bureau of Economic 2. Prior Human Genome Project
Analysis (BEA) national accounts data, supplement- Economic Impact Results
ed with state level employment data from the U.S. For context both in terms of size and breadth,
Bureau of Labor Statistics (BLS) and other economic values from the authors’ prior work on the
data from the U.S. Bureau of the Census. Currently, the Economic Impact of the Human Genome Project
IMPLAN model reflects and represents 546 sectors of are provided in Table 2. These values reflect the
the U.S. economy. The core data and structures devel- full breadth of genetic and genomic research and
oped within an IMPLAN model can be used to analyze the nascent involvement of industry as of 2010.
the economic impacts of institutions, projects, or
entire industries. Employment and expenditure data By comparison, the current study, to be described
developed and estimated as part of this study provide and discussed in the following pages, focuses
the direct impacts to drive the overall economic im- solely on the human genetics and genomics
pact models and estimations. Ultimately, the impact domain for a period one decade later, 2019.
model generates estimates of the additional indirect

23 Note, the authors followed the same I-O methodology by using a prior year’s IMPLAN model to estimate the economic impacts of the Human
Genome Project.

12
Table 2. Core Metrics from Economic Impact of HGP Study

Impact Employment (Jobs) Output ($M)

Direct Effect 51,655 $22,627.5

Total Impact 310,360 $67,146.0

Source: Economic Impact of the Human Genome Project, Battelle Memorial Institute, May 2011.

B. Drivers of Economic Impacts: of Health (NIH) becomes the principal governmental

agency funding research in this domain. However,
Methodology and Assumptions even within NIH, the role of human genetics and
Three types of economic inputs or “drivers” are used genomics in its research portfolio is subject to inter-
to develop and estimate the impacts of human pretation and perspective—ranging from fundamental
genetics and genomics—research expenditures, research into human genetics and genomics to the
core industry employment, and extended industry use of genetics and genomics as an enabling “tool” in
sales or employment. For this analysis, 2019 data research focused on specific diseases or conditions.
was captured to the extent practicable using the
fiscal year or calendar year. The following specifies To account for this, TEConomy established three
the conservative methodology and assumptions funding scenarios for NIH, each differentiated by
used in developing these economic impact drivers. size and breadth of funding, developed through an
analytical approach that eliminates double count-
1. Research Drivers— ing of funded research efforts and builds upon the
Investments in Research previous scenario. The structure of these scenarios
A significant driver of human genetics and genomics and the research funding that is captured within
economic impacts comes in the form of focused each scenario is built using internal NIH classifica-
research funding from federal agencies and other tions and keywords.24 These scenarios include:
non-profit organizations. This section describes and
captures this funding mechanism for use in driving • Core NIH Human Genetics and
the economic impact model. It captures the value Genomics Funding
of human genetics and genomics research funded • Includes all research funding from
by these organizations and ultimately performed NHGRI (524 projects, $416.3 million)
by universities, research institutes, federal agencies, • Research reviewed and approved by spe-
and other non-profit research organizations. cific genetic and genomic-related proposal
review study sections (e.g., Genetics of
National Institutes of Health Health and Disease Study Section and
With the focus of this study specifically on human ge- others) (1,434 projects, $611.1 million)
netics and genomics impacts, the National Institutes

24 For the purposes of this study “NIH research funding” was limited to research-oriented grants or contracts (external and intramural) to U.S.
researchers. Grants to non-U.S. research performers, U.S. firms (via SBIR/STTR awards), or construction and training awards were excluded from
the analysis. For FY 2019, this NIH total research funding reached $28.939 billion. Note: grants to U.S. firms were excluded as individual firms
are typically captured in the core industry drivers analysis.

13
• Research classified in specific and relat- A striking finding from this assessment of NIH
ed NIH Research, Condition, and Disease research funding is the pervasive nature of
Categories (RCDC) EXCEPT the broadest genetics and genomics in human biomedical
Genetics category (e.g., Cancer Genomics, research. Nearly half of all NIH research fund-
Gene Therapy, Gene Therapy Clinical Trials, ing specifies some connections with human
Genetic Testing, and Human Genome) genetics and genomics, at least as an inves-
(5,424 projects, $2,107.3 million) tigative tool to support other research.

• Core + Additional Expanded NIH Funding To maintain a conservative perspective on the role
• Additional research within the specific NIH research funding plays in the overall econom-
Genetics RCDC funding category, not cap- ic impact of human genetics and genomics, the
tured above (10,493 projects, $3.884 billion) remainder of this chapter focuses on the impacts
generated with the inclusion of the smallest, core
• Core + Additional Expanded +
funding scenario. Economic impact results estimated
Additional Use as Tool Funding
using the additional more expansive NIH research
• Additional research listing genetics or ge-
funding scenarios are included in the Appendix.
nomics as a Principal Investigator-provided
keyword in the funding information not cap-
Other Federal Agencies
tured above. A review of these awards showed
Beyond NIH, other federal agencies pro-
that most were non-genetics and genomics
vide significant human genetics and ge-
focused yet were using genetics or genomics
nomics-related research funding.
as a key analytical approach or tool enabling
the research. (13,448 projects; $7.184 billion)
Department of Veterans Affairs
Table 3 shows the value and incremental additions In FY 2019, the Department of Veterans Affairs (VA)
to each scenario and the share of total NIH research Office of Research and Development invested a total
funding. of $107.0 million in genomics research and infra-
structure. Of this, $26.0 million was towards funding
genomics research projects, $44.0 million towards the

Table 3: NIH Research Funding Captured by Each Scenario

NIH Human Genetics 2019 NIH Research Scenario Cumulative

2019 NIH Research
and Genomics Funding Investment Share of 2019 NIH
Scenario Value ($B)
Scenario Component ($B) Research Funding

Core Funding $3.135 $3.135 10.8%

Core + Additional
$3.884 $7.018 24.2%
Expanded Funding

Core + Additional
Expanded + Additional $7.184 $14.202 49.1%
Use as Tool Funding

Source: TEConomy analysis of NIH research awards using the RePORT website’s ExPORTER Project file for FY 2019

14
Million Veteran Program (MVP) core infrastructure Other Health and Human Services (HHS)
for recruitment, enrollment as well as clinical and Undoubtedly, other HHS agencies beyond NIH in-
genomic data curation, and $37.0 million towards clude some level of human genetics and genomics
genotyping and whole genome sequencing DNA research and/or research funding. However, given
samples from the MVP. With over 830,000 Veterans the limited detailed information upon which to
enrolled to date, MVP is one of the largest healthcare assess the connections to human genetics and
system-based genomic cohorts in the world. 25
genomics, only within the National Institute for
Occupational Safety and Health (NIOSH) was this
National Science Foundation information as well as funding information available.
The National Science Foundation (NSF) funds substan- For FY 2019, TEConomy identified nearly $384,000
tial research efforts within the broad context of genet- in human genetics and genomics-related funding.
ics and genomics through research programs in ge-
netic mechanisms, phylogenetic systematics, and the Voluntary Health Associations and
large-scale Plant Genome Research Project. For the Other Non-Profit Funding
purposes of this study, NSF awards that were active at An important funding stream for human genetics
any time within FY 2019 were considered and exam- and genomics research is provided by a wide variety
ined to find those that met the requirement of fund- of voluntary health associations, patient groups,
ing research primarily aimed at human genetics and and other non-profit funders. Likely included with-
genomics understanding. Included in these awards in this set of funders are many of the members of
are significant research funding for big data and/or National Organization for Rare Disorders that are
bioinformatics research that was primarily aimed at fa- funding research efforts to understand the genet-
cilitating or enhancing the ability to manage and ana- ic and genomic traits of these rare disorders.
lyze human genetics and genomics data. The included
research reflects 212 awards funded at $19.3 million. 26 The difficulty in including funding from these asso-
ciations and non-profits is the limited information
on human genetics and genomics research within

25 For additional information on the Million Veteran Program see: www.mvp.va.gov.

26 Multi-year awards that extended into FY 2019 were weighted by the number of FY 2019 days
as a share of the total project’s estimated duration.

15
their specific research grants and the requirement Following a similar approach to the authors’ prior
to gather this information, if it exists, from liter- work analyzing the genetics and genomics industry,
ally hundreds of organizations across the U.S. a database of firms with their total employment was
developed. The database was initiated by starting with
To reflect at least some level of funding from these the previous work’s 2010 database of firms, exclud-
groups, TEConomy worked to develop a conservative ing those that were primarily in the plant/animal/
estimate. Building off of prior work, TEConomy first agricultural domain and determining whether these
estimated a 2019 value for total research funding from firms were still in business in 2019, and correcting
voluntary health associations.27 An assumption is then for considerable mergers and acquisition activity
made that, at a minimum, these organizations fund that has occurred within the industry over the past
human genetics and genomics research at approxi- decade. For the purposes of this study, firms that are
mately the same “share” that NIH does. To stay most part of the important instrumentation (e.g., Illumina,
conservative, the “core” percentage of NIH funding, ThermoFisher) or bioinformatics subsectors are
10.8% (see Table 3), is applied to the estimated FY 2019 included in this database even though their prod-
voluntary health association total funding level of $1.56 ucts and services may also be used outside of the
billion to generate a human genetics and genomics specific human genetics and genomics domain.
research funding estimate of $169.1 million in 2019.
The actual level of funding from these organizations To supplement this existing firm database, lists of
is likely to be considerably larger. Anecdotally and via firms from a variety of organizations, websites, and
website information, it appears the cutting-edge re- market research publications were curated to gen-
search funded by these groups is becoming more and erate an additional set of U.S. firms for review and
more engaged with genetic and genomic exploration. inclusion. These firms were then evaluated using
web-based research to determine their fit within the
Research Funding Summary human genetics and genomics domain and whether
Combined, human genetics and genomics research they were still in business. If they met these criteria, an
funding as captured from funding organizations employment value was developed using third-party
reaches $3.4 billion under the most conservative databases such as Dun and Bradstreet and PitchBook
estimate of NIH funding. Using the IMPLAN model (a provider of angel and venture capital information)
this level of research funding is estimated to directly and, at times, the firm’s website or LinkedIn pages.28
employ 13,800 researchers throughout the U.S.
The impacts are modeled as an aggregation of
2. Core Industry Drivers—Employment of IMPLAN sectors, as appropriate, to capture the extent
Core Human Genetics and Genomics Firms and variety of research and corporate activities by
The previous section captures the level of human using employment to drive the direct impacts of
genetics and genomics research activity stem- the economic impact model. These firms and their
ming from federal and other sources of funding. employment were classified into one of six human
This section develops an employment-based genetics and genomics core industry subsectors
estimate of the size and scope of the core firms (Table 4). The employment figures reflect the total
operating primarily, if not exclusively, within employment of firms in each industry subsector.
the human genetics and genomics domain.
Within this employment of more than 89,000, some
specific caveats and specifications are warranted. The

27 U.S. Investments in Medical and Health Research and Development 2013 – 2018. Research!America, Fall 2019.
28 Developing true employment values from these sources can be difficult due to reasons such as outdated data, self-reported data, and the
effects of M&A activity. Conservative employment estimates were made, if required.

16
Table 4: Employment by Human Genetics and Genomics Core Industry Subsectors

Industry Subsector Est. of 2019 Employment

Core Analytical/Biomedical Instruments and Equipment Manufacturers 26,758

Core Small Biopharma Manufacturers 22,383

Core R&D/Biotech Firms 21,797

Core Medical/Diagnostic Laboratories 14,639

Core Software/IT/Bioinformatics Service Firms 3,729

Core Genetic Counselor and Other Related Services 158

Total Core Firms’ Employment 89,464

Sources: Lists of firms developed from various industry and professional websites. Employment estimates from corporate websites and Dun &
Bradstreet data. Additionally, LinkedIn information was used, at times, to update and correct some firms’ employment levels.

data only include small/mid-sized biopharmaceutical Core Industry Drivers Summary

focused firms’ employment—the impact of large bio- Across six industry subsectors, the economic im-
pharmaceutical firms is captured via sales estimates pact model is driven by direct employment within
in the next section. Dun & Bradstreet and corporate the core industry drivers of 89,464 employees.
website information was used to determine whether
to include firms within the R&D/biotech firms’ catego- 3. Extended Industry Drivers
ry versus small biopharma category. The core medical/ Two subcomponents of the industry analysis ef-
diagnostic laboratories category does not include forts required different approaches to estimating
employment for Quest Diagnostics and Laboratory their size and importance in driving the human
Corporation of America (LabCorp); rather their role is genetics and genomics economic impacts.
estimated in the next section. An assessment of the
list of genetic counselors available from the National Pharmaceutical Manufacturing
Society of Genetic Counselors was used to identify U.S. The core industry employment analysis captured
firms. These firms were then classified into medical/ small and/or nascent biopharmaceutical firms whose
diagnostic laboratories or genetic counselor practices sole focus is the development of pharmacogenetic/
as warranted as many medical/diagnostic laboratories genomics drugs (drugs associated with a genetic test)
include genetic counselor employees. The specific and other genetic and genomic therapies. However,
category for genetic counselor and other related larger pharmaceutical manufacturers with develop-
services was used to capture, as best as possible, ment efforts ranging from small molecule chemistries
the employment of those firms operating without a to large molecule biologics also are a significant
direct testing capability. It should be noted that the component of human genetics and genomics-related
final economic impact assessment also included economic activities. For these firms, a different ap-
1,752 individual counselors, including those practicing proach is used to apportion part of their operations
within the VA’s Million Veteran Program, that are not (sales) to the human genetics and genomics domain.
captured within the employment figures in Table 4.

17
The original Economic Impact of the Human Genome Biomarkers in Drug Labeling.31 This subset of biomark-
Project study also treated these large pharmaceutical er-labeled medicines account for 28% of global sales
firms in a slightly different manner from core indus- of these 102 medicines. To generate a U.S. specific
try employment. In the previous study, an estimate estimate, this 28% was then applied to a market
of genetic and genomic research expenditures was study value of 2019 total U.S. prescription drug sales
used to reflect these firms’ involvement in the human of $177.7 billion yielding an estimated $49.5 billion in
genetics and genomics domain—one that was just U.S. prescription drug sales with one or more genetic
beginning to see the opportunities that genetics biomarkers.32 This estimate is considered conservative
and genomics would provide in the development of due to the higher usage rate of more expensive phar-
modern medicines. In the decade since these esti- maceuticals within the U.S. Total global sales of these
mates were developed, the role of human genetics 26 medicines reached $96.5 billion, nearly twice the
and genomics in biopharmaceutical development value used to drive the U.S. economic impact estimate.
is still evolving. However, its use has extended its
impact on these large biopharmaceutical firms National Medical Testing Laboratories
beyond simply research and further into targeted drug Two medical/diagnostic laboratories, Laboratory
development and the labeling, use, and efficacy of Corporation of America (LabCorp) and Quest
existing products ultimately driving corporate sales. Diagnostics, together account for more than $16.5
billion in total U.S. sales and more than 90,000 U.S.
Lists of the U.S.-based members of the Pharmaceutical workers.33 While human genetic and genomic testing
Research and Manufacturers Association (PhRMA) 29
is becoming more common in U.S. healthcare, it is still
and pharmaceuticals by sales for 2019 were exam- a smaller share of overall medical and diagnostic test-
ined.30 Using a sales cut-off value of $1.5 billion to ing. Using corporate websites and reporting as well
represent the most active biopharmaceutical products as third party market studies, TEConomy developed
generates a list of 102 medicines. Of these, 26 are estimates for these two firms’ human genetic and
currently listed in the FDA Table of Pharmacogenomic genomic-related sales and employment.34 Together,

29 PhRMA. “Members.” www.phrma.org/en/About/Members. Accessed 12 May 2021.

30 PhRMALive and Outcomes LLC. “Top 200 Medicines Annual Report: Climbing Mount Humira.”
31 U.S. Food & Drug Administration. “Table of Pharmacogenomic Biomarkers in Drug Labeling.”
www.fda.gov/media/124784/download. December 2020.
32 Spitzer, Dan. Brand Name Pharmaceutical Manufacturing in the U.S. IBISWorld Industry Report 32541a, August 2020.
33 Data obtained and calculated from corporate 10-K filings reflecting 2019 performance.
34 Curran, Jack. Diagnostic & Medical Laboratories in the U.S. IBISWorld Industry Report 62151, November 2020.

18
these two firms are estimated to account for just un- values, it is estimated that the U.S. human genetics
der 22,000 workers and more than $3.77 billion in sales and genomics research and industrial domain
within the human genetics and genomics domain. employs nearly 166,000 workers as a direct result
of these operations (Table 5). This number includes
Extended Industry Drivers Summary human genetics researchers, medical geneticists,
The revenue and employment size of the firms cap- and genetic counselors, as well as a large number of
tured within the Extended Industry Drivers warrant workers in adjacent, corporate, or operational roles
special and distinct attention. For both subcompo- in firms developing lab equipment and software,
nents, the use of human genetics and genomics performing clinical genetics and genomics testing,
technologies and techniques constitutes a relatively or manufacturing pharmacogenomic drugs. Overall,
small share of overall operations. However, due to this combined set of drivers directly generate over
the sheer size of these corporate operations, these $108 billion within the U.S. economy. With this
two subcomponents directly add more than $53.3 set of direct drivers, the IMPLAN model is used to
billion and nearly 61,000 jobs to the U.S. economy. estimate the total impacts of human genetics and
genomics domain on the U.S. economy (Table 5).

C. Economic Impact Analysis

From an employment perspective, these impacts
of Human Genetics and show the U.S. human genetics and genomics do-
Genomics in the U.S. main supporting an additional 684,000 jobs (indirect
The combination of the three economic impact drivers and induced effects) within the U.S. economy for
presented above—Research Drivers, Core Industry a total employment impact of more than 850,000
Drivers, and Extended Industry Drivers—yields a signif- workers, reflecting an employment multiplier of
icant direct economic presence in the U.S. economy. 5.12. For every direct job in the human genetics and
Using the most conservative NIH research funding genomics domain, 4.12 additional jobs are generated
levels and using the IMPLAN model to estimate throughout the U.S. economy. On average, due to
employment from sales (or research funding levels) the higher technical and educational requirements,

Table 5: Economic (Expenditure) Impacts —

Core NIH Human Genetics and Genomics Funding Scenario (2019)

State/
Labor Value Federal
Output Local Tax
Impact Type Employment Income Added Tax Reve-
($B) Revenues
($B) ($B) nues ($B)
($B)

Direct Effect 165,973 $21.66 $52.59 $108.16 $2.90 $5.18

Indirect Effect 288,866 $24.81 $43.59 $87.04 $2.90 $5.38

Induced Effect 395,425 $22.40 $39.44 $70.15 $3.67 $4.95

Total Impacts 850,263 $68.88 $135.62 $265.35 $9.47 $15.51

Multiplier 5.12 3.18 2.58 2.45

Source: TEConomy analysis of Human Genetics and Genomics Input Dataset; IMPLAN 2019 U.S. Impact Model.

19
the direct jobs generate more than $130,000 in sales in 2019. Direct output was estimated to be $22.6
annual compensation (income and benefits) per billion in 2010 compared to $108.2 billion in 2019.
worker while overall, the total jobs supported by the
human genetics and genomics domain still aver- The economic importance of U.S. human genet-
age over $81,000 in compensation per employee. ics and genomics cannot be denied. The HGP
impact study found that the broader genetics
In terms of value added, or the contribution to U.S. and genomics field, for which the human do-
GDP, the human genetics and genomics domain main is just one component, had an economic
directly adds more than $50 billion to U.S. GDP, and impact of $67 billion in 2010. The growth of the
through the economic ripple effects these efforts human genetics and genomics field over the
support, in total, nearly $136 billion of U.S. GDP. past decade has been substantial, with this one
domain area now representing a total econom-
The direct output also leads to considerable additional ic impact of more than $265 billion in 2019.
economic activity in the U.S. For every $1 of output
(e.g., sales or research expenditures), $1.45 of additional
sales are generated in the U.S. economy leading to
D. Healthcare Costs
an overall economic impact of U.S. human genetics for Genetic Diseases
and genomics of more than $265 billion in 2019. The application of human genetics and genomics,
as discussed in the next chapter, is providing a wide
The federal tax revenues of $5.18 billion generated range of functional benefits in healthcare in terms
by the direct operations of the human genetics and of identification of patient predisposition to genetic
genomics domain alone surpasses the single year fed- disease, diagnosis of diseases, identification of targets
eral investment in human genetics and genomics of for new drugs, precision drug dosing and limitation
approximately $3.26 billion across all federal agencies. of adverse drug events, and development of new
In the simplest of terms, from a federal investment approaches to treatments and cures through gene
perspective, the overall economic impacts of U.S. therapy and gene editing. As will be shown, human
human genetics and genomics generates a return genetics and genomics are very much at an inflection
on investment (ROI) of more than 4.75 to 1.00. point where many benefits are now occurring as
research discoveries translate into clinical innovations.
Progress Over the Past Decade
At the outset of this chapter, the 2010 impact Because the large-scale clinical application of
estimates for the Human Genome Project were human genetics and genomics is a relatively new
provided. By comparison, this current analy- phenomenon, there is relatively limited literature on
sis shows the dramatic increase in impact over the economic impacts of its applications to clinical
the past decade that human genetics and care. Longitudinal studies tracking impacts over time
genomics has had on the U.S. economy. are particularly scarce and indeed are challenging
to interpret given that the cost of gene sequencing,
Even though this current effort is focused solely on up to and including whole-genome sequencing,
“human” genetics and genomics, the size of the has plummeted. Sequencing the genome was, just
workforce directly employed in these endeavors has a few years ago, prohibitively expensive. However,
more than tripled over the decade from just under advancements in technology mean that cost is
52,000 workers in 2010 to nearly 166,000 in 2019. no longer a primary barrier to use in the clinic.
Similarly, direct output has dramatically surpassed the
previous estimate as human genetics and genomics One way to evaluate the economic impacts of human
developments are leading to actual and significant genetics and genomics is to examine the cost bur-
den of disease imposed on the economy by diseases

20
that are predominantly genetic in their etiology. The only estimates the burden for 379 diseases for which
majority of what is labelled “rare diseases and disor- survey data were available (versus in excess of 7,000
ders” falls into this category, often being single-gene rare diseases identified36)—but the results speak to the
disorders. As such, the cost of these diseases can serve large-scale costs of such disease to society, to patients,
as a surrogate for at least understanding the scale of and to patients’ families. The study finds the total
disease burden related to rare diseases, and by exten- cost of the 379 assessed diseases to be $966 billion
sion, provide intelligence on the kinds of economic for 2019. This total cost burden is shown in Table 6.
costs that may be ameliorated through advancements
in genetic and genomic diagnosis and treatments. A The Lewin authors do not choose to extrapolate their
recent study conducted by the Lewin Group for the findings for 379 rare diseases to the more than 7,000
EveryLife Foundation for Rare Diseases makes an such diseases that exist because they were unsure of
important contribution to the literature and provides whether the 379 comprise a representative sample of
robust evidence for the very substantial burden im- rare diseases extant. The measures shown in Table 6
posed by predominantly genetic rare disease. The re- 35 are thus conservative. What they do provide, however,
search program, titled “The National Economic Burden is a window into the very large-scale cost of these (pre-
of Rare Disease Study,” uses data on medical care dominantly genetic) diseases—a cost that in just one
costs, together with a detailed survey of rare disease year in the U.S. imposed a burden of almost $1 trillion.
patients and caregivers, to derive estimates for the The direct cost of the 379 rare disease impacts studied
burden of 379 rare diseases measured in terms of their by Lewin ($418 billion) can be put in context by exam-
one year impact (2019). The study is conservative and ining total healthcare expenditure data maintained

Table 6: Economic Burden of 379 Rare Diseases in the United States (2019)

Cost Element Description 2019 Impact

Includes inpatient hospital or outpatient care,

Direct medical costs physician visits, Rx medications, durable medical $418 billion
equipment.

Includes forced retirement, absenteeism,

Indirect costs: productivity loss presenteeism, and a reduction in community $437 billion
participation and volunteer service.

Includes paid daily care, necessary home and vehicle

modifications, and transportation and education
Non-medical and uncovered
costs. Also includes health care services not covered $111 billion
healthcare costs
by insurance: experimental treatments, medical
foods, and more.

$966 billion

Source: Lewin Group. “The National Economic Burden of Rare Disease Study.” Prepared for: EveryLife Foundation for Rare Diseases. February 25, 2021.

35 35. Yang, Grace, et al. The National Economic Burden of Rare Disease Study. Lewin Group for EveryLife Foundation for Rare Disease, 25 Feb. 2021.
36 Liu, Zhichao, et al. “Toward Clinical Implementation of Next-Generation Sequencing-Based Genetic testing in Rare Diseases: Where Are We?”
Trends in Genetics, vol. 35, no. 11, Nov. 2019.

21
by the Centers for Medicare and Medicaid Services Research and Quality (AHRQ) estimates that the direct
(CMS). CMS data for 2019 show total healthcare costs medical costs (total of all health care costs) for cancer
for hospital, physician and other provider services, in the U.S. in 2015 were $80.2 billion”38—with 52% of
medications, and durable medical equipment being this cost being for hospital outpatient or doctor office
$2.4 trillion in 2019.37 It is evident, therefore, that the visits, and 38% of the cost for inpatient hospital stays.
high amount of care required in diagnosing and
treating rare diseases comprises a significant portion While a definitive total cannot be calculated with
of overall healthcare costs. At $418 billion (again, available data, there should be little doubt that the
just for 379 rare diseases), the direct care costs of economic burden of genetic and genomic-related
these diseases equate to 17.4% of total national direct diseases in the U.S. reaches into the trillions of dollars
spending across equivalent expenditure categories. on an annual basis. However, as examined in the
next chapter, researchers and clinicians in research
Of course, many common diseases also have genetic institutes, universities, industry, and government
involvement. Cancer is fundamentally a genetic dis- labs are making far-reaching contributions to re-
ease, whereby gene mutations cause uncontrolled cell ducing the many burdens associated with genetic
growth. Many more diseases, including cardiovascular and genomic diseases and disorders—making deep
diseases, gastrointestinal diseases, autoimmune disor- progress in the clinical application of genetics sci-
ders, psychiatric and neurological disorders, musculo- ence and technology advancements to make a very
skeletal disorders, etc., have genetic involvement, typi- real difference in the lives of millions of patients.
cally involving many genes (i.e., polygenic). Quantifying
the overall cost burden of these diseases, where
genetics is part of the equation, is particularly chal-
lenging. Still, just referencing cancer, the American
Cancer Society reports that “the Agency for Healthcare

37 Centers for Medicare & Medicaid Services. “National Health Expenditures 2019 Highlights.” www.cms.gov/files/document/highlights.pdf.
Accessed 12 May 2021.
38 American Cancer Society. “Economic Impact of Cancer.”
www.cancer.org/cancer/cancer-basics/economic-impact-of-cancer.html. Accessed 12 May 2021.

22
III. The Functional Impacts of
Human Genetics and Genomics

A. The Structure of Functional Impacts

(Application Domains of Human Genomics)
The application of genetics and genomics advance- genetics information informs molecular targeting
ments to healthcare can certainly be viewed through in drug design; pharmacogenomics, which enables
an economic lens, and the economic impact of this the personalized prescription of drugs best suited
dynamic science and technology-driven sector is to the person’s genetics (with a goal of increasing
extremely large. However, the generation of busi- effectiveness and reducing adverse events); gene
ness income and jobs is not the raison d’etre for editing and gene therapy, whereby genes associ-
medical genomics. Human genetics and genomics ated with disease are modified to treat or cure the
are pursued for the scientific and clinical insights disease; and two more “emerging” areas in which
they enable, and for their functional impacts, human-microbe genetic interactions and hu-
these being the domains of application of the sci- man-environmental metagenome interactions are
ence and technologies of genetics and genomics being examined for association with human gene
to preserving and improving human health. expression, regulation, mutation, and disease.

Genomics has become fundamental to advancement In addition to applications to human medicine,

of biomedical research, and the insights, tools, and there are also several additional human applica-
technologies provided by genetics and genomics are tion domains relevant for non-medical uses. These
now seeing increasingly widespread deployment in are briefly discussed herein, covering applications
clinical healthcare. This chapter seeks to provide a in forensic science, anthropology and genealogy,
broad overview of the key areas (domains) in which evolutionary biology, and paternity testing.
human genetics and genomics are being applied
in clinical research and healthcare. The functional
impacts are divided into eight medical domains
(Figure 3): minable big data, whereby large data sets
of multi-patient data are providing deep insights
into disease biology (and also identifying charac-
teristics associated with health); identification of
genetic predisposition to diseases and disorders;
diagnosis of diseases and disorders though genetic
signatures; rational drug development, whereby

23
Figure 3: Functional Biomedical Impact Domains
(Applications) of Human Genetics and Genomics

Examining the impact Analyzing sequencing

of human interactions data from large and
with the environment diverse populations to
on the human genome, provide deep insights
gene regulation, muta- into disease biology and
tion, and disease identify characteristics
etiology. associated with health.

Environmental Genomics Minable Big Data

and Metagenomics (Discovery Science)
Examining the human Genetic and genomic
genome’s impact testing to identify
upon hosted microbial 8 1 carrier status, and
populations, and identify predisposition
microbe impacts upon Biomedical for genetic disease via
Human-Microbe Identifying Predisposition
the human genome 7 Application
Biomedical 2 prenatal, newborn and
and gene expression Interaction to Diseases and Disorders adult screening.
Domains of
Application
Human of
Domains
Genetics
Human Genetics
and
6 and Genomics 3
Modifying the genes Gene Editing Diagnosing Diseases Using biomarkers
associated with a and gene signatures
disease or disorder
and Gene Therapy Genomics and Disorders
to diagnose the
to treat or cure the presence of diseases
5 4
disease or disorders that are
associated with
Pharmacogenomics Rational Drug specific genes or
(Personalized Medicine) Development gene products.

Using sequencing data Using genetic

to enable the information and gene
prescription of drugs associated biomarkers
best suited to the to inform molecular
patient’s genotype targeting in drug design.
(increasing efficacy and
reducing adverse events)

Source: TEConomy Partners, LLC.

B. Fundamental Knowledge Genetics can inform us of our past evolution, and

genetics and genomics as disciplines have themselves
Advancement been evolving. Fundamental scientific research,
Before discussing the clinical impact domains facilitated by advancements in genomics technolo-
of human genetics and genomics, it is import- gies and analytics, has provided a stream of notable
ant to note that applied and clinical research discoveries, with just some highlighted below:
depends upon a healthy base of discoveries and
fundamental insights that are derived through • The ENCODE project (ENCyclopedia of DNA
basic research, which may be defined as: Elements) revealed that non‐coding DNA, previ-
ously termed “junk DNA” because it was thought
Systematic study directed toward greater to be a relic of evolution with little biological
knowledge or understanding of the function, instead has specific functionality in
fundamental aspects of phenomena and of transcription and translational regulation of
observable facts without specific applications protein-coding. In other words, most of it is not
towards processes or products in mind.39

39 Cornell Law School. “32 CFR § 272.3 - Definition of Basic Research.” www.law.cornell.edu/cfr/text/32/272.3. Accessed 12 May 2021.

24
The importance of basic science derives from its contribution to knowledge deeper within the tree
of information and, consequently, its greater potential for integration with other facts. In contrast,
the importance of translational science lies in its practicality. Hence, we do not view basic and
translational science as one being more important than the other but rather as complementary
areas of human endeavor, with the important distinction that basic science findings often precede
advances in translational science. We also note that observations in translational or applied science
can generate new questions for fundamental research, as illustrated from the fact that vaccination
preceded the field of immunology. Hence, the epistemological flow is bidirectional, and investments
in both types of science are needed.”

Ferric C. Fang and Arturo Casadevall. “Lost in Translation—Basic Science in the Era of Translational
Research.” Infection and Immunity, vol. 78, no. 2, Feb. 2010.

junk at all; it is central to life functions (although remains to be studied in this area to better
not fully understood in terms of functionality). understand “mosaic variation in both nuclear
and mitochondrial DNA, the mechanisms that
• Basic research into gene silencing led to funda- generate mosaicism, and the roles of mosa-
mental discoveries regarding RNA, messenger
icism in physiology and human disease.”41
RNA (mRNA), and development of techniques
for RNA interference that enabled human • Recent work is focused on “studying patterns of
genes to be disabled in a very precise man- gene expression in individual cells, a step that
ner to better study their effect and function. has been driven by new methods for single-cell
Further research has elucidated the presence RNA sequencing and chromatin analysis. Tens
of multiple types of non-coding RNAs and of millions of cells have been characterized
their impacts on gene expression, one class thus far on route to a complete cell Atlas of the
of which, microRNAs (mnRNAs), may be reg- human body. This effort is revealing hundreds
ulating more than half of all human genes. of new cell types and characterizing the ways
in which cell types differ between healthy
• Ongoing refinement to the reference human people and people with various diseases.”42
genome has occurred, closing many of the gaps
in the original sequences and uncovering previ- • Basic research has found that “not all genes
ously uncharacterized parts of the human ge- are expressed in all tissues and that not all
nome with potential for significant discoveries. 40 genes are expressed during all developmen-
tal stages.”43 This has important downstream
• Recent studies have been elucidating “mo- implications in drug development, where, for
saicism”, which is the term used to describe
example, a research team developing a drug
genomic variation among cells (both germline
for infantile epilepsy would need to know
and somatic) within an individual. Much still

40 Miga, Karen H. “Human Genome: Bridging the Gaps.” Nature, vol. 590, no. 11, Feb. 2021.
41 Green, Eric D., et al. “Perspective: Strategic Vision for Improving Human Health at the Forefront of Genomics.” Nature, vol. 586, 29 Oct. 2020.
42 Collins, Francis S., et al. “Perspective: Human Molecular Genetics and Genomics – Important Advances and Exciting Possibilities.” The New
England Journal of Medicine, vol.384, no. 1, 7 Jan. 2021.
43 Pharmaphorum Connect. “The Future of Genomic Medicine: Can it Fulfil its Promises?” www.pharmaphorum.com/views-analysis-patients/the-
future-of-genomic-medicine-can-it-fulfil-its-promises/. Accessed 12 May 2021.

25
whether a drug target is “expressed in the cancer (enabling development of targeted
brain and also during early development.” 44
therapeutic agents), noninvasive prenatal
genetic screening, and genomics-based
It should also be noted that the Human Genome
tests for a growing set of pediatric conditions
Project, and the ongoing development of genomic
and rare disorders, among others.46
tools and datasets, generated a rather seismic shift
in the way in which fundamental research is per- For some diseases, especially those where a sin-
formed. The big data, information mining approach gle or only a few genes are involved, real break-
that gene sequencing enables has “transformed throughs are occurring. The section that follows
the nature of medical discovery, enabling scien- describes the domains of health sciences and
tists to undertake comprehensive and powerful clinical care where these impacts are being felt.
explorations rather than being confined to testing
hypothesis focused on candidate pathways.”45
C. Functional Applications
What is clear is that the human genome is immensely for Human Health
complex, and there is much still to be discovered As fundamental genomic knowledge has expanded,
through fundamental research into its structure, the enhanced understanding of genetic mecha-
mechanisms of action, and its interface with biochem- nisms, in concert with access to rich whole exome
ical signals from non-genomic origin. In some diseas- and genome datasets (and associated reference
es, hundreds of individual genes are being found to compendia of human gene variants), has opened
have an effect on disease development and progres- the door to a new era of discovery and progress
sion, often in concert with multiple environmental in medicine. The impacts of these advancements
and physiological factors. Solving such multigenic are now increasingly reverberating across medi-
and multifactorial challenges is no small task, but cine, a fact highlighted by Eric Green, the Director
distinct progress is being made, aided by tremendous of the NHGRI, and colleagues who note that:
technological advancements in sequencing and data
analytics platforms. Any scientist, or group of scien- With insights about the structure and function
tists, embarking on finding solutions to individual of the human genome, and ever improving
human diseases will typically recognize that the path laboratory and computational technologies,
from question to discovery to therapy or cure is long genomics has become increasingly woven
(sometimes spanning their career, if successful at all). into the fabric of biomedical research, medical
Modern genetics and genomics are, however, provid- practice, and society. The scope, scale, and
ing new, more brightly lit paths informed by quantita- pace of genomic advances so far were nearly
tive datasets that can be mined for insights and ther- unimaginable when the human genome
apeutic targets. As noted in NHGRI’s strategic vision: project began. Even today, such advances are
yielding scientific and clinical opportunities
…the past decade has brought the initial beyond their initial expectations, with many
realization of genomic medicine, as more anticipated in the next decade.47
research successes have been converted
into powerful tools for use in health care, Much of the advancement being seen is enabled by

including somatic genome analysis for dramatic progress in genome sequencing technology
performance and cost effectiveness. A virtuous cycle

44 Ibid.
45 Collins, Francis S., et al. “Perspective: Human Molecular Genetics and Genomics – Important Advances and Exciting Possibilities.” The New
England Journal of Medicine, vol.384, no. 1, 7 Jan. 2021.
46 Green, Eric D., et al. “Perspective: Strategic Vision for Improving Human Health at the Forefront of Genomics.” Nature, vol. 586, 29 Oct. 2020.
47 Ibid.

26
has occurred, whereby the speed increases and cost resolution), we are very much in a phase
decreases in sequencing have facilitated the assembly where we are letting the data lead.51
of exabytes 48
of genomic information that can be
Studying one person’s genome (or in the case of the
mined (assisted by highly advanced and automated
“reference” human genome, a composite of a few peo-
analytical systems) for unique insights into genome
ple) has provided valuable information regarding the
structure and function.49 As highlighted by Green:
structure of the human genome and the number of
protein-coding genes. It has also allowed for compar-
Leading the signature advances has been
ison to an expanding library of reference genomes for
a greater than one million-fold reduction in
other organisms, helping to identify regions of similar-
the cost of DNA sequencing. This decrease
ity and difference that could help illuminate function-
has allowed the generation of innumerable
ality. At a time when whole-genome sequencing cost
genome sequences, including hundreds of
many millions of dollars per genome, the field was
thousands of human genome sequences (both
limited to small volumes of sequenced genomes to
in research and clinical settings), and the
work with. As sequencing costs declined and sequenc-
continuous development of assays to identify
ing speed increased, the ability to generate data from
and characterize functional genomic elements.
a large number of individuals started to become real-
These new tools, together with increasingly
istic, and this has opened new horizons for research.
sophisticated statistical and computational
methods, have enabled researchers to create
Currently, whole genome sequencing and whole
rich catalogs of human genomic variants,
exome (the part of the genome formed from exons
to gain an ever deepening understanding
that code proteins) sequencing is fast and affordable
of the functional complexities of the human
(requiring just a day and $689 for whole genome
genome, and to determine the genomic
sequencing), and as affordability and speed have
bases of thousands of human diseases.50
increased, the number of sequenced individuals
This leads us to the first functional impact domain of has expanded exponentially. In a recent edition of
genetics and genomics in human medicine, minable Science, it is noted that “today, more than 30 million
big data, and what it enables, discovery science. individuals have access to their detailed genomic
datasets,”52 while Ewan Birney of the European
1. Minable Big Data (Discovery Science) Bioinformatics Institute notes that “estimates show
Laurence Hurst highlights the central role that over 60 million patients will have their genome
that data are playing in advancing function- sequenced in a healthcare context by 2025.”53
al applications of genomics, noting that:
Having access to an extremely large volume of se-
Genomics is in an age of exploration and quenced individuals creates a dramatically enlarged
discovery. Whether we are discovering the platform for discovery. Each of us has a unique
genomes of more species, the genomes genome. While 99.9% of the genome between
of more individuals in a species, or more individuals will be the same,54 the 0.1% differenc-
genomes within an individual (at single-cell es can add up to profoundly dissimilar physical
characteristics and differential predisposition to

48 An exabyte = 10006 bytes (1,000,000,000,000,000,000 bytes).

49 Stephens, Zachary D., et al. “Big Data: Astronomical or Genomical?” PLOS Biology, vol. 13, 7 July 2015. doi:10.1371/journal.pbio.1002195.
50 Green, Eric D., et al. “Perspective: Strategic Vision for Improving Human Health at the Forefront of Genomics.” Nature, vol. 586, 29 Oct. 2020.
51 Cheifet, Barbara. “Editorial: Where is genomics going next?” Genome Biology, vol. 20, no. 17, 22 Jan. 2019. doi:10.1186/s13059-019-1626-2.
52 Zielinski, Dina and Janiv Erlich. “Genetic Privacy in the Post-Covid Word.” Science, vol. 371, no. 6529, 5 Feb. 2021.
53 Birney, Ewan. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics Magazine, vol. 6, no. 2, March-
April 2019.
54 National Human Genome Research Institute. “Genetics vs. Genomics Fact Sheet.” www.genome.gov/about-genomics/fact-sheets/Genetics-vs-
Genomics#:~:text=All%20human% 20beings%20are%2099.9,about%20the%20causes%20of%20diseases. Accessed 12 May 2021.

27
Table 7: Large Population Precision Medicine Initiatives

Common Rare diseases

Country Project/program name Expected size
diseases (and cancers)
Australia Genomics Health Futures Mission 200,000 
Canadian Genomics Partnership
Canada for Rare Diseases and Canadian Nationwide  
Longitudinal Study on Aging
100,000–
China Precision Medicine Initiative  
100 million
Denmark Danish National Genome Center 60,000  
Dubai Dubai Genomics Nationwide 
Estonia Personalised Medicine Programme 150,000 
European Union 1+ Million Genomes Initiative 1,000,000+ 
Finland FinnGen 500,000 
235,000
France Genomic Medicine France 2025  
each year
Hong Kong Hong Kong Genome Project 50,000 
Italy SardiNIA Project 60,000 
Japan GEnome Medical alliance Japan Nationwide  
Saudi Arabia Saudi Human Genome Program 100,000  
Singapore (And
Genome Asia 100 K 100,000 
International)
Thailand Genomics Thailand 50,000  
100,000–
Turkey Turkish Genome Project  
1,000,000
United Kingdom 100,000 Genomes Project 100,000 
United Kingdom Accelerating Detection of Disease 5,000,000 
United States NHGRI Genomic-Medicine Nationwide  
United States All of Us Research Program 1,000,000+ 

Source: Identified in Chung, B.H.Y., Chau, J.F.T. & Wong, G.KS. “Rare versus common diseases: a false dichotomy in precision medicine.” npj Genom.
Med. 6, 19 (2021).

disease, rates of metabolizing drugs, and other genomic variant pathogenicity (variants associated
factors. Identifying and understanding these differ- with causation of disease). To-date, the vast majority
ences becomes more feasible the more sequences of larger-scale whole genome sequences have been
and data are available. The devil is in the details, produced in Western nations, with the result that
and more sequences provide more details. the available data skew quite significantly in terms
of individuals of European ancestry. This bias in the
Large-scale sequencing implementation is enabling data is being addressed through multiple initiatives
the ongoing assembly of robust, evidence-based worldwide that will contribute greatly to a broader
resources for the identification and classification of base of represented humanity. Recent research by

28
Brian Hon Yin Chung, Jeffrey Fong Ting Chau, and
Gane Ka-Shu Wong summarizes many of the larg-
Increasing Sequenced
er (>20,000 subject genomes) precision medicine
Population Diversity to Enhance
projects (for which sequencing is primarily a major
Studies of Genetic Variation.
element), showing how in forthcoming years, the
richness of sequenced populations will be enhanced Up until relatively recently the participants in-
volved in genomic research have largely been of
significantly. The global distribution of these studies
55
European ancestry.
(Table 7) holds promise for the development of reliable
Multiple initiatives are now underway to substan-
genomic data on many different populations and tially increase diversity in genomic datasets. For
sub-populations, helping to build a more inclusive example, the Human Heredity and Health in Africa
(H3Africa) initiative has enrolled more than 60,000
atlas of genome variability across the human species. research participants and engaged more than 500
African scientists.
The expanding diversity in the base of human
genome sequence data is further highlighted by
Rotimi, Callier, and Bentley who recently note that:
genetic, health, and environmental data for more than
Growing prioritization of diverse populations one-million participants, providing a robust resource
in genomics research has begun to respond for evaluating genotype-to-phenotype associations.
to these gaps. Programs, such as TOPMed, Another federally initiated program is the “Million Vets
All of Us, International Common Disease Program” (MVP) that, similar to the NIH program, is
Alliance, Human Heredity and Health in collecting deep data to allow the study of links be-
Africa (H3Africa), Million Veteran Program, tween genes, lifestyle, and military exposures and their
GenomeAsia, and the COVID global consortium, associated impacts on health and illness. Since launch-
contribute to advances in diversity and ing in 2011, over 825,000 veterans have signed up to
inclusion among research participants. 56 participate. The VA notes that “in addition to common
health conditions that affect everyone, such as cancer,
In the U.S., several large-scale sequencing initiatives cardiovascular disease, and diabetes, MVP researchers
are ongoing. Among the largest is the NIH’s “All of Us” are also looking at conditions specific to Veterans. This
program, which began in 2018 and is consolidating

Research in genome biology is often descriptive in nature, sequencing genomes and metagenomes,
profiling epigenomes and transcriptomes, charting evolutionary history, and cataloging disease
linked risk loci. Thanks to major technological advances, we can now generate such descriptive
datasets using high throughput platforms.”

Christoph Bock, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, quoted in Barbara
Cheifet. “Editorial: Where is Genomics Going Next?” Genome Biology, vol. 20, no. 17, 22 Jan. 2019.

55 Chung, B.H.Y., et al. “Rare versus Common Diseases: a False Dichotomy in Precision Medicine.” npj Genomic Medicine, vol. 6, no. 19, 24 Feb.
2021. doi.org/10.1038/s41525-021-00176-x.
56 Rotimi, Charles N., et al. “Lack of Diversity Hinders the Promise of Genome Science.” Science, vol. 371, no. 6529, 5 Feb. 2021.

29
includes PTSD [post-traumatic stress disorder], suicide targets; multi-gene to disease associations; environ-
prevention, TBI [traumatic brain injury], and tinnitus.” 57
mental effects on gene regulation and expression;
gene expression effects of prior infectious diseases,
While advances in the technologies for gene se- etc. The combination of genomics and phenomics
quencing are at the forefront in generating large big data and advanced analytics provides a powerful
and deep datasets from diverse populations, equally pathway forward for modern life science discovery
important, have been advancements in advanced and healthcare improvement. This is highlighted
data analytics comprising the use of analytical by Liu, Zhu, Roberts, and Tong who note that: “AI
computer algorithms and statistical techniques is starting to realize its potential in augmenting
acting upon large-scale sets of structured and phenome-wide and genome-wide data profiles to
unstructured data to derive actionable insight improve clinical utility and diagnostic power.”58
(see sidebar definition for advanced analytics).
Evidence for this technological convergence of bio-
Genetic and genomic data, health record data, and medical big data and AI is seen in evident clusters
environmental data each provide important insights of new business ventures forming to pursue com-
on their own but promise far greater intelligence when mercialization of associated opportunities. Research
examined together. This presents the challenge of by TEConomy recently used machine learning to
analyzing extremely large-scale heterogenous data identify clusters of U.S. activity focused on advanced
compiled from multiple sources. Fortunately, as these analytics applications.59 Figure 4 illustrates three
big data resources have been built, there has been distinct clusters of venture capital funded enter-
parallel advancement in the science and technology of prises forming in this space, comprising: 1) drug
advanced data analytics, up to and including artificial discovery and precision medicine, 2) healthcare
intelligence (AI) based systems. Advanced analytics analytics, and 3) wearable health monitoring de-
provides a pathway forward in terms of mining big vice analytics. The growth and interaction of these
genome and genome-phenome datasets to provide clusters builds upon the promise of big data ana-
functional insights and impacts in broad areas such as: lytics using genome and phenome information to
biomarker discovery and identification of druggable derive clinical health insights and improvements.

Advanced Analytics is the autonomous or semi-autonomous examination of data or content using

sophisticated techniques and tools, typically beyond those of traditional business intelligence (BI),
to discover deeper insights, make predictions, or generate recommendations. Advanced analytic
techniques include those such as data/text mining, machine learning, pattern matching, forecasting,
visualization, semantic analysis, sentiment analysis, network and cluster analysis, multivariate
statistics, graph analysis, simulation, complex event processing, neural networks.”
Gartner. “Gartner Glossary.” www.gartner.com/en/information-technology/glossary/advanced-analytics.
Accessed 12 May 2021.

57 VA Million Veteran Program. “About the Million Veteran Program.” www.mvp.va.gov/webapp/mvp-web-participant/#/public/about. Accessed 12
May 2021.
58 Liu, Zhichao, et al. “Toward Clinical Implementation of Next-Generation Sequencing-Based Genetic testing in Rare Diseases: Where Are We?”
Trends in Genetics, vol. 35, no. 11, Nov. 2019.
59 Tripp, Simon, et al. Artificial Intelligence and Advanced Analytics in Indiana: An Initial Discussion of Industry Needs and University
Capabilities. TEConomy Partners, LLC for BioCrossroads, Jan. 2020.

30
Figure 4: Biomedical-Related Clusters Identified in the Innovation Landscape Net-
work of U.S. AI Companies Receiving Significant VC Investment, 2014-2018

Source: TEConomy Partners, LLC

New genetic and genomic analytical tools are also techniques such as CRISPR single cell sequencing
in development and coming online, which promise and single-cell RNA-seq (scRNAseq) will generate data
additional high-throughput analytical capabilities that provides new insights into biological function.
and assessment. It is anticipated that new analytical

31
Case Study: Example of Minable Big Data (Discovery Science)
Geisinger is an integrated healthcare system headquartered in Pennsylvania integrating “primary care
and specialists, hospitals and trauma centers, insurance, medical education and research.”60 Geising-
er has been at the foref ront in terms of recognizing the clinical insights and utility that genomic data
and health record data that are mined together provide. Begun in 2007, Geisinger’s MyCode Commu-
nity Health Initiative has seen over 250,000 patients consent to participate in a research program that
has been performed in collaboration with Regeneron’s genetics research center. More than 100,000
whole exomes had been sequenced (as of reporting in April 2019). Motivated by the MyCode experience,
Geisinger launched a “clinical whole-exome population screening program in mid-2018 as part of rou-
tine clinical care in a variety of Geisinger clinics, developing an end to end implementation platform—
from patient engagement and consenting, to whole exome sequencing in a certified clinical laboratory,
to physician education, to genetic counseling at scale, and to integration of clinical results into the
electronic health record.”61 The main focus of MyCode is finding and confirming new disease-causing
variants (changes) in patient genes, with research programs directed at:

• Searching for changes in genes that protect against disease.

• Targeting new drug development.
• Researching and learning what are the best ways to share medically-actionable genetic results with
patient-participants, and then how to facilitate the sharing of that information with other potential-
ly affected family members.
• Translating the results into clinical care.

The CEO of Geisinger, Jaewon Ryu, notes that:

About 90 percent of the patients we ask let us look at their entire genomes. That’s huge trust; a typ-
ical rate is 15 percent. Our patients come f rom an unusually stable population—giving us volumes
of data from more than 15 years of electronic health records. MyCode therefore provides unprece-
dented opportunity for early diagnosis and developing new and tailored treatments, or precision
medicine. MyCode is already letting us help participants and their families prevent or mitigate the
impacts of some identified genetic risk factors, including cancer and heart disease.62

Some of the results emanating f rom MyCode in terms of advancements in breast cancer genetics
have been called out as among the most significant applications of medical genetics in the “Genomic
Medicine Year in Review.” BRCA1 and BRCA2 are genes associated with hereditary breast/ovarian cancer
syndrome. They have a high degree of sequence variation, but the population prevalence of “pathogen-
ic” and “more likely pathogenic” variance (P/LP) has not been known. The research team used 50,000+
whole exome sequences from MyCode to examine the f requency of P/LP variants, finding a f requency
significantly higher than other estimates. Importantly, it was found that “almost half of all variant car-
riers did not meet current criteria for clinical testing, and of those meeting testing criteria, nearly half
had not undergone clinical testing. Thus, 3/4 of at-risk women were not identified as such and are not
benefiting from evidence based interventions; this is a significant care gap with implications for popu-
lation health.”63 This represents a prime example of how the assembly and analysis of big data enables
robust functional impacts to be generated in clinical care.

60 Geisinger. “About Geisinger.” www.geisinger.org/about-geisinger. Accessed 12 May 2021.

61 Willard, Huntington. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics Magazine,
vol. 6, no. 2, March-April 2019.
62 Geisinger. “About Geisinger.” www.geisinger.org/about-geisinger. Accessed 12 May 2021.
63 Manolio, Teri A., et al. “Genomic Medicine Year in Review: 2019.” The American Journal of Human Genetics, vol. 105. 5 December
2019. Reporting on findings from Manickam, K. et al. “What We’re Missing: Most BRCA1 and BRCA2 Variant Carriers are
Undetected.” JAMA Network Open.

32
2. Identifying Predisposition
to Diseases and Disorders
One of the primary research and clinical applica- decision making. The library of gene-disease as-
tions of human genetics and genomics is its use in sociations has expanded rapidly, and as Figure 7
identifying potential predisposition to developing illustrates, there are genes within every human
diseases and health disorders. The BRCA gene ex- chromosome associated with disease. Notably, all
ample from Geisinger is an example of this, where but three of the diseases or disorders listed in Figure
the identification of these genes in the patient 5 now have a genetic test associated with them.
identifies risk for breast cancer and guides clinical

Figure 5: The human chromosome set, indicating examples of locations for patho-
genic gene variants causing hereditary diseases

Note: Conditions that can be diagnosed using DNA analysis are indicated by a red dot.
Source: By Ігор Пєтков - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=57928376

33
Figure 5 illustrates only a small sampling of the a. Carrier Screening
diseases and health disorders that have genetic As noted by NHGRI:
associations. The number identified is growing, and Carrier screening is a type of genetic testing
at the time of writing 4,395 genes are noted by the performed on people who display no
Online Mendelian Inheritance in Man (OMIM) project symptoms for a genetic disorder but may
as being identified with a disease or disorder-causing be at risk for passing it on to their children.
mutation (phenotype-causing mutation), and 6,828 A carrier for a genetic disorder has inherited
diseases or disorders have a known genetic basis. 64
one normal and one abnormal allele for a
gene associated with the disorder. A child
One of the key applications of this knowl- must inherit two abnormal alleles in order
edge, and an extremely valuable one, is the for symptoms to appear. Prospective parents
development of genetic testing for predis- with a family history of a genetic disorder
position to disease. Genetic testing is: are candidates for carrier screening.66

The use of a laboratory test to look for genetic Carrier screening has generated significant impacts
variations associated with a disease. The on decision making for potential parents. This particu-
results of a genetic test can be used to confirm larly comes into play when two individuals each carry
or rule out a suspected genetic disease or to a single copy of a disease allele that, while harmless to
determine the likelihood of a person passing on them, has a serious risk of manifesting into a serious
a mutation to their offspring. Genetic testing genetic disease in their offspring. Carrier screening
may be performed prenatally or after birth. 65 can be used by individuals, in advance of marriage or
long-term partnering, to assess genetic risks, and by
The above definition from NHGRI implies two principal couples contemplating starting a family. The appli-
uses for genetic tests: 1) diagnosis of present disease cation of carrier screening in some communities and
(which was discuss previously), and 2) identification populations has had profound effects, limiting, for
of the presence of a gene variant that may predispose example, the birth of children with devastating, often
an individual or their offspring to the development fatal, diseases such as Tay-Sachs disease and highly
of a disease associated with that gene. This latter debilitating disorders such as Sickle Cell Anemia and
use of genetic testing is becoming increasingly Beta-thalassemia. The rise of low cost, high accuracy
deployed as more gene-disease associations are whole genome sequencing is greatly expanding the
established. Genetic testing for predisposition to potential to perform DNA-based carrier screening
diseases or health disorders may be divided into across a broad range of autosomal recessive, sin-
three categories: 1) carrier screening, which tests a gle-gene disorders. Carrier screening may also be used
prospective parent for the presence of gene variants by at-risk couples pursuing in vitro fertilization (IVF),
that have been shown to be associated with risk of allowing their clinician to test for potential genetic
passing down a hereditary disorder (thereby helping abnormalities before implantation of fertilized eggs
to inform family planning and associated decisions); (this is termed “preimplantation genetic diagnosis”)
2) pre-natal and post-natal testing, which focuses or to select embryos with normal chromosomes for
on testing for genetic predisposition to disease in implantation (“preimplantation genetic screening”).
the fetus or in newborns; and, 3) child and adult
testing. Each application is introduced below.

64 OMIM®, Online Mendelian Inheritance in Man®. OMIM is a comprehensive, authoritative compendium of human genes and genetic
phenotypes that is freely available and updated daily. OMIM is authored and edited at the Johns Hopkins University School of Medicine. For
more information see: www.omim.org/statistics/geneMap.
65 National Human Genome Research Institute. “Genetic Testing.” www.genome.gov/genetics-glossary/Genetic-Testing. Accessed 12 May 2021.
66 National Human Genome Research Institute. “Carrier Screening.” www.genome.gov/genetics-glossary/Carrier-Screening. Accessed 12 May
2021.

34
b. Pre-natal and Post-natal Testing DNA fragments in maternal blood to screen for fetal
Not every potential parent is in a position to access genetic conditions, such as the common trisomies67
carrier screening and, of course, a great many preg- (e.g., Down syndrome) and deletion or duplication
nancies are unplanned. As a result, many (indeed syndromes. A non-invasive prenatal screening (NIPS)
most) pregnancies occur without prior carrier screen- is more accurate, with fewer false positives for the
ing. Once a pregnancy is underway, pre-natal screen- most common trisomies, than other screening
ing provides the ability for clinicians to evaluate the tests—leading to fewer invasive procedures.68
healthy development of the baby (through established
diagnostics such as ultrasounds and maternal blood NIPS can now test for:
tests) and can also include genetic tests to screen for • Trisomy 21 (Down’s syndrome)
whether the baby may be born with certain genetic • Trisomy 18 (Edwards syndrome)
conditions and chromosomal disorders (such as • Trisomy 13 (Patau syndrome)
Down’s syndrome). Such genetic testing has tradition- • XXY chromosome (Klinefelter syndrome)
ally been reserved for mothers with a certain risk pro- • XO chromosome (Turner syndrome)
file (such as family history of genetic disease, mothers • Microdeletions in chromosomes
who are older, or persons who know they carry certain • Rh factor (positive or negative determination)
monogenic alleles that confer risk). Such genetic • Multiple other less common triso-
prenatal testing has required invasive procedures, mies and single-gene disorders.
such as amniocentesis, that carry a measure of risk
At the present time, these NIPS tests are not con-
to the pregnancy. Increasingly, however, physicians
sidered fully diagnostic, and follow-up testing is
are able to order non-invasive prenatal screening (or
recommended using other procedures if a posi-
“cell-free DNA screening”) that uses cell-free placental
tive result is achieved through NIPS. Ultimately,

67 A “trisomy” is a condition in which an extra copy of a chromosome is present in the cell nuclei, causing developmental abnormalities.
68 Dondorp, Wybo, et.al. “Non-invasive Prenatal Testing for Aneuploidy and Beyond: Challenges of Responsible Innovation in Prenatal Screening.”
European Journal of Human Genetics, vol. 23, no. 11, 18 Mar. 2015.

35
pre-natal diagnostics can help mothers make Newborn genetic screening represents a
informed decisions regarding their pregnancy highly visible and successful approach to
and discuss options for care with their health- identification of inherited health conditions.
care provider, help families prepare for a poten-
tial challenge to their baby’s health, and help c. Child and Adult Testing
ensure that clinicians are ready to support any The clinical reality of whole genome, or whole exome,
special health needs of the resulting newborn. sequencing is a relatively new phenomenon. Thus,
the vast majority of the present U.S. population did
Finally, post-natal testing is a suite of genetic and ge- not benefit from access to this valuable screening
nomic tests that are employed to evaluate newborn and diagnostic tool at birth. Having sequencing
health and diagnose present or emerging health is- performed at any stage in life will, however, still
sues. As noted by Holm, “the greatest opportunity for have potentially significant clinical utility, with utility
lifelong impact of genomic sequencing is during the obviously maximized the earlier in life the sequencing
newborn period.” 69
Having a whole-genome sequence, is performed. With the expanding library of identified
or at least a whole-exome sequence, completed as gene-disease linkages and the assurance that this
soon as possible after birth provides a broad spectrum library will continue to grow as more research findings
of genetic information for significant immediate use accumulate, it is only a matter of time before full
and expanding clinical utility across the lifespan. As sequencing of everyone is a clinical reality and con-
noted above, 6,828 diseases or disorders currently have sidered standard of care—with our genome sequence
a known genetic basis, and a whole-genome se- ideally connected to a lifelong electronic health record.
quence provides an increasingly accessible pathway to The cost/benefit ratio of such a data structure has
evaluating common or rare genetic mutations associ- been consistently shifting in its favor as the cost of
ated with immediate health challenges or the devel- sequencing dramatically declines and information
opment or emergent health issues over a life span. on gene-disease associations increases. Indeed, the
The most immediate benefit of newborn screening is promise of universal sequencing in clinical application
as a contributor to achieving a diagnosis of a genetic is being realized in some health systems, as shown in
disease or disorder in the newborn—the advantages the Geisinger MyCode example. Multiple other health
of which are discussed in the diagnosis section. systems have large-scale pilot projects underway, in-
cluding examples such as Mayo Clinic, Intermountain

69 Holm, Ingrid A., et al. “The BabySeq Project: Implementing Genomic Sequencing in Newborns.” BMC Pediatrics, vol. 18, no. 225, 9 July 2018.
doi:10.1186/s12887-018-1200-1.

36
Healthcare, Mount Sinai Healthcare System, Kaiser (PRS), which are an “emerging technology for aggre-
Permanente, and the Veterans Administration. It is gating the small effects of multiple polymorphisms
also increasingly the case that “centers for person- across a person’s genome into a single score.” 70 It has
alized medicine” have been established at leading been noted, “In medicine and public health, PRSs
healthcare centers that offer whole-genome or could, in the future, be used for initiating additional
whole-exome sequencing to selected patients, often risk screening or motivating behavior change.” 71 It
with an initial focus on cancers or rare disorders. is an area of research interest and potential prom-
ise. Writing in early 2019, Liz Worthy notes that:
Today, with thousands of genes associated with
thousands of diseases, it is perhaps not surprising that Over the last 18 months we are seeing increased
genetic and genomic tests are becoming increas- application of polygenic risk score analysis
ingly applied in medicine across the lifespan. A key making use of large GWAS [genome wide
application is in determining the “risk” for patients in association studies] and WGS [whole genome
developing a disease that is associated with particular sequencing] data. PRS seeks to estimate an
alleles. The previously mentioned BRCA gene tests individual’s propensity towards particular
for risk of hereditary breast cancers are one example, phenotype… These methods have a variety of
with the BRCA1 and BRCA2 genes accounting for uses including human disease risk assessment
20-25% of hereditary breast cancers. Testing positive in research settings and there is increased focus
for these gene variants allows a patient to enter into on their application within healthcare settings.72
informed discussions with their physicians regarding
For the patient, the advantages afforded through
potential risk reduction approaches, such as increased
the application of genetic tests for disease pre-
screening frequency or prophylactic breast removal
disposition are potentially significant—providing
surgery. Multiple cancers now have genetic tests
a pathway for adopting risk reduction lifestyle or
associated with them for risk evaluation, including
medicinal approaches, more frequent use of early
breast, colorectal, cutaneous melanoma, gastric,
disease detection screenings, and prophylactic
ovarian, pancreatic, prostate, renal cell, thyroid, and
surgeries in selected instances. It is important to
uterine cancers. Cardiovascular-related tests are also
note that genetic and genomic testing for the
available to evaluate risks for developing aortopathies,
predisposition of disease is best performed in
arrhythmias, cardiomyopathies, genetic forms of high
consultation with a patient’s physician and with
blood pressure and high cholesterol, and thrombophil-
genetic counselors—skilled personnel who can
ia. The above are just some of the areas of disease in
interpret the results and provide recommendations
which genetic testing for risk is seeing application, and
for health strategies rooted in evidence-based clinical
the library of available tests will continue to expand.
practice. While there are direct-to-consumer tests,
there is risk attached to non-professional test result
Because most common diseases have been found
interpretation that could lead to unnecessary anxiety
to have associations with many individual genes (i.e.,
or pursuit of unnecessary/unproven interventions.
they are polygenic, as opposed to monogenic), a
new area of science and practice is in development
focused on determining potential risk based on
the presence of multiple gene variants. This testing
results in the generation of “polygenic risk scores”

70 Ossorio, Pilar N. “Polygenic Risk in a Diverse World.” Science, vol. 371, no. 6529, 5 Feb. 2021.
71 Ibid.
72 Worthy, Liz. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics Magazine, vol. 6, no. 2, March-
April 2019.

37
Case Study in Genetic Screening: Detecting
At-Risk Carriers Not Detected Through Other Methods
Results from a large cohort study conducted at Renown Health in Nevada show how genetic carrier
testing results in the identification of risk in patients where it was not previously suspected. Describing
the study, Manolio noted that:

The value of genetic screening in an unselected population for identifying individuals carrying P/
LP genomic variants for HBOC [Hereditary Breast and Ovarian Cancer], Lynch syndrome, and FH
[Familial Hypercholesterolemia] has not been widely explored. The Healthy Nevada Project at Re-
nown Health performed exome sequencing in 26,906 participants with available electronic med-
ical records and analyzed genomic variants in nine risk genes for these conditions. Roughly 1.3%,
90% of whom had not been previously identified, carried P/LP variance. Among carriers, 22%, 70%
of whom were diagnosed before age 65, were diagnosed with clinically relevant disease. Less than
20% of carriers had medical record documentation of inherited genetic disease risk or relevant
family history.73

The researchers conclude that: “this suggests that genomic screening for inherited cancer and cardio-
vascular risk conditions can identify a significant number of at-risk carriers who are not detected by
standard medical practice and who may benefit f rom earlier clinical risk screening.” 74

73 Manolio, Teri A., et al. “Genomic Medicine Year in Review: 2020.” The American Journal of Human Genetics, vol. 105, 5 December
2019. Reporting on findings from Grzymski, J.J. et al. “Population Genetic Screening Efficiently Identifies Carriers of Autosomal
Dominant Diseases.” Nature Medicine, vol. 26, 27 July 2020.
74 Ibid.

3. Diagnosing Diseases, mysterious severe bowel disease of unknown

Rare Diseases, and Disorders origin. Searching for an explanation and
Genetic or genomic tests can not only determine treatment, doctors turned to next-generation
potential risk for developing a disease, they can DNA sequencing technology. They identified a
also be highly informative in guiding the diagnosis mutation in the XIAP gene as the likely cause of
of a present disease or disorder. As noted by the his illness, knowledge that suggested a course
precision medicine program at Duke University: of treatment that led to his recovery, ending
his diagnostic odyssey. Early results from some
Whole genome and whole exome sequencing clinical sequencing programs estimate the
are increasingly being used in the clinic to aid success rate of disease gene identification at
in the diagnosis of rare congenital disorders about 25-30%, offering hope to thousands of
and solve diagnostic dilemmas. One of the first individuals with previously undiagnosed or
and most high-profile examples of using clinical untreated rare disorders, while recognizing that
sequencing to end a diagnostic dilemma is sequencing will not provide all of the answers.75
the case of 6 year old Nic Volker at the Medical
College of Wisconsin, who suffered from a

75 Duke Center for Applied Genomics and Precision Medicine. “Clinical Whole Genome Sequencing.” https://precisionmedicine.duke.edu/
researchers/precision-medicine-programs/clinical-whole-genome-sequencing. Accessed 12 May 2021.

38
Genetic and genomic tests for disease diagnosis The Genetic and Rare Diseases Information Center
are being deployed across a broad range of rare reports that 25-30 million people in the U.S. have a
and more common diseases and disorders. rare disease, and over 350 million people worldwide
are afflicted.77 Approximately 1 in 10 individuals
a. Diagnosis of Rare Diseases and Disorders has a rare disease, so collectively rare diseas-
Rare diseases, by their inherent nature, present es have a significant population impact.
diagnostic challenges because so few physicians have
encountered them. Often these diseases may present Liu, Zhu, Roberts, and Tong further report that:
symptoms seen in other, more common diseases
resulting in an understandable misdiagnosis and An incomplete knowledge of the natural history
inappropriate treatment strategies being adopted. of each rare disease can make a substantial
Patients and their families may embark on long proportion (~60%) of rare diseases intractable
“diagnostic odysseys”, seeing dozens of practitioners, and undiagnosable. Panel-based NGS or
undergoing multiple tests and procedures, enduring targeted sequencing tests are designed to
fruitless attempts at treatment over many years reveal causal mutations for genes known to
without ever getting a definitive, accurate diagnosis. be associated with a specific rare disease.
Genetic and genomic testing has been a pathway Since the NGS gene panel is predesigned or
to solving this dilemma in multiple diseases and expert-selected, ultradeep, uniform coverage
disorders impacting many thousands of patients. allows for high sensitivity and also for specific
variant calling for rare genetic variants.78
While individual rare diseases are, by definition, rare,
By deploying genetic and genomic testing, up to
they collectively impact a large global and domestic
and including whole genome sequencing, diagnos-
population. Liu, Zhu, Roberts, and Tong estimate that:
tic odysseys may be ended for many patients—not
only providing a pathway to appropriate treatment
Approximately 7000 rare diseases have been
but also reducing significant waste in the health-
recognized, a substantial number of which
care system and the associated costs of incorrect
are life threatening or chronically debilitating.
diagnosis. Even if no treatment is available, peace of
Around 80% of rare diseases are genetic in
mind can result through simply having an “answer”
origin. A single rare disease affects a small
and being able to end the costly hunt for diagnosis.
number of the population (defined as <1/15,000
In discussing rare diseases and the application of
in the US and <1/2000 in Europe)… Most rare
sequencing, Chung, Chau, and Wong report on
disease patients (50 to 75%) show onset at
impressive results from sequencing adoption:79
birth or in childhood. As many as 30% of
rare diseases patients die before the age of
Affected individuals often endure years of
five years. Furthermore, each rare disease
diagnostic odyssey, which is not only fruitless
patient has been estimated to cost a total
but more expensive than sequencing their
of $5 million throughout their lifespan.76

76 Liu, Zhichao, et al. “Toward Clinical Implementation of Next-Generation Sequencing-Based Genetic testing in Rare Diseases: Where Are We?”
Trends in Genetics, vol. 35, no. 11, Nov. 2019.
77 National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center. “FAQs About Rare Diseases.” https://
rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases. Accessed 12 May 2021.
78 Liu, Zhichao, et al. “Toward Clinical Implementation of Next-Generation Sequencing-Based Genetic testing in Rare Diseases: Where Are We?”
Trends in Genetics, vol. 35, no. 11, Nov. 2019.
79 Chung, B.H.Y., et al. “Rare versus Common Diseases: a False Dichotomy in Precision Medicine.” npj Genomic Medicine, vol. 6, no. 19, 24 Feb.
2021. doi:10.1038/s41525-021-00176-x.

39
Whole genomic sequencing and whole exome sequencing are eliminating the phenomenon of the
diagnostic odyssey for rare genetic disease: it’s realistic today to have a genome or exome test ordered at
first subspecialist outpatient visit and to have a diagnosis by the time of the second visit . This is clearly
the most powerful diagnostic tool ever developed for the millions of children with rare diseases.”
Stephen Kingsmore. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics
Magazine, vol. 6, no. 2, March-April 2019.

genomes upfront80,81. For infants admitted b. Diagnosing Single Gene (Mendelian)

to intensive care within the first 100 days of Disease and Disorders
life, sequencing produced diagnostic yields Mendelian, single-gene diseases represent an ex-
of 36.7%; and in 52.0% of the diagnosed, tremely large compendium of diseases and disorders.
medical management was affected.82 Results As noted by Collins, Doudna, Lander, and Rotimi, “The
improved to 50.8% and 71.9%, respectively, discovery of genes responsible for more than 5000 rare
when trio sequencing was conducted. Other mendelian diseases has facilitated genetic diagnostics
studies have given similar results.83 for many patients, pregnancy-related counseling, new
drug treatments, and in some cases, gene therapies.”85
Ranging from individual genetic tests through to
A number of these single gene-associated diseas-
complete whole-genome sequencing, the full range
es and disorders have a substantial impact across
of genetic and genomic tools and technologies are
populations and within certain sub-populations.
now being deployed in clinical diagnostic testing.
Some of the more widely known examples include:
“Besides targeted sequencing, there are increasing
applications of whole-genome sequencing/whole-ex-
• Cystic Fibrosis (CF)—a progressive, genetic
ome sequencing (WGS/WES) to detect complex
disease that causes persistent lung infections and
genetic variants and provide complete genetic
limits the ability to breathe over time. In people
information in support of rare disease diagnosis.”84
with CF, mutations in the cystic fibrosis trans-
This statement recognizes that while many rare
membrane conductance regulator (CFTR) gene
diseases may be associated with a single gene (i.e.,
cause the CFTR protein to become dysfunctional.
Mendelian), there are also many challenging diseases
CF affects approximately 30,000 Americans.86
where multiple genes come into play (polygenic).
• Alpha- and beta-thalassemias—inherited
genetic blood disorders causing the body to

80 Tan, T. Y., et al. “Diagnostic Impact and Cost-effectiveness of Whole-exome Sequencing for Ambulant Children with Suspected Monogenic
Conditions.” JAMA Pediatrics, vol. 171, Sept. 2017.
doi:10.1001/jamapediatrics.2017.1755.
81 Farnaes, L., et al. “Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization.” npj Genomic Medicine, vol. 3, no.
10, 4 Apr. 2018. doi:10.1038/s41525-018-0049-4.
82 Meng, L., et al. “Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-gene Disorders and Effect on
Medical Management.” JAMA Pediatrics, vol. 171, no. 12, 4 Dec. 2017. doi:10.1001/jamapediatrics.2017.3438.
83 Wright, C. F., et al. “Pediatric Genomics: Diagnosing Rare Disease in Children.” Nature Reviews Genetics, vol. 19, no. 325, 5 Feb. 2018.
doi:10.1038/nrg.2017.116.
84 Liu, Zichao, et al. “Editorial: Advancing Genomics for Rare Disease Diagnosis and Therapy Development.” Frontiers in Pharmacology, vol. 11, no.
598889, 25 September 2020.
85 Collins, Francis S., et al. “Perspective: Human Molecular Genetics and Genomics – Important Advances and Exciting Possibilities.” The New
England Journal of Medicine, vol.384, no. 1, 7 Jan. 2021.
86 Centers for Disease Control and Prevention. “Sickle Cell Disease.” www.cdc.gov/ncbddd/ sicklecell/data.html#:~:text=In%20the%20United%20
States&text=It%20is%20estimated%20that%3A,every%2016%2C300%20Hispanic%2DAmerican%20births. Accessed 12 May 2021.

40
make fewer healthy red blood cells and less cells in the brain. Huntington’s Disease is esti-
hemoglobin than normal. Beta-thalassemia mated to affect more than 40,000 Americans.90
affects at least 1,000 people in the U.S.; how-
ever, the exact prevalence is not known.87

• Sickle cell disease—an inherited group of dis-

orders in which red blood cells are misshapen
into a sickle shape. The cells die early, leaving
a shortage of healthy red blood cells (sickle
cell anemia), and can block blood flow. The
Centers for Centers for Disease Control and
Prevention (CDC) estimate that the disease
affects approximately 100,000 Americans.88

• Fragile X Syndrome (FXS)—a genetic disease

that causes mild to severe intellectual disability,
with typical associated symptoms including
delays in talking, anxiety, and hyperactive be-
havior. The exact number of people who have
FXS is unknown, but a review of research studies
estimated that about 1 in 7,000 males and about 1
in 11,000 females have been diagnosed with FXS.89

• Huntington’s Disease—a fatal genetic disorder

that leads to progressive breakdown of nerve

The undiagnosed diseases network (UDN), a multidisciplinary collaboration evaluating patients

who have with complex presentations and have remained undiagnosed despite extensive clinical
investigation, performed in depth clinical evaluations along with exome and whole genome
sequencing, metabolomics testing, and studies in model organisms. From 2015 to 2017, the UDN
accepted 601 of 1519 patients referred for evaluation. Of the first 382 patients with a completed
evaluation, 132 (35%) received a diagnosis; these included 31 (11%) with new syndromes. Among
diagnosed patients, the majority (58%) had medical care changes, such as changes in therapy or
shortening of the diagnostic odyssey.”
Teri A. Manolio et al. 2019. “Genomic Medicine Year in Review: 2019.” The American Journal of Human Genetics, vol. 105, 5
Dec. 2019. Reporting on original research by Splinter, K., et al. The New England Journal of Medicine, vol. 379, 2131-2139, 2018.

87 Challenge TDT. “Beta-Thalassemia Overview.” www.challengetdt.com/beta-thalassemia-overview. Accessed 12 May 2021.

88 Centers for Disease Control and Prevention. “Sickle Cell Disease.” www.cdc.gov/ncbddd/ sicklecell/data.html#:~:text=In%20the%20United%20
States&text=It%20is%20estimated%20that%3A,every%2016%2C300%20Hispanic%2DAmerican%20births. Accessed 12 May 2021.
89 Centers for Disease Control and Prevention. “Fragile X Syndrome.” www.cdc.gov/ncbddd/fxs/ data.html. Accessed 12 May 2021.
90 Yohrling, George, et al. “Prevalence of Huntington’s Disease in the US.” Neurology, vol. 94, no. 15, 14, Apr. 2020.

41
Case Study in Whole Genome Sequencing for Diagnosis: Project
Baby Bear, California
As noted in ClinicalOmics, a pilot program in California funded by the state “showed that precision
medicine for critically ill babies enrolled in California’s Medicaid program reduced their suffering and
yielded better health outcomes, while decreasing the cost of their healthcare, saving the Golden State
$2.5 million.”91 The initiative, named Project Baby Bear, deployed rapid Whole Genome Sequencing
(rWGS) as the core approach. Stephen Kingsmore, the President and CEO of Rady Children’s Institute
for Genomic Medicine, which led the project, notes that:

For seriously ill children who are hospitalized in intensive care units, the most significant advance
has been ultra-rapid whole-genome sequencing. It’s routinely possible now to examine nearly
every genetic disease and either make a diagnosis or rule out genetic disease, in 36 hours. That’s
fast enough to guide weighty management decisions in even the most seriously ill children. Where
rapid whole-genome sequencing is absolutely transformative is in seriously ill children in whom a
genetic disease was not suspected at test order. Those children were, with the best intentions in
the world, being treated for the wrong diagnosis.92

In describing the results of the pilot project, Kingsmore reports that the project (which used WGS for Medi-
Cal-enrolled infants in intensive care units at five California children’s hospitals) had compelling results:

In 720 infants in intensive care units tested so far, one in three received the genetic disease di-
agnosis, and in about 1/3, we are able to exclude genetic disease as the course of illness. One in
four infants has a change in care as a result of rapid whole genome sequencing. One in five has a
change in outcome.93

A recent review report on the results of Project Baby Bear shows that over 23 months, the project:

• Completed rWGS on 178 babies and families.

• Provided diagnoses for 76 babies (43%).
• Led to a change in the management of 55 babies (31%) that resulted in fewer hospital days, fewer
procedures or new therapies.
• Diagnosed 35 rare conditions that occur in less than one in one million births.
• Achieved a three-day turnaround time for provisional results.94

The study also demonstrated that this clinical application of whole genome sequencing “reduced
healthcare costs and downstream spending, primarily by empowering doctors to eliminate unneces-
sary procedures and discharge babies sooner.”95 In a retrospective analysis of the program’s economic
impacts, it is concluded that:

By introducing Medi-Cal babies into a coordinated system of care that included physicians trained
in identifying babies likely to benefit f rom whole genome sequencing, lab interpretation scien-
tists, genetic counselors and others, the state of California saved millions of dollars in healthcare
expenses due to avoided procedures and shorter hospital stays… The avoided procedures and
reduced hospital time amounted to $2.5 million in cost savings. These cost savings stemmed from
changes in the medical management of just 29 babies who received significant benefit f rom ge-
nome sequencing.96

91 “Rady Children’s Helps California’s Project Baby Bear Improve Outcomes, Save $2.5M.” Clinical Omics Magazine, 19 June 2020.
92 Kingsmore, Stephen. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics Magazine,
vol. 6, no. 2, March-April 2019.
93 Ibid.
94 Rady Children’s Hospital – San Diego. “Project Baby Bear Final Report: Period Covering July 1, 2018 – June 1, 2020.” Report to the
State of California.
95 Ibid.
96 Ibid.

42
c. Diagnosing Complex (Polygenic)
Multifactorial inheritance disorders are caused by a
Diseases and Disorders combination of environmental factors and mu-
Most common debilitating diseases are not caused by tations in multiple genes. For example, different
genes that influence breast cancer susceptibility
mutation of a single gene, rather they are influenced
have been found on chromosomes 6, 11, 13, 14, 15, 17,
by combinations of mutations in many genes each and 22. Some common chronic diseases are multi-
factorial disorders, with examples including:
having a small effect (but combining to have the
potential for large effects). Complicating the situation • heart disease
• high blood pressure
is that the expression, regulation, or products of these
• Alzheimer’s disease
genes may be a result of interactions with a multiplic- • arthritis
ity of environmental factors. There is thus a complex • diabetes
• cancer, and
“soup” of genetic and environmental factors at play in • obesity.
many common diseases. While these diseases have
Eric D. Green, et al. “Perspective: Strategic Vision Medi-
a complex etiology that does not mean that progress cineNet. “Genetic Diseases (Disorder Definition, Types, and
Examples). www.medicinenet.com/genetic_disease/article.
cannot be made. Indeed, with the sophisticated tools htm. Accessed 12 May 2021.
of next generation sequencing and advanced compu-
tational analytics, significant biological and mechanis-
tic insights are being produced. As noted in a recent
perspective in the New England Journal of Medicine: conditions, although additional rigorous
testing of such scores is needed, including
The discovery of more than 100,000 robust
evaluation of clinical outcomes.97
associations between genomic regions
and common diseases has pointed to new For many common diseases, the challenge of
biologic mechanisms, such as the role of identifying and characterizing genetic effects
microglia in Alzheimer’s disease, autophagy is not insignificant. In the case of epilepsy, for
in inflammatory bowel disease, and synaptic example, analysis of the ClinGen Epilepsy Gene
pruning in schizophrenia. It has also enabled Curation Expert Panel indicates 2,702 genes as-
the development of polygenic risk scores sociated with epilepsy, a disorder that affects
to identify patients at increased risk for approximately 50 million people worldwide.98
heart disease, breast cancer, and other

Building on the recent successes of unraveling the genetic underpinnings of rare and undiagnosed
diseases, the field is poised to gain a more comprehensive understanding of the genetic
architecture of all human diseases and traits. However, myriad complexities can be anticipated. For
example, any given genomic variant may affect more than one disease or trait; can confer disease
risk or reduce it; and connect additively, synergistically, and/or through intermediates.”
Eric D. Green, et al. “Perspective: Strategic Vision for Improving Human Health at the Forefront of Genomics.” Nature,
vol. 586, 29 October 2020.

97 Collins, Francis S., et al. “Perspective: Human Molecular Genetics and Genomics – Important Advances and Exciting Possibilities.” The New
England Journal of Medicine, vol.384, no. 1, 7 Jan. 2021.
98 Helbig, I. et al. “The ClinGen Epilepsy Gene Curation Expert Panel—Bridging the Divide Between Clinical Domain Knowledge and Formal Gene
Curation Criteria”. Human Mutation, vol. 39, no. 11, Nov. 2018.

43
4. Rational Drug Development treatment of a more common human disease,
Pharmaceuticals (drugs) are a fundamental part of the rather than relying on information gained from
armamentarium of medicine, providing the means less predictive animal or cellular models.” 100
to treat and ameliorate the symptoms of disease, and
The application of genetics and genomics to drug
in some cases, cure the disease. Pharmaceuticals
development has resulted in multiple clinical success-
bring relief to millions worldwide and have greatly
es. Monoclonal antibodies for the treatment of various
extended the average human lifespan and quality of
immune-mediated conditions (targeting the protein
life across that lifespan. Traditionally, drug discovery
interleukin-23 for example, produced by the IL23R
has used a trial-and-error approach whereby a library
gene) are already used clinically. Similarly, mutations
of chemical substances is tested on cultured cells or
in the PCSK9101 gene were identified in families with
animals and evaluated for its effects. Molecules gen-
autosomal dominant hypercholesterolemia, and
erating an apparent positive effect are then brought
pursuing PCSK9 as a drug target resulted in the FDA
forward into clinical trials to evaluate effectiveness
“approving two monoclonal antibodies (alirocumab
on a disease in humans. Rational drug development,
and evolocumab) for the treatment of high cholesterol
however, takes a different approach, one in which
not adequately controlled by statins or diet.” 102 Put
biomarkers or preidentified druggable targets that
simply, since genes code for proteins, and proteins
are present in, or generated by, a disease may serve
(and nucleic acids) are typical biomolecular targets
as molecular targets for purposefully designed drugs
for drugs, understanding the relationship between
designed to bind to the target. Human genetics and
genes and disease provides potential for rationally
genomics assist in this approach in multiple ways:
identifying drug targets. Kalydeco, a targeted drug for
cystic fibrosis, approved by FDA in 2012, resulted from
• Helping to identify biomarkers, protein targets,
rational drug development informed by genomics.
etc. through comparative analysis of disease
Cystic fibrosis is characterized by physical responses
affected patients versus healthy individuals.
to the abnormal flow of salt and fluids in and out
• Identifying genetic variations across indi- of the cells in different parts of the body. Kalydeco
viduals impacted by the disease that may specifically “acts on the gating defect associated
influence the effectiveness of a designed with the CFTR protein [coded by the CFTR gene],
drug (often related to differences in metab- helping to open up the blocked chloride channels.” 103
olism) and potential adverse side effects.
It is interesting to note that, in some regards, ge-
• As noted by Dugger, Platt and Goldstein,99 netics and genomics advancements have helped
sequencing can inform understanding of “the to rebalance pharmaceutical research in terms of
phenotypic effects of a spectrum of rare muta- work on chronic diseases versus rare diseases. Given
tions ranging from loss-of-function to gain-of- the prior trial-and-error model, it was in the best
function mutations within a single gene” and can interests of the industry to concentrate resources
provide “information on the putative efficacy and/ on major chronic conditions in search of blockbust-
or toxic effects resulting from the modulation er drugs. Costly and with a high failure rate, drug
of that particular gene product in humans. This companies had to triage their funds towards areas
knowledge thereby builds confidence in the with the most promise for financial return. Modern
rationale for targeting that gene product for the genomics, however, and the large-scale identification

99 Dugger, Sarah A., et al. “Drug Development in the Era of Precision Medicine.” Nature Reviews Drug Discovery, vol. 17, no. 3, 8 Dec. 2017.
100 Ibid.
101 The PCSK9 gene provides instructions for making a protein that helps regulate the amount of cholesterol in the bloodstream.
102 Dugger, Sarah A., et al. “Drug Development in the Era of Precision Medicine.” Nature Reviews Drug Discovery, vol. 17, no. 3, 8 Dec. 2017.
103 Ciriello Pothier, Kristen. Personalizing Precision Medicine. A Global Voyage from Vision to Reality. John Wiley & Sons, Inc., 2017.

44
of gene-disease associations has provided a more of personalized medicine. Indications are
target-rich environment to address rarer, typically increasingly segmented by biomarkers in
monogenic, disorders104—while at the same time order to match patients with the treatments
showing that many of the more common diseases are most likely to show the greatest benefit,
highly complex genetically, with sometimes hundreds according to the underlying drug mechanism
and even thousands of genes engaged. The result is and disease pathophysiology. We identified
noted in a recent 2021 study by the Biotechnology 767 phase transitions out of 12,728 (6%) that
Innovation Organization (BIO), which reports that: incorporated patient preselection biomarkers
in their corresponding clinical trial design.
Throughout the last decade, industry investment This was accomplished by mapping Informa
and drug development have pivoted towards Pharma Intelligence’s Biomedtracker
rare, congenital diseases. Specific examples and Trialtrove databases, to provide the
of clinical and commercial successes have supplemental level of clinical trial detail.107
encouraged this transition. Drivers of these
This later statement is important—showing that phar-
successes include targeting molecularly defined
maceutical companies are now able to use genetic
causes of disease, regulatory incentives, and
and genomic information to target the trials of their
favorable reimbursement environments.105
biopharmaceutical molecules to patients who have
The BIO report provides a review of two longitudinal been preselected through the presence of biomarkers
datasets on drug development, and notes that: (often genetic). This has the potential to advance
more drugs successfully towards market since they
One large difference between this 2011–2020 are more likely to demonstrate efficacy in their trials
dataset and the previous 2006–2015 iteration by virtue of being rationally targeted. The BIO authors
is the intensifying focus on rare diseases. Our conclude that the data they have reviewed “builds
latest analysis includes 1,256 phase transitions confidence in the pursuit of drug development
within rare diseases, a considerable increase over programs targeted at biomarker-enriched patient
the 521 noted in the previous study. This spans populations. Such assets are likely to advance through
685 different lead developers (not including clinical development with lower levels of attrition and
those listed solely as partners). This indicates should in theory improve patient outcomes via the
that companies view pivoting to rare disease advent of increasingly personalized medicine.” 108 What
clinical development as a sound strategy. 106
is evident is that advancements in human genetics
and genomics are not only delivering definitive
The BIO authors note that drug development for
diagnoses for patients, guiding their care; they
rare disorders has had “notably more successful
are also highly contributory to the development of
than industry averages—and in particular chronic,
new therapeutics to treat identified conditions.
highly prevalent diseases.” They also note that:

A greater understanding of human disease—

whether at the molecular or genomic
level—ultimately leads to the investigation

104 Rare diseases have often been termed “orphan diseases” in that they represent a class of disease that had not been “adopted” by the
pharmaceutical industry.
105 Thomas, David. Clinical Development Success Rates and Contributing Factors 2011–2020. BIO, Informa Pharma Intelligence, and QLS, Feb.
2021.
106 Ibid.
107 Ibid.
108 Ibid.

45
Case Study: Genomics and Rational Drug Development in Cancer
As noted by Collins, Doudna, Lander, and Rotimi: “Studies of cancer genomes have revealed hundreds of genes in
which somatic mutations propelled tumor initiation and growth, information that has fueled the development of
new drugs.” 109 Two long-standing cancer drugs, developed with the help of genetics and genomics, are illustrative:

• Approved by the FDA in 1998, Herceptin is a drug that targets metastatic breast cancer cells that overproduce
the HER2 protein (a product of the HER2 gene). It was the first approved targeted drug based on an individu-
al’s genetics, and also came with development of an FDA approved companion diagnostic called HercepTest.
Herceptin has had robust results in achieving improved outcomes in patients. Pothier reports that an October
2014 study showed the overall 10-year survival rate for patients to be 84% for those treated with Herceptin and
chemotherapy, versus 75% for patients treated with chemotherapy only.110

• Another example of rational drug development for cancer is Gleevec (imatinib). Chronic myeloid leukemia
(CML) is fundamentally a genetic disease caused by mutations in a patient’s DNA that translocate genes be-
tween chromosomes 9 and 22. The translocated genes generate a hybrid gene that produces a novel protein
that causes greatly accelerated production of white blood cells in bone marrow (i.e., a cancer, as defined by
uncontrolled cell proliferation). According to the American Cancer Society, CML comprises circa 15% of leuke-
mias in adults. Without a cure, a diagnosis of CML used to mean a best-case survival of 5 years post diagnosis
through aggressive cytotoxic chemotherapy with severe side effects. The discovery of the gene translocation
causation of CML provided scientists with a target for therapeutic development. Oncologist Brian Druker de-
veloped a targeted drug, Gleevec (imatinib) and collaborated with Novartis to bring the drug forward through
clinical trials. The drug was a success, effectively blocking the effect of the translocated genes. For the great
majority of CML patients, Gleevec is a highly effective treatment—providing a pathway to normal life expec-
tancy through a pill taken once a day with only mild side effects. Gleevec is not a “cure”, because the mutated
genes are still present, but the drug is highly effective at stopping these genes f rom causing leukemia. In up to
30% of cases, patients start to develop resistance to Gleevec, but ongoing research has resulted in the develop-
ment of two alternative drugs aimed at the hybrid gene, Sprycel (dasatinib) and Tasigna (nilotinib) enabling
a patient to switch between drugs if resistance develops. Through increasingly sensitive diagnostic tests of
BCR-ABL gene expression and blood analysis, clinicians are able to monitor the effect of the administered drug,
modify dosage, and switch drugs if resistance development is detected. In effect, the treatment of CML became
one of the pioneers in a personalized approach to genetic medicine.

Other examples are Tarceva (erlotinib) and Iressa (gefitinib) both of which restrict activation of a protein (epidermal
growth factor, or EGFR) which is abnormally active in a subset of lung cancers due to mutations in the protein.111

The National Cancer Institute (NCI) reports that “as a result of research into the genomic changes associated with
cancer, drugs have been developed to fight the disease in several ways:

• Inhibiting enzymes that trigger the abnormal growth and survival of cancer cells.
• Blocking aberrant gene expression characteristic of cancer cells.
• Halting molecular signaling pathways that are in overdrive in cancer cells.112

The NCI notes that “these “targeted therapies” specifically combat characteristics of cancer cells that are different
from normal cells of the body. This makes them less likely to be toxic for patients compared to other treatments
such as chemotherapy and radiation that can kill normal cells.” 113

109 Collins, Francis S., et al. “Perspective: Human Molecular Genetics and Genomics – Important Advances and Exciting Possibilities.” The
New England Journal of Medicine, vol.384, no. 1, 7 Jan. 2021.
110 Ciriello Pothier, Kristen. Personalizing Precision Medicine. A Global Voyage from Vision to Reality. John Wiley & Sons, Inc., 2017.
111 National Cancer Institute. “Cancer Genomics Overview.” www.cancer.gov/about-nci/organization/ccg/cancer-genomics-overview.
Accessed 12 May 2021.
112 Ibid.
113 Ibid.

46
The ability to tailor a drug regimen to a specific genetic code that is truly personalized to that
specific DNA double helix has been a dream of researchers, physicians, and patients alike. Advances
in precision medicine, specifically around the genome…are making this dream a reality.”
Kristen Ciriello Pothier. 2017. Personalizing Precision Medicine. A Global Voyage from Vision to Reality. John Wiley &
Sons, Inc., 2017.

5. Precision Medicine and Targeted term pharmacogenomics is often used

Therapeutics (Pharmacogenetics) interchangeably with pharmacogenetics,
Having an ability to sequence a patient’s whole ge- but there are some subtle differences.
nome rapidly and cost-effectively has opened the door Pharmacogenetics mainly deals with
to a new paradigm in healthcare termed “precision single drug-gene interactions. In contrast,
medicine” whereby an individual’s genetic profile is pharmacogenomics incorporates genomics
used to guide decisions made in regard to the preven- and epigenetics to look at the effect of multiple
tion, diagnosis, and treatment of disease. As noted by genes on drug responses. Pharmacogenomics
NHGRI, “knowledge of a patient’s genetic profile can is considered the future of drug therapy
help doctors select the proper medication or therapy and is a rapidly growing field in the area
and administer it using the proper dose or regimen.” 114 of precision (personalized) medicine.115

Pharmacogenetics and pharmacogenom-

The discipline of “pharmacogenomics” (also “phar-
ics enable three principal pathways to the
macogenetics”) has grown to be able to deploy
improvement of clinical outcomes:
genetic and genomic knowledge and tools to help
physicians select the “right drug and the right dose”
1. Selection of the therapeutic (among multiple
for a patient based on their genome (assuming
choices) that is likely to prove most efficacious
there is statistically significant clinical information
based on the patient’s genome and a drug’s
linking a drug to specific gene variants in terms of
proven efficacy for their specific genotype.
efficacy and side effects). Pharmacogenetics is an
2. Ruling-out a therapeutic (among multiple
area of research and, increasingly, clinical practice,
choices) based on the patient’s genome and
that addresses the genetically determined varia-
a drug’s potential for unacceptable adverse
tion in how individuals respond to specific drugs in
side effects given their specific genotype.
terms of differences in dose requirement, efficacy,
3. Development of an optimized drug dosage for a
and the risk of adverse drug reactions (ADRs).
patient based on their genotype’s influence on
the rate at which they will metabolize the drug.
David Khan, in the Journal of Allergy and
Clinical Immunology, notes that: In terms of this last benefit, Namandie
Bumpus notes that:
At its most basic, the term pharmacogenetics
describes any influence that genetics Owing to genetics, people can be categorized
can have on drug therapy. The newer as poor, intermediate, extensive, or ultrarapid

114 National Human Genome Research Institute. “ Glossary of Genetic Terms: Personalized Medicine.” www.genome.gov/genetics-glossary/
Personalized-Medicine. Accessed 12 May 2021.
115 Khan, David A. “Pharmacogenomics and Adverse Drug Reactions: Primetime and Not Ready for Primetime Tests.” Journal of Allergy and
Clinical Immunology, vol. 138, no. 4, Oct. 2016. doi:10.1016/j.jaci.2016.08.002.

47
metabolizers of certain drugs. For example, in and occur at doses normally used in human
the case of a drug that is pharmacologically subjects. ADRs can be related to a number of
active and its metabolites inactive, a drug may factors, including known pharmacologic activity
accumulate in the body of a poor metabolizer of a drug, drug interactions, drug toxicity, and
and toxicity could occur as a result. By contrast, drug hypersensitivity. ADRs are a relatively
someone who is an ultrarapid metabolizer of common cause of morbidity and mortality.117
the same drug may not achieve concentrations
He further notes that “genetic factors can play a role
of the drug in their blood that are high enough
in pharmacokinetics, pharmacodynamics, and sus-
to be effective. For prodrugs, where the parent
ceptibility to hypersensitivity responses. The degree
drug is inactive or substantially less active
to which genetics contributes to ADRs is not entirely
than its metabolite, genetically encoded
clear and varies by drug, as well as the type of ADR.” 118
variation in drug metabolism could affect the
ability of a person to activate the drug.116
Keeping up with the research literature in regard to
In regard to adverse drug reactions, pharmacogenetics and pharmacogenomics findings
David Khan points out that: regarding specific drugs has been an expanding
challenge for clinicians. However, several leading
Medications are a cornerstone of the therapeutic organizations have been collaborating, and reliable
armamentarium for most clinicians. The goal of peer-reviewed compendia resources for recom-
pharmacotherapy is to cure or control a specific mendations have come online. This is highlighted
condition or disease without causing adverse by Mary Relling, who reports that the application of
effects. Unfortunately, adverse drug effects are pharmacogenomics to improving healthcare is being
common and not always predictable. Adverse codified through “a number of users converging
drug reactions (ADRs) have been defined as on key peer reviewed, nonprofit curated genomic
reactions that are noxious and unintended medicine resources to guide clinical actions, such
as ClinVar, ClinGen, the Clinical Pharmacogenetics
Implementation Consortium (CPIC), and PharmGKB.” 119

a. Targeting to Increase Effectiveness

In cancer, tumor profiling is typically When a healthcare provider is considering prescribing
performed for patients: with cancer with a drug the knowledge of the patient’s genotype can
an unknown primary; with cancer that has now be used in many cases to guide the therapeutic
not responded to standard treatments; strategy, identify the most effective drug, determine
and, to help guide decision-making when appropriate dosing, and assess the risk of toxicity or
there are multiple treatment options. De- other negative side effects. The U.S. Food and Drug
pending on the clinical situation, the test- Administration (FDA) provides a list of pharmaco-
ing method may be a single gene, a gene genetic associations that it has evaluated and for
panel, whole exome, or less commonly, which it considers there to be “sufficient evidence
whole genome sequencing. to suggest that subgroups of patients with certain
genetic variants, or genetic variant-inferred pheno-
types, are likely to have altered drug metabolism,

116 Bumpus, Namandje N. “For Better Drugs, Diversity Clinical Trials.” Science, vol. 371, no. 6529, 5 Feb. 2021. doi:10.1126/science.abe2565.
117 Khan, David A. “Pharmacogenomics and Adverse Drug Reactions: Primetime and Not Ready for Primetime Tests.” Journal of Allergy and
Clinical Immunology, vol. 138, no. 4, Oct. 2016. doi:10.1016/j.jaci.2016.08.002.
118 Ibid.
119 Relling, Mary. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics Magazine, vol. 6, no. 2, March-
April 2019.

48
Table 8: Analysis of FDA Recognized Pharmacogenetic Associations

A1 = Data support therapeutic management recommendations

A2 = Data indicate a potential impact on safety or response
A3 = Data demonstrate a potential impact on pharmacokinetic properties only

Macro Category Disease or Condition A1 A2 A3 Sum

Cancer Cancer - Breast 2 1 3

Cancer Cancer - Leukemia 2 1 3

Cancer Cancer - Colon 2 2

Cancer Cancer - Lung 2 2

Cancer Cancer - Peripheral T-Cell Lymphoma 1 1

Cancer Cancer - Rectal 1 1

Cancer Cancer - Bladder 1 1

Cancer Cancer - Skin 1 1

Cancer Cancer - Kidney 1 1

Cancer Cancer - Soft Tissue Sarcoma 1 1

Cardiovascular Heart Attack or Stroke (blood thinners) 2 2

Cardiovascular Hypertension (high blood pressure) 1 1 2

Cardiovascular Cardiac Arrythmia 1 1 2

Cardiovascular Hypercholesterolemia 1 1

Dermatologic Eczema 1 1

Gastroenterological Nausea and Vomiting (antiemetics) 3 3

Gastroenterological GERD/Acid Reflux 2 1 3

Gastroenterological Ulcerative Colitis 1 1 2

Hematologic Thrombocytopenia 1 1

Immunologic Transplant Rejection (immune suppression) 1 1

Infectious Disease HIV/AIDS 2 1 1 4

Infectious Disease Tuberculosis 1 1

Infectious Disease Bacterial Infections 1 1

Metabolic Obesity 1 1

Metabolic Gaucher’s Disease 1 1

Muscle Rare Muscle Disorders 2 2

Muscle Muscle Relaxation for Surgery/Intubation 2 2

Neurologic Convulsions/Seizures 3 2 1 6

Neurologic Pain (treated by anti-inflammatories, narcotics, etc.) 3 1 1 5

Neurologic Nerve Pain (treated by antidepressants) 4 4

49
Macro Category Disease or Condition A1 A2 A3 Sum
Neurologic Tourette’s Syndrome 2 2

Neurologic Huntington’s Disease (Chorea) 2 2

Neurologic Narcolepsy 1 1

Neurologic Opioid Withdrawal 1 1

Neurologic Multiple Sclerosis 1 1

Neurologic Tardive Dyskinesia 1 1

Neurologic Alzheimer’s Disease/Dementia 1 1

Neurologic Insomnia 1 1

Psychiatric Depression 5 5 10

Psychiatric Schizophrenia 6 1 7

Psychiatric ADHD 2 2

Psychiatric Bipolar Disorder 2 2

Psychiatric Obsessive Compulsive Disorder 1 1

Psychiatric Anxiety 1 1

Psychiatric Female Hypoactive Sexual Desire Disorder 1 1

Rheumatologic Rheumatoid Arthritis 2 1 3

Rheumatologic Osteoarthritis 2 2

Rheumatologic Gout 1 1

Rheumatologic Dry Mouth in Sjogren’s Syndrome 1 1

Urologic Overactive Bladder/Incontinence 1 1 2

Urologic Kidney Stones 1 1

Note: An individual drug may have more than one disease or condition for which it has application. For example, the drug Irinotecan is used for both
colon cancer and small cell lung cancer, and the UGT1A1 gene is associated with the metabolism of the drug and thus is of effect for both types of
cancers for which Irinotecan may be prescribed.
Source: TEConomy Partners analysis of FDA Table of Pharmacogenetic Associations.

and in certain cases, differential therapeutic effects, diseases and disorders, infectious diseases, neuro-
including differences in risk of adverse events.” 120
logical diseases and disorders, psychiatric conditions,
and rheumatologic disease. Pharmacogenetic
While cancer is perhaps the most well recognized associations now span a range from relatively rare
cluster of disease for which genetic tests may impact diseases such as Tourette’s syndrome and Tardive
drug selection and dosing, analysis of FDA data dyskinesia to common conditions such as hy-
(Table 8) shows that pharmacogenetic associations percholesterolemia and depression (with over 50
are in place for multiple chronic diseases and con- listed in Table 8). There are more than 100 drugs for
ditions, covering applications in major categories which the associations are now listed by the FDA.
such as cardiovascular disease, gastroenterological

120 U.S. Food & Drug Administration. “Table of Pharmacogenomic Associations.” www.fda.gov/ medical-devices/precision-medicine/table-
pharmacogenetic-associations. 25 Feb. 2020.

50
Case Study: Pharmacogenetics/Pharmacogenomics
and Cancer Treatment Eff icacy
Cancer is a genetic disease. As noted by the National Cancer Institute (NCI):

Cancer is a group of diseases caused by changes in DNA that alter cell behavior, causing uncon-
trolled growth and malignancy. These abnormalities can take many forms including DNA muta-
tions, rearrangements, deletions, amplifications, and the additional removal of chemical marks.
These changes can cause cells to produce abnormal amounts of particular proteins or make
misshapen proteins that do not work as they should. Oftentimes a combination of several genomic
alterations work together to promote cancer . Genetic alterations can be inherited from one’s par-
ents, caused by environmental factors, or occur during natural processes such as cell division. The
changes that accumulate over one’s lifetime are called acquired or somatic changes and account
for 90 to 95% of all cases of cancer. The field of cancer genomics is a relatively new research area
that takes advantage of recent technological advances to study the human genome, meaning our
full set of DNA. By sequencing the DNA and RNA of cancer cells and comparing the sequences to
normal tissues such as blood, scientists identify genetic differences that may cause cancer. This
approach, called structural genomics, may also measure the activity of genes encoded in our DNA
in order to understand which proteins are abnormally active or silenced in cancer cells, contribut-
ing to their uncontrolled growth.121

The NCI reports that “genomic information about cancer is leading to better diagnosis and treatment
strategies that are tailored to patients’ tumors, an approach called precision medicine. As a result of
research into the genomic changes associated with cancer, drugs have been developed to fight the
disease in several ways:

• inhibiting enzymes that trigger the abnormal growth and survival of cancer cells
• blocking aberrant gene expression characteristics of cancer cells, and
• halting molecular signaling pathways that are in overdrive in cancer cells.” 122

It should also be noted that terms such as breast cancer, pancreatic cancer, or lung cancer, for example,
denote the location in which the cancer presents in the body, but that does not mean that every occur-
rence of these cancers is the same. Each form of cancer is typically characterized by there being many
cancer subtypes that can vary considerably between patients. The NCI notes that genetics and genom-
ics are proving to be an effective tool in characterizing cancer types and subtypes and elucidating their
comparative response to different therapeutic approaches. The NCI reports, for example, that:

Cancer genomics research also contributes to precision medicine by defining cancer types and
subtypes based on their genetics. This molecular taxonomy of cancer can provide patients with
more precise diagnosis, and therefore a more personalized treatment strategy. There are several
ways in which the molecular definition of cancer already benefits patients:

• Breast cancer is classified based on molecular characteristics into distinct subgroups—Lumi-

nal A, Luminal B, triple-negative/basal-like, and HER2 type—that vary in their aggressiveness
and respond differently to therapies. Breast cancer patients may benefit f rom diagnosis and
treatment guided by knowledge of their tumor’s molecular subtype.

• Diffuse large B cell lymphoma can be divided into the ABC and GCB subtypes by genomic
profiling, identifying patients who respond differently to current chemotherapy regimens and
molecularly targeted therapies.

121 National Cancer Institute. “Cancer Genomics Overview.” www.cancer.gov/about-nci/organization/ccg/cancer-genomics-overview.

Accessed 12 May 2021.
122 Ibid.

51
• In 2013, The Cancer Genome Atlas project identified four subtypes of endometrial cancer—
POLE ultramutated, microsatellite instability (MSI) hypermutated, copy-number (CN) low,
and CN high—that correlate with patient survival. This research has already given rise to new
clinical trials and investigation of how these subtypes can improve the future of endometrial
cancer care.

• Lung cancer patients who have a gene fusion involving the ROS1 gene often respond well to
treatment with a targeted therapy called crizotinib. In these cases the disease is best defined and
treated based on its unique genetic change.123

Elaine Mardis reviewing major advancements in omics sciences notes that:

In my opinion, the most significant advances are the increasing numbers of FDA-approved tar-
geted and immunotherapies in cancer, most of which can be correlated to genomic aspects of
cancers including specific genes/mutations of known cancer driver genes, and immunogenomic
metrics such as increased neoantigen load, microsatellite instability in the setting of mismatch
repair defects that predict sensitivity to immune checkpoint blockade inhibitors, or sensitivity to
PARP inhibitors in the setting of homologous repair defects.124

Because of its nature as a “genetic disease”, cancer has long been on the f rontlines in the clinical appli-
cation of advanced genetics and genomics. This has paid off considerably, such that “today, biomarkers
directly connected to drugs, or to crucial outcomes in the human body, allow physicians to identify
drugs that are most likely to help a patient, and those drugs can be used to target cancerous cells only,
which reduces the side effects that the patient experiences.” 125

123 Ibid.
124 Mardis, Elaine. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics Magazine, vol. 6,
no. 2, March-April 2019.
125 Ciriello Pothier, Kristen. Personalizing Precision Medicine. A Global Voyage from Vision to Reality. John Wiley & Sons, Inc., 2017.

b. Reducing Drug Side Effects an estimated 1 million emergency department visits,

According to the U.S. Department of Health and and approximately 125,000 hospital admissions.127
Human Services (DHHS), an “adverse drug event (ADE)
is an injury resulting from medical intervention related Variations in individual genomes have been found
to a drug. This includes medication errors, adverse to have significant impact on risk for adverse drug
drug reactions, allergic reactions, and overdoses.” 126
In reactions, and there is increasing evidence helping
inpatient settings, the DHHS reports that adverse drug to guide physician decisions regarding which drugs
events account for an estimated 1 in 3 of all hospital to prescribe, which to avoid, and what dosing should
adverse events, affecting about 2 million hospital stays be used to lessen the risk of an adverse event. The
each year and prolonging hospital stays by 1.7 to 4.6 previously cited data for FDA pharmacogenetic
days. In outpatient settings, adverse drug events each associations lists several drugs for which genetic tests
year account for over 3.5 million physician office visits, can identify patients at higher risk for adverse drug
reactions. Examples are shown on Tables 9 and 10.

126 U.S. Department of Health and Human Services. “Adverse Drug Events.” https://health.gov/our-work/health-care-quality/adverse-drug-events.
Accessed 12 May 2021.
127 Ibid.

52
Table 9: Examples of Drugs with Pharmacogenetic Associations with Adverse Reactions

Drug Disease or Disorder Treated Gene Affected Subgroups

Abacavir HIV/AIDS HLA-B *57:01 allele positive

Seizures (anticonvulsant), also used in

Carbamazepine HLA-B *15:02 allele positive
peripheral neuropathy and bipolar disorder

Lapatinib Breast cancer HLA-DRB1 *07:01 allele positive

521 TC or 521 CC
Simvastatin Hypercholesterolemia and high triglycerides SLC01B1 (intermediate or poor
function transporters)

Blood thinner used in patients with risk of

Warfarin CYP4F2 V433M variant carriers
heart attack or stroke

Source: TEConomy Partners analysis of FDA Table of Pharmacogenetic Associations.

Table 10: Examples of Drugs with Pharmacogenetic Associations

with Poor Drug Metabolism which may Result in High Systemic
Concentration and Associated Adverse Reactions

Drug Disease or Disorder Treated Gene Affected Subgroups

Amifampridine Rare muscle diseases NAT2 Poor metabolizers

Amphetamine ADHD, Narcolepsy, Obesity CYP2D6 Poor metabolizers

Intermediate and
Fluorouracil Skin cancer and actinic keratosis DPYD
poor metabolizers

Iloperidone Schizophrenia CYP2D6 Poor metabolizers

Tolterodine Overactive bladder CYP2D6 Poor metabolizers

Source: TEConomy Partners analysis of FDA Table of Pharmacogenetic Associations.

53
Case Study: Avoiding Adverse Drug Events in HIV Treatment
Ziagen (abacavir) is a f requently prescribed antiviral for HIV patients. It is an example of an important
medication that, unfortunately, has significant adverse effects for a proportion of patients taking it. Ap-
proximately 3-5% of patients taking Ziagen are hypersensitive to it and may have significant reactions
(including potentially fatal reactions). In the early 2000s, a family of genes were discovered to be asso-
ciated with Ziagen hypersensitivity (those with the HLA-B*57:01 gene variant). Genetic testing defini-
tively identifies whether an HIV positive patient has the gene variant, and it has been found that those
patients without the variant will be f ree of the hypersensitivity.

As noted by David Khan:

Approximately 3% to 5% of patients treated with abacavir have a hypersensitivity syndrome that

typically appears within the first 6 weeks of therapy and rarely can be fatal. Multiorgan symptoms,
including fever, rash, gastrointestinal symptoms, respiratory symptoms, and hypotension, can occur
along with liver and renal involvement.”… “A landmark study was performed to determine whether
screening patients with HIV-1 for HLA-B*5701 before treatment with abacavir would reduce the inci-
dence of the hypersensitivity reaction. This study was the first to show in a very rigorous manner the
benefits of pharmacogenetic testing in reducing the risk of hypersensitivity reactions. In 2008, the US
Food and Drug Administration issued an alert recommending that all patients should be screened
for the HLA-B*5701 allele before starting or restarting therapy with abacavir or abacavir-containing
medications.128

128 Khan, David A. “Pharmacogenomics and Adverse Drug Reactions: Primetime and Not Ready for Primetime Tests.” Journal of Allergy
and Clinical Immunology, vol. 138, no. 4, Oct. 2016. doi:10.1016/j.jaci.2016.08.002.

54
6. Gene Editing and Gene Therapy
Much of the important work of genetics and genomics There are a variety of types
has come in the form of identifying gene variants that of gene therapy products,
are associated with a disease. The identification of a including:
gene variant that codes for a malformed protein, or
• Plasmid DNA: Circular DNA molecules can be
fails to produce an important protein, or otherwise genetically engineered to carry therapeutic
effects disease etiology, provides potential biomarkers, genes into human cells.
or targets, for developing diagnostics and, hopefully, • Viral vectors: Viruses have a natural ability to
therapeutic drugs—very useful tools in the clinical deliver genetic material into cells, and therefore
some gene therapy products are derived from vi-
toolkit. But what if instead of treating the effects of ruses. Once viruses have been modified to remove
a miscoded gene, we could instead correct (edit) the their ability to cause infectious disease, these
modified viruses can be used as vectors (vehicles)
gene itself? If we could do that, then the application to carry therapeutic genes into human cells.
of genetics and genomics would not just be to treat
• Bacterial vectors: Bacteria can be modified to
the symptoms of a disease, it would potentially cure
prevent them from causing infectious disease
it (particularly in the case of a monogenic disease or and then used as vectors (vehicles) to carry ther-
apeutic genes into human tissues.
disorder). This is the basis of the development of the
field of gene therapy, which the FDA describes as: • Human gene editing technology: The goals of
gene editing are to disrupt harmful genes or to
repair mutated genes.
A technique that modifies a person’s genes
to treat or cure disease. Gene therapies can • Patient-derived cellular gene therapy prod-
ucts: Cells are removed from the patient, genet-
work by several mechanisms: replacing a ically modified (often using a viral vector) and
disease-causing gene with a healthy copy then returned to the patient.

of the gene; inactivating a disease-causing U.S. Food & Drug Administration. “What is Gene Therapy.”
www.fda.gov/vaccines-blood-biologics/cellular-gene-thera-
gene that is not functioning properly, [or] py-products/what-gene-therapy. Accessed 12 May 2021.
introducing a new or modified gene into
the body to help treat a disease.129

Ultimately, gene editing and gene therapy repre-

sent new pathways to the treatment and curing of
from a largely observational (‘reading DNA’)
diseases, but these approaches are still in the early
to more experimental (‘writing’ and ‘editing’
stages of clinical application. Part of the caution in
DNA) approaches. Enabling true synthetic
clinical application currently arises from a need for
genomics (that is the synthesis modification and
further study of the potential for off-target gene
perturbation of nucleic acid sequences at any
edits (mutagenesis) to occur in non-targeted genes
scale) will allow for more powerful experimental
and for unintended mosaicism to occur. Researchers
testing of hypothesis about genome variation
note, however, that the utility of gene editing is not
and function and improve opportunities for
only in its potential clinical application, but also
linking genotype to phenotypes. Genome
as a powerful tool for investigating gene variation,
editing is increasingly being used for practical
function, and linkages to diseases and disorders:
applications in medicine such as in gene
therapy, biotechnology and agriculture.130
Advances in DNA synthesis and genome
editing allow the field of genomics to progress

129 U.S. Food & Drug Administration. “What is Gene Therapy.” www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-
therapy. Accessed 12 May 2021.
130 Green, Eric D., et al. “Perspective: Strategic Vision for Improving Human Health at the Forefront of Genomics.” Nature, vol. 586, 29 Oct. 2020.

55
For research, the key advantage of modern gene
editing is the ability to precisely change a gene to
A Key Consideration
experimentally examine the effect of the change.
Modern technology using CRISPR-Cas9 provides It should be noted that the discussion of gene edit-
ing and gene therapy pertains to changing non-he-
a highly refined way to silence genes and insert reditable (somatic) genes—that is changes to an
genes, and even modify a single letter in the ge- individual’s genes that will impact the individual but
not then be passed to any children they may subse-
nome. In describing it, Nessa Carey highlights that: quently have.

There is also ongoing discussion and public debate

A breakthrough in 2012 ripped open the about the potential use of gene editing for making
genetic fabric of every organism on this heritable genetic changes (changes to the germ-
line). Such genome edits would result in changes to
planet, from humans to ants and from rice
an individual’s DNA being passed to their progeny
to butterflies. It’s giving every biologist in the and subsequent generations. At the present time,
world the tools to answer in a few months the general consensus of leading organizations in
medical genetics, genetics research, and genetic
questions that some scientists have spent counseling is that genome editing that culminates
half their careers trying to address.131 in human pregnancy should not be currently un-
dertaken and that further research is required into
the scientific, clinical, and ethical implications of
As a result of both technological and scientific germline editing.
advancement, the application of gene editing has
progressed from the benchtop, through animal
models, and onwards into human clinical trials and
approved clinical therapeutics. Gene editing is still The thousands of rare monogenic diseases and
in its early days in terms of clinical use, with issues disorders may particularly lend themselves to gene
remaining to be resolved in terms of risk of unintend- therapy approaches. However, the development of
ed off-target changes that may happen along with such therapies will, at least early on, be limited to
intended changes. More work needs to be done before those diseases and disorders that meet some fairly
the full promise of this technology can be realized, stringent criteria, which are noted by Carey as follows:
but emerging application areas point to gene editing
and gene therapies’ potential to become import- There is a whole list of key factors. Can you be
ant additional clinical tools for addressing genetic 100% certain that patients you have diagnosed
diseases and disorders. Collins, Doudna, Lander, with the condition all have the same disease?
and Rotimi capture this optimism, writing that: This rules out disorders like schizophrenia where
there are probably many different forms of the
After years of ups and downs, some dramatic illness. Do you know exactly how the disease
successes of gene therapy are emerging, such is caused in your patients? This rules out type
as for spinal muscular atrophy and hemophilia. 2 diabetes where it isn’t clear which is the key
The pace of this research could increase step in the development of the condition. Do you
dramatically in the future; precisely targeted know what genetic change you need to create?
genome editing technologies (e.g., CRSPR-Cas9) This rules out multiple sclerosis, where we think
now provide new avenues to therapeutics… multiple minor genetic variations interact with
as these technologies continue to mature, the environment to trigger the condition. Can
it will become increasingly possible to alter you be sure that making the specific edit you
cellular genomes efficiently and accurately. 132 have in mind will prevent or reverse pathology?
This rules out Alzheimer’s disease. Drug trials

131 Carey, Nessa. Hacking the Code of Life. How Gene Editing Will Rewrite our Futures. Icon Books, Ltd., 2020.
132 Collins, Francis S., et al. “Perspective: Human Molecular Genetics and Genomics – Important Advances and Exciting Possibilities.” The New
England Journal of Medicine, vol.384, no. 1, 7 Jan. 2021.

56
targeting what we thought was the key pathway degrees, followed by progressive deterioration
failed spectacularly recently, and the companies of vision, hearing, and motor function.” 135
involved have probably lost billions of dollars as
a consequence. Can you get the gene editing
• Leber congenital amaurosis (LCA)—is a rare
genetic eye disorder. Affected infants are of-
reagents to the tissues where they are most
ten blind at birth, and other symptoms may
needed, in high enough levels? This probably
include crossed eyes; rapid, involuntary eye
excludes Parkinson’s disease as the brain is
movements; unusual light sensitivity; cataracts;
quite a difficult tissue to access. … Many of the
and/or, keratoconus. In 2017, the gene therapy
most common and debilitating conditions aren’t
Luxturna (voretigene neparvovec-rzyl) was
likely to be good candidates for gene editing
approved by the FDA to treat children and
anytime soon, because they are too challenging
adults with two mutations in the RPE65 gene
in one or more of these problem areas.133
which includes a type of LCA called LCA2.136
Even with the above challenges, biomedical research-
ers and clinicians have identified many diseases and
• Beta-thalassemia—is a rare genetic blood
disorder that reduces the production
disorders that meet the criteria. Significant prog-
of hemoglobin, leading to severe ane-
ress has been made in advancing gene therapies
mia and the need for transfusions.
through clinical trials, with examples including:

• Spinal muscular atrophy—is a genetic de-

• Metachromatic leukodystrophy (MLD)—a rare generative disorder that starts in the central
storage disorder caused by mutations in the nervous system and progressively affects all the
gene coding for arylsulfatase A that results in muscles in the body. The therapy Spinraza is an
affected children failing to develop motor skills, FDA-approved synthetic antisense oligonucle-
typically leading to their death by age 10. otide that binds to RNA, which corrects splicing
errors in the causative genes. Gene therapy with
• Lipoprotein lipase deficiency—a rare disor-
Zolgensma adds a functional version of the gene.
der in which “patients as young as two have
extremely high levels of cholesterol and suffer • Hemophilia B—is a rare genetic bleeding
recurring, life-threatening bouts of pancreati- disorder in which affected individuals have
tis.” 134 The drug Glybera resulted and is the first insufficient levels of a blood protein called factor
approved gene therapy product in clinical use. IX. “The gene therapy etranacogene dezapar-
vovec substantially increased production of
• Childhood X-linked adrenoleukodystro-
the blood-clotting protein factor IX among
phy (CCALD)—is a genetically determined
52 patients in the largest and most inclusive
metabolic disorder. Those affected typically
hemophilia B gene therapy trial to date.” 137
experience “normal development until they
reach 4–10 years of age, at which time behav- Gene-based therapies are also being successfully
ioral changes including memory impairment applied in the treatment of selected cancers. An
and emotional instability manifest to varying approach proving successful is CAR-T therapy, which

133 Carey, Nessa. Hacking the Code of Life. How Gene Editing Will Rewrite our Futures. Icon Books, Ltd., 2020.
134 Reilly, Philip R. Orphan: The Quest to Save Children with Rare Genetic Disorders. Cold Spring Harbor Laboratory Press, 2015.
135 Kim, Ji Hyung and Hyon J. Kim. “Childhood X-linked Adrenoleukodystrophy: Clinical-Pathologic Overview and MR Imaging Manifestations at
Initial Evaluation and Follow-up.” RadioGraphics, vol. 25, no. 3, 1 May 2005.
136 National Organization for Rare Disorders. “Rare Disease Database.” www.rarediseases.org/rare-diseases/leber-congenital-amaurosis/. Accessed
12 May 2021.
137 The American Society of Hematology. “Gene Therapy for Hemophilia B Found Safe and Effective in First Phase III Trial.” American Society of
Hematology, 8 Dec. 2020, www.hematology.org/newsroom/press-releases/2020/gene-therapy-for-hemophilia-b-found-safe-and-effective-in-
first-phase-iii-trial. Accessed 12 May 2021.

57
is an abbreviation for chimeric antigen receptor (CAR) • CAR-T Retroviral vector, ex vivo, used for re-
T-cell therapy. The process is described as follows: lapsed or refractory large B-cell lymphoma.

First, T cells, a type of immune cell, are taken 7. Human-Microbe Interactions

None of us go through life truly alone. Each of us
from a person’s blood. Then, in the laboratory,
is host to communities of trillions of microbes,
gene replacement therapy is used to add a new
an amount that is considerably larger than the
gene to T cells. This new gene adds a special
total count of human cells in our bodies. Ed Yong
receptor, called a chimeric antigen receptor
highlights this fact quite effectively in the title of
(CAR), to T cells to make CAR-T cells. CAR-T cells
his book I Contain Multitudes and notes: “how
are able to bind to and attack certain cancer
ubiquitous and vital microbes are: they sculpt our
cells. Large numbers of the CAR-T cells are
organs, defend us from disease, break down our
made in the laboratory, and once a sufficient
food, educate our immune systems, guide our
amount has been produced, the cells are put
behavior, bombard our genomes with their genes,
back into the body to fight certain cancers.138
and grant us incredible abilities.” 139 As Yong’s quote
At its heart, CAR-T cell therapy uses genet- highlights, there is significant biological interaction
ics to change a person’s own immune cells between the human genome and microbes.
to recognize and fight cancer cells inside the
body. Currently, there are two FDA approved a. The Human Microbiome
CAR-T therapies used in clinical oncology: Even though our microbiome has a considerable effect
on our health, for a report focused on human genetics
• CAR-T Lentiviral vector, ex vivo, used and genomics it might be asked why one would con-
for acute lymphoblastic leukemia. sider microbes to be within the bounds of this study.

138 Explore Gene Therapy. “Get to Know the Different Types of Gene-Based Therapies.” AveXis, Inc. www.exploregenetherapy.com/how-gene-
replacement-therapy-is-different. Accessed 3 Feb. 2021.
139 Yong, Ed. I Contain Multitudes: The Microbes Within us and a Grander View of Life. Ecco, 2016.

58
Each microbe has its own unique genome, but this re- b. Infectious Diseases
port is focused on the human genome. It is a fair point, While many microbes serve important positive life
but two very interesting findings from recent research functions for humans, for example aiding digestion
into our microbial passengers points to a distinct hu- and the breakdown of micronutrients, many are
man genome effect—with impacts going in two direc- pathogenic—the viruses and bacteria that cause
tions (microbes impacting our genes and gene expres- infectious diseases. For 2020 and into 2021, COVID-19
sion, and human genotype impacting the make-up of has been very much on the minds of all. Clearly,
the microbial communities humans’ host). In effect, understanding the genetic structure of the SARS-
it has been found that humans are, loosely speaking, CoV-2 virus has been highly important in the global
genetic symbiotes. It is a difficult subject matter to mission to control the pandemic, and genetics and
research, requiring access to human sequencing and genomics as disciplines have been on the front-
metagenomic sequencing of the human microbiome, lines contributing to many areas (see sidebar).
but the data collected by the Human Microbiome
Project (HMP) can now be referenced to completed In terms of advancing understanding of the effect of
human genome sequences to make important find- the human genome on infectious disease response
ings. Providing a signpost to potentially interesting and susceptibility, it has been serendipitous that the
genetic interactions is the fact that the gut microbi-
omes of monozygotic (“identical”) twins are found to
be significantly more similar than those of dizygotic
(non-identical) twins. The findings in human twins
confirm findings in mouse models that show that
Genomics in the
the host (the mouse) genome influences microbiota COVID-19 Pandemic
composition and that host genotype explains a signif- “Genomics rapidly assumed crucial roles in COVID-19
icant proportion of variation in the gut microbiome. 140 research and clinical care in areas such as: (1) the
deployment of DNA and RNA sequencing technol-
ogies for diagnostics, tracking of viral isolates, and
Additional research on whole genome sequencing and environmental monitoring; (2) the use of synthetic
nucleic acid technologies for studying SARS-CoV-2
microbiome metagenome sequencing of participants virulence and facilitating vaccine development;
in the HMP are compelling, showing that “most mi- (3) examination of how human genomic variation
influences infectivity, disease severity, vaccine effi-
crobes are correlated to genetic principal components, cacy, and treatment response; (4) the adherence to
especially in stool, but also in oral samples.” 141 The au- principles and values related to open science, data
sharing, and consortia based collaborations; and (5)
thors note that they “identified associations between the provision of genomic data science tools to study
high level genetic features and various microbiome COVID-19 pathophysiology. The growing adoption of
genomic approaches and technologies into myriad
features; however, the mechanistic forces of those
aspects of the global response to the COVID-19 pan-
associations remain unclear.” 142 It is a very interesting, demic serves as another important and highly visible
albeit nascent area of human genomics research, but example of the integral and vital nature of genomics
in modern research and medicine.”
given the sheer complexity of microbiota and the im-
Eric D. Green, et al. “Perspective: Strategic Vision for Improv-
pact on health of human microbiomes, interesting and ing Human Health at the Forefront of Genomics.” Nature,
clinically relevant future findings are to be anticipated. vol. 586, 29 Oct. 2020.

140 Benson, Andrew K., et al. “Individuality in Gut Microbiota Composition is a Complex Polygenic Trait Shaped by Multiple Environmental and Host
Genetic Factors.” Proceedings of the National Academy of Sciences, vol. 107, no. 44, Oct. 2010. doi:10.1073/pnas.1007028107.
141 Kolde, Raivo, et al. “Host Genetic Variation and its Microbiome Interactions within the Human Microbiome Project.” Genome Medicine, vol. 10,
no. 6, 29 Jan. 2018. doi: 10.1186/s13073-018-0515-8.
142 Ibid.

59
pandemic hit at a time when widespread human • Single-gene variants, rare or common, which
genetic sequencing is relatively inexpensive. While se- make certain individuals resistant to the infec-
quencing the virus itself is not “human” genomics, the tion by the SARS-CoV2 itself, despite repeated
discipline has been contributing important research exposure, or resistant to the development of
that may influence future approaches to diagnosis and clinical manifestations despite infection.” 147
treatment of infectious disease. The COVID-19 Host
Multiple U.S. research centers and labs are
Genetics Initiative, for example, has brought together
active participants in both of the above
multiple stakeholders in the human genetics’ commu-
referenced international consortia.
nity to “generate, share, and analyze data to learn the
genetic determinants of COVID-19 susceptibility, sever-
Some interesting research contributions have
ity, and outcomes.” 143 The Initiative formed to help ad-
also been made as a result of the growth of di-
vance research that could lead to potential discoveries
rect-to-consumer genetic testing, where the service
that “could help to generate hypotheses for drug re-
of AncestryDNA has built a deep repository of DNA
purposing, identify individuals at unusually high or low
information for its participants. There have been
risk, and contribute to global knowledge of the biology
separate genome-wide association studies (GWAS),
of SARS-CoV-2 infection and disease.” 144 Worldwide
performed in hospitals with COVID-19 patients that
engagement in the Initiative has been considerable,
indicated hereditary genetic associations with higher
with participation of “over 2000 scientists from over
levels of disease impact and infection. However, as
54 countries working collaboratively to share data,
noted in a news article by Lakshmi Supriya,148 these
ideas, recruit patients and disseminate findings.” 145
studies have the inherent bias of examining those who
are infected, typically with a more severe case (since
Another example is the COVID Human Genetic
they are hospitalized). AncestryDNA took a different
Effort, which is an international consortium aiming
approach. Recognizing that their deep resource of
to “discover the human genetic and immunological
customer DNA may contain clues to COVID-19 ge-
bases of the various clinical forms of SARS-CoV-2
netic protection or susceptibility associations, they
infection.” 146 In particular, the COVID Human
surveyed their customers to capture self-reported
Genetic Effort is directing work to search for:
information on “exposure, risk factors, symptoms and
demographics, most of whom had mild disease.” 149
• “Monogenic or digenic inborn errors of im-
With a large sample of over 700,000 respondents, the
munity (IEI), rare or common, underlying
AncestryDNA research team had a deep resource to
severe forms of COVID-19 in previously healthy
work with, ultimately finding gene associations related
individuals, including severe pneumonia,
to immunity and others associated with susceptibil-
multisystem inflammatory syndrome in chil-
ity and disease severity—some of which represent
dren (MIS-C), Long COVID, COVID Toes, etc.
new findings, and some confirming associations
• Phenocopies of these monogenic IEI, such identified by other researchers. As Supriya notes, “the
as auto-antibodies neutralizing gene prod- study provides a complementary analysis to stud-
ucts of loci whose variants underlie these ies focusing on severe disease, which is promising
IEI (e.g., auto-antibodies to type I IFNs
mimicking inborn errors of type I IFNs).

143 COVID-19 Host Genetics Initiative. “About.” www.covid19hg.org/about/. Accessed 12 May 2021.
144 Ibid.
145 Ibid.
146 COVID Human Genetic Effort. “Our Mission.” www.covidhge.com/. Accessed 12 May 2021.
147 Ibid.
148 Supriya, Lakshmi, Ph. D. “Study Finds Protective Genetic Associations with Mild COVID-19.” News Medical, 29 Jan. 2021, Life Sciences sec.
149 Ibid.

60
for finding new genetic associations, in particular (DNMTs).” 153 They note that “viruses elect to turn off
those that provide protection against the virus.” 150 genes like interferon-b that the immune system
regularly enlist to fight foreign pathogens which
The degree of susceptibility or immunity to various allows them to replicate quickly and run rampant.
infectious disease organisms has shaped the human This could lead to cancer development.” 154
genome throughout our evolution as a species.
Historic pandemics, involving large-scale deaths due Human genetics and genomics as a discipline has
to smallpox, plague, or influenza, for example, have much more to discover regarding the complex relation-
been “natural selection” events, favoring ongoing ship between the human genome and the pathogenic,
reproduction of genotypes with disease resistance and potentially positive, effects of microbial infections.
traits and down selecting genotypes with high
susceptibility to the disease. It is also the case that 8. Metagenomics and
some of the protective genotypes may serve to help Environmental Genomics
an individual resist certain pathogens, but then be All the above discussion of genetics and genomics
related to negative repercussions also. 151
This has been research, clinical application, and impacts will have
found to be the case with sickle cell disease where the hopefully resulted in an appreciation for the incred-
genes that are associated with the disease also appear ible complexity of not just the human genome but
to be associated with a positive immunity to Malaria. the vast network of interfaces between the genome
and other biological and environmental systems.
Another area of important research at the inter- Each of us walks a slightly different path through
face between the human genome and infectious life, experiencing different influences upon our
disease is the affect that infection can have on physiology in terms of the food we eat, the amount
the human genome and upon gene regula- of sun we expose ourselves to, the environments we
tion and expression. As noted by the National are exposed to in our jobs, the pathogens that we
Institute of General Medical Sciences (NIGMS): by chance encounter, etc. Any and all of these and
more may be subtly changing (mutating) letters
When viruses infect us, they can embed in our genome or periodically influencing gene
small chunks of their genetic material in our regulation or expression. If you want a challenging
DNA. Although infrequent, the incorporation career, working on unravelling genome-environment
of this material into the human genome interactions and effects would have to be high on
has been occurring for millions of years. the list. There is a specific area of research inquiry
As a result of this ongoing process, viral in genetics and genomics that provides perspective
genetic material comprises nearly 10 percent on the subject—it is termed “metagenomics”
of the modern human genome. 152
Rob Knight, in considering the future of
Interestingly, recent research at the University of
human genetics and genomics, notes that:
Colorado Cancer Center by Sharon Kuss-Duerkop and
Dohun Pyeon finds that viruses are not just cutting Genomics is a key underpinning for
and pasting code within DNA; they are also engaged metagenomics. This is the case because
in “suppressing gene expression via DNA methylation, reference-based approaches are dramatically
specifically by targeting DNA methyltransferases

150 Ibid.
151 Pittman, Kelly J., et al. “The Legacy of Past Pandemics: Common Human Mutations That Protect against Infectious Disease.” PLOS Pathogens,
vol. 12, no. 7, 21 July 2016.
152 NIH, National Institute of General Medical Sciences (NIGMS). “Our Complicated Relationship with Viruses.” ScienceDaily, 28 November 2016.
153 University of Colorado Anschutz Medical Campus. “Here’s How Viruses Inactivate the Immune System, Causing Cancer.” ScienceDaily, 2 March
2018.
154 Ibid.

61
Metagenomics. Also known as environmental genomics or community genomics, metagenomics
investigates the communal genome contained within an environmental sample. It enables
the study of the symbiosis and interactions of organismal genomes and genetic products as a
biological system.”
Simon Tripp and Martin Grueber. Economic Impact of the Human Genome Project. Battelle Memorial Institute, May 2011.

faster and more accurate than reference-free 9. Non-Medical Applications

approaches whenever the reference database of Human Genomics
is complete and correct. However, with a few Each of the functional impact domains of human
exceptions (such as bacteria in the human genetics and genomics discussed above (domains 1
gut of healthy western adults), we are far from through 8) have been viewed through the primary
having adequate reference data. Sequencing lens of medical science—the application of genetics
efforts such as the Genomic Encyclopedia of and genomics to understanding genomic struc-
Bacteria and Archaea (GEBA) projects have tures and mechanisms and their effect on human
been extremely valuable in filling in missing health and pathology. There are, however, multiple
branches of the tree of life, but projects such as other areas of scientific research and functional
microbial earth which seeks to sequence all type application of human genetics and genomics that
strains, and 1000 fungal genomes project remain are not principally directed at medical questions.
under-resourced. Building these references and Three such applications are highlighted briefly
augmenting them with new clinical isolates and below, focused on: forensic science, anthropology
with isolates from remote human populations and evolutionary biology, and paternity testing.
and from a panel of diverse environmental
samples, such as those provided by the Earth a. Forensic Science
Microbiome Project, could dramatically Genetics, and more recently genomics, has become
accelerate progress in all metagenomic studies, an essential tool for forensic scientists in criminal
whether targeted at human or animal health or justice systems. In the late 1980s, genetic analysis
at the environment. The benefits that could be entered forensic use through examination of non-cod-
achieved would greatly outweigh the modest ing region repeats in DNA that are highly variable
investment required to complete these studies. 155
among individuals. This became known as DNA
“fingerprinting,” helping to identify crime suspects.
There are countless research questions that
The technology was revolutionary for forensic science
metagenomics will be used to pursue, and each
in that, as noted by Melissa Lee Phillips, “for the first
will benefit from the speed, accuracy, and afford-
time, forensic scientists could create genetic profiles
ability of gene sequencing in combination with
so specific that the only people who share them are
ongoing advancement in bioinformatics and
identical twins.” 156 Phillips notes that “DNA fingerprint
artificial intelligence-based approaches to the
techniques evolved subtly over the next several years,
mining of genomic and metagenomic big data.
until the polymerase chain reaction (PCR), developed
by Kary Mullis, was introduced into forensic work. By

155 Cheifet, Barbara. “Editorial: Where is genomics going next?” Genome Biology, vol. 20, no. 17, 22 Jan. 2019. doi:10.1186/s13059-019-1626-2.
156 Phillips, Melissa Lee. “Crime Scene Genetics: Transforming Forensic Science through Molecular Technologies.” BioScience, vol. 58, no. 6, June
2008. doi:10.1641/B580604.

62
allowing the selective amplification of any desired
stretch of DNA, PCR ushered in unprecedented sen- Identifying the
sitivity in low-level DNA detection at crime scenes.” 157 “Golden State Killer”
For decades, police sought to identify the individ-
Analysis of DNA provides a pathway to definitively ual responsible for 12 murders and 45 rapes across
identify the individual associated with DNA evidence California between 1976 and 1986. The police had
DNA evidence from crime scenes, but the DNA did
at a crime scene, and also may be used to establish not match any individuals in existing criminal DNA
the identity of human remains. Forensic genetics is databases, and without a suspect there was no way
to identify the offender.
an evolving discipline, with new technologies en-
abling varied use in criminal justice applications: The recent growth of ancestral DNA databases
provided a pathway to a breakthrough in the case.
Police analyzed one of the databases and were able
to narrow the DNA to a particular family. Standard
investigative procedures were then able to be used
to narrow the family members down to one suspect
The U.S. Department of Justice The U.S. Department of Justice – resulting in a con-
fession and conviction.
on Advancing Justice Through
DNA Technology
DNA can be used to identify criminals with incredi- Forensic genetics is slowly transitioning into
ble accuracy when biological evidence exists. By the
same token, DNA can be used to clear suspects and forensic genomics… Genomic, transcriptomic,
exonerate persons mistakenly accused or convicted and epigenomic principles, data, and
of crimes. In all, DNA technology is increasingly vital
to ensuring accuracy and fairness in the criminal technologies are applied to identify and analyze
justice system. useful DNA and RNA markers to address
For example, in 1999, New York authorities linked various forensic questions that cannot be
a man through DNA evidence to at least 22 sexual answered, or only in a limited way, via genetic
assaults and robberies that had terrorized the city.
In 2002, authorities in Philadelphia, Pennsylvania, or other approaches. Human genome data
and Fort Collins, Colorado, used DNA evidence produced with SNP microarray technologies,
to link and solve a series of crimes (rapes and a
murder) perpetrated by the same individual. In the
and increasingly whole exome and whole
2001 “Green River” killings, DNA evidence provided genome data established via massively
a major breakthrough in a series of crimes that had
parallel sequencing (MPS) technologies, are
remained unsolved for years despite a large law en-
forcement task force and a $15 million investigation. used to identify DNA markers for individual
identification, as well as for appearance and
DNA is generally used to solve crimes in one of
two ways. In cases where a suspect is identified, a ancestry prediction. The latter is forensically
sample of that person’s DNA can be compared to relevant for finding unknown perpetrators of
evidence from the crime scene. The results of this
comparison may help establish whether the sus- crime who are unidentifiable with standard DNA
pect committed the crime. In cases where a suspect profiling. Human transcriptome data of various
has not yet been identified, biological evidence
from the crime scene can be analyzed and com- tissues generated with expression microarray
pared to offender profiles in DNA databases to help technologies, and increasingly with whole
identify the perpetrator. Crime scene evidence can
also be linked to other crime scenes through the transcriptome sequencing via MPS technologies,
use of DNA databases. are used to identify RNA markers to determine
The United States Department of Justice. “Advancing Justice the cellular source of crime scene sample. This
Through DNA Technology: Using DNA to Solve Crimes.” is forensically relevant for reconstructing the
www.justice.gov/archives/ag/advancing-justicethrough- dna-
technology-using-dna-solve-crimes. Updated 7 March 2017. course of events that may have happened at the

157 Ibid.

63
Information about the relationships amongst species or populations within species and the time
of their divergence from each other can be found in the DNA. It is the job of the evolutionary
geneticist to interpret this information from DNA. A subset of anthropology—anthropological
genetics—uses the evolutionary geneticist’s tool kit to infer human evolutionary history from our
and our closest relative’s DNA.”
Jason Hodgson & Todd Disotell. “Anthropological Genetics: Inferring the History of Our Species Through the Analysis of
DNA.” Evolution: Education and Outreach, vol. 3, Sept. 2010.

scene of crime and to support the use of DNA at have enabled researchers in evolutionary biology,
the activity level of evidence interpretation.158 physical anthropology, archaeology, and associated
disciplines to answer many questions regarding
Genetics and genomics are also being used by
our evolutionary biology, our genetic linkages to
researchers in the field of criminology to examine
other species, our population migrations, and our
genetic correlates to offenders, drawing upon ad-
genealogy. Modern genetics and genomics have,
vancements in understanding genetic factors that
for example, enabled substantial advancement in
influence human behavior. An example of this is the
anthropology such that Judith Fridovich‐Keil writes:
work of Eric Connolly and Kevin Beaver that incorpo-
“comparative DNA sequence analyses of samples
rated behavioral genetic methods to “assess gene-en-
representing distinct modern populations of humans
vironment interplay between anger, family conflict,
have revolutionized the field of anthropology.” 161
and violence using a subsample of kinship pairs
drawn from the Child and Young Adult Supplement While genetics and genomics are proving funda-
of the National Longitudinal Survey of Youth.” 159 Their mental to advancements in the above-cited aca-
analysis reveals “a significant shared genetic liability demic research disciplines, they have also enabled
for anger and exposure to family conflict indicating the development of commercial services that offer
gene-environment correlation” and they conclude genetic ancestry testing (genetic genealogy) to the
that findings from the study “underscore the impor- general population—providing insights regarding
tance of using genetically informed methodologies ancestry that supplement traditional methods of
to identify underlying risk factors involved in both review of family records and historical documentation.
exposure and response to different forms of strain.” 160 Interest levels have been high, to the extent that two
private companies 23andMe and Ancestry now have
b. Anthropology and Evolutionary Biology among the largest repositories of human genetic
Our DNA codes for us as individuals in the present,
data in the world. 23andMe, for example, reports
but it is also a molecular historical record of our
that it has “more than 12,000,000 customers.” 162
ancestry—providing coded documentation of our
Consumer interest in these services has created a
lineage (ancestry) and our evolution as a species.
rather rich resource of genetic data that is being
Advancements in human genetics and genomics
used now to advance research, with 23andMe, for
have provided important scientific capabilities that

158 Kayser, Manfred and Walther Parson (Editors). “Special Issue: Forensic Genomics.” Gene, 2017.
159 Connolly, Eric and Kevin Beaver. “Assessing the Salience of Gene–Environment Interplay in the Development of Anger, Family Conflict, and
Fhysical Violence: A Biosocial Test of General Strain Theory.” Journal of Criminal Justice, vol. 43, no. 6, November–December 2015.
160 Ibid.
161 Fridovich‐Keil, Judith. “Human Genome Project.” Encyclopedia Britannica Scientific Project.
162 23andMe. “Your DNA is Amazing!” www.23andme.com/about. Accessed 12 May 2021.

64
example, noting that it has published more than legal rights to Social Security benefits and inheritance.
150 peer-reviewed studies in scientific journals. 163
Some applications of paternity testing could also
be listed under the previous discussion of medical
c. Paternity testing applications of human genomics because there
While connecting a baby to his or her mother is rather is utility in establishing paternity for identification
easily accomplished, by the obvious nature of birth— of links to genetic conditions and for determining
the question of paternity is less obvious. Before genet- potential compatibility for organ or tissue donation.
ic tests were available, blood tests and other methods
were deployed, but they were less than fully conclu-
sive. Today, however, as noted by the Cleveland Clinic:
D. Summary
Whether for medical or non-medical applications,
A DNA paternity test is nearly 100% accurate at it is clear that human genetics and genomics
determining whether a man is another person’s advancements provide extremely large-scale ben-
biological father. DNA tests can use cheek efits across a broad variety of functional impact
swabs or blood tests. You must have the test domains. Genetics and genomics are considered
done in a medical setting if you need results fundamental within modern biological science,
for legal reasons. Prenatal paternity tests can providing answers to basic biological research
determine fatherhood during pregnancy. 164 questions, and they underpin a diverse range
of applied innovations and applications that are
Determining paternity may be performed simply to greatly enhancing human health and well-being.
inform a father and parenting decisions, but it may
also be required as part of a legal process—providing a
determinative path to legal rights in child support cas-
es and child custody cases, and also for determining

163 Ibid.
164 The Cleveland Clinic. “DNA Paternity Test.” https://my.clevelandclinic.org/health/diagnostics/ 10119-dna-paternity-test. Accessed 12 May 2021.

65
66
IV. Into the Future
The primary purpose of this report is to provide a current overview, or
point-in-time snapshot, of the economic impact of human genetics
and genomics in the U.S., and to provide a useful overview of the
principal application domains of human genetics and genomics that are
generating positive advancements in human health and well-being.

Since the authors first wrote the impact study for • Advancing knowledge of gene-disease
the Human Genome Project on its 10th anniver- relationships, especially (but not exclu-
sary, genetics and genomics technologies, and sively) in regard to common complex,
the cost-effectiveness of their application, have polygenic diseases and disorders.
advanced astonishingly quickly. The literature of
fundamental and applied research discoveries
• Overcoming the current skewing of genomic
data towards northern European genotypes by
in genetics and genomics has expanded equally
supporting the concerted effort to build more
rapidly, and the application of human genetics
diversity of data across humanity worldwide.
and genomics is evident in almost every branch of
This is an important effort to help ensure health
human medicine and modern biological science.
disparities are better understood and addressed,
and an equitable future secured in the appli-
While the accomplishments of genetics and ge-
cation of genetic medicine advancements.
nomics scientists have been many and varied, with
key categories of application highlighted herein, an • There is significant need to translate the research
overused analogy still applies. We are probably just and innovation advancements already being
looking at the “tip of the iceberg” in terms of the made into much more widespread clinical appli-
future of human genomics. There are still multiple cation, and a distinct need to connect patient ge-
large outstanding areas to pursue, including: nome data to medical records and family history.

• Understanding of the full structure of Generating predictions for the future of fields of
the human genome and the biologi- science, technology, and their application is no
cal activity it produces or influences. easy task, especially in areas as large and diverse
as those driven by human genetics and genomics.
• Developing additional knowledge regarding The frontiers of genetics knowledge are constantly
the functional relationships between genotype
expanding, and it is impossible to predict in advance
and phenotype and the influence that environ-
the breakthroughs that may occur that will open-up
mental interactions have on gene expression,
new pathways to discovery, innovation, and applica-
regulation, and mutation over lifespans.
tion. CRISPR is a recent example that quite suddenly

67
and unexpectedly is making available to scientists an fundamental questions to be pursued with higher
exquisitely precise and flexible tool for gene editing resolution regarding gene functions and the impact of
that is greatly accelerating progress in both research genetic variation on diseases and disorders (many of
inquiry and practical application. Similarly, the con- which are particularly endemic in certain geographic
tinued convergence of genetics and genomics with regions and associated regional population subtypes).
the rapidly advancing field of advanced analytics and
artificial intelligence promises a dynamic future. One of the key advances to be anticipated is devel-
opment of an enhanced understanding of genomic
Researchers have regularly unveiled increasing variation among diverse population groups spread
complexity in human genome functionality and across the world. The limitations imposed by current
its interactions with other biological systems, and data being skewed to genotypes associated with
that tendency makes it somewhat challenging European ancestry will be overcome as sequencing
to fully predict future status. That said, there are programs in Africa (where the most genetically
certain observable trends—in sequencing speed, diverse population is located) and Asia, for example,
in emerging areas of inquiry, in expanding clinical expand significantly. It may be anticipated that more
applications—that point to near-term directionality diversity in the data will reveal interesting findings,
with some degree of confidence. Several anticipated as was the case in genes for sickle cell disease being
future areas of advancement are highlighted below. associated with protection against malaria. More
diversity in sequenced populations will also be im-
portant for further advancing precision medicine,
A. Ongoing Fundamental
likely unveiling many more mutations associated
Discovery with drug efficacy and adverse drug reactions.
The population of fully sequenced human genomes
already encompasses millions of individuals, and Computational data sciences are also progressing
further rapid expansion of this universe is to be an- rapidly, with significant progress being made in
ticipated. As this report highlights, there are many advancing automated analysis tools rooted in artificial
large-scale sequencing projects presently being intelligence advancements. It is likely that computa-
conducted around the world. As these datasets are tional and analytical sciences will be as important as
built, they increase opportunities to identify inter- biological sciences in contributing to a rich discovery
esting variation across human genomes enabling environment. A challenge area that will need to be

68
One of the biggest challenges is most health care systems are not built to prevent adverse
events, but mostly to treat adverse events. Another is the lack of a centralized, organized health
care system designed to support life-long results such as genomic testing. For example, we can
conduct a preemptive screen for pharmacogenetic tests in a single test, and these results are
more likely to be applicable as the patient grows older and is exposed to more high-risk drugs. But
we don’t have a good system for making these results available when needed. There is no uniform
electronic health record. At any one time, patients may have multiple prescribers and pharmacies
with little to no coordination, much less with common access to genetic test results that can
inform prescribing and capitalize on the availability of clinical decision support. The lack of logical
prescribing based on laboratory tests is just one small example of the disconnectedness and lack
of computationally informed medicine that impacts all levels of our healthcare.”
Mary Relling. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics
Magazine, vol. 6, no. 2, March-April 2019.

addressed, given the importance of data analytics, is associated with aging, genotoxic injuries, and
data access and data interoperability. The ability to the accumulation of such mosaic mutations.165
analyze data and make discoveries can only occur if
This is also echoed by Jernej Ule, noting that “we
scientists have access to data, and there is still much
will be able to move beyond the static picture of
that needs to be done to provide access to health
genomic data towards studies of the dynamic
records and other non-genomic data that can be
transitions that cells make on a genomic scale
matched to genomic data for analysis. There are
in response to external and internal cues.” 166
also issues in terms of data needing to be format-
ted and archived in ways that facilitate analysis.
It should also be anticipated that fundamental and ap-
plied research in genetics and genomics will increas-
It should also be anticipated that significant ad-
ingly uncover linkages not just between gene varia-
vancements in fundamental knowledge will be
tions and disease but also gene variations and health.
advanced though studies at a single-cell resolution,
Some institutions are already focusing on this oppor-
assisted by recent advancements in technology
tunity. For example, the Institute for Systems Biology
and techniques. As noted by Olivier Harismendy:
(ISB) in Seattle is a proponent of medicine that can be
predictive, preventive, personalized, and participatory
DNA sequencing at deep coverage or at
(termed P4 medicine), and is working on quantifying
single-cell resolution is revealing a vast genetic
wellness—integrating genomics as a component in
heterogeneity of normal or dysplastic tissues.
helping individuals improve their health, longevity, and
At present these insights are mostly at the
quality of life. As Lee Hood, the cofounder of ISB notes:
stage of observations, but future studies will
address the consequences of such heterogeneity
Systems biology will revolutionize the practice
in tissue homeostasis and function. The new
of health care in the coming decades. Today,
information that is provided will provide a better
medicine is largely reactive. It waits until a
understanding of diseases and conditions
person is sick and then treats a disease with

165 Cheifet, Barbara. “Editorial: Where is genomics going next?” Genome Biology, vol. 20, no. 17, 22 Jan. 2019. doi:10.1186/s13059-019-1626-2.
166 Ibid.

69
varying levels of success. The revolution will of established genomics tools and practice ad-
emerge from the convergence of systems vancements. In some locations (for example, central
biology and the digital revolution’s ability to Pennsylvania within the Geisinger health system),
create consumer devices, generate and analyze genomics is becoming integral to the management of
“big data” sets and deploy this information the healthcare of covered patient populations; how-
through business and social networks. By ever, this is far from the norm. There is a long way to
providing an understanding of disease at go before all patients across the nation have access to
the molecular level, systems medicine will state-of-the-art genomics and the personalized med-
eventually be able to predict when an organ will icine and the improved outcomes they enable. The dis-
become diseased or when a perturbation in a connected nature of the U.S. health system structure
biological network could progress to disease.167 also hampers effective cascade screening since pa-
tients move and their records do not follow-them, and
B. Expanding the Clinical family members may reside in different health systems

Application of Genomics across the nation. As the National Academies note

“the benefits of screening will be multiplied if systems
It is safe to predict that the application of genetics for affective cascade screening can be implemented,
and genomics in clinical medicine will continue but there is currently no roadmap for such testing.” 168
to expand substantially. Currently, there is a large
observable difference between genetics and ge- It should also be anticipated that new classes of
nomics having ubiquitous use in biological research medicines, developed through synthetic biology
versus a far less uniform application of discoveries and gene editing, will expand in clinical use. At the
and advancements into actual clinical practice. present time, gene therapies and gene editing see
limited clinical application. However, the degree of
In the U.S., a key challenge is imposed by the hetero- editing precision provided by CRISPR technology will
geneous structure of the nation’s healthcare system. lead to more widespread therapeutic applications
Rather than a single system, the U.S. comprises a developed using gene editing procedures, which
patchwork quilt of individual health systems, to- themselves cause editing within the patient’s genome.
gether with intermediate insurance organizations
and third-party payers, that influence the adoption

Now that the sequencing technology has advanced to the point where delivering high quality,
cheap, and rapid genomes is a commodity – and where robust, reproducible, and accessible
methods exist for analysis and interpretation of these datasets – it is clear that the largest hurdle
relates to the integration of these types of methods into clinical practice. Tools, methods, and
processes need to be developed in order to deliver this information in ways that care providers can
digest it and use it for the treatment of their patients.”
Liz Worthy. “Luminaries Share Their Thoughts on Advances in ‘Omics Over the Past Five Years.” Clinical Omics Maga-
zine, vol. 6, no. 2, March-April 2019.

167 Institute for Systems Biology. “Scientific Wellness.” https://isbscience.org/research/ scientificwellness/. Accessed 12 May 2021.
168 National Academies of Sciences, Engineering, and Medicine. Implementing and Evaluating Genomic Screening Programs in Health Care
Systems: Proceedings of a Workshop. Washington, DC: The National Academies Press, 2018. doi:10.17226/25048.

70
C. Educating and D. Ethical Considerations
Updating Providers Particularly in biological sciences, the frontiers of sci-
Part of the widespread clinical adoption challenge ence may raise ethical considerations. Such is certainly
with genomic medicine relates to the education of the case in human genetics and genomics where
medical professionals. Genetics and genomics are abilities to edit the genome, up to and including
complex and fast-moving fields, rendering it difficult to hereditary germline DNA, present challenges requir-
keep physicians up-to-speed in the latest findings and ing ethical debate. Should we edit carrier genomes to
clinical practice implications and recommendations. prevent passing down of genetic disease to progeny,
and if so, which diseases should qualify? Some dis-
It remains to be seen what model for the practice of eases are relatively easily managed with medicines,
genomic medicine will predominate. For example: while some have no treatments at all. Should we
reserve gene editing as a last resort for these cur-
• There may be development and adoption of
rently intractable diseases, or should it only be used
computational clinical decision support tools
in diseases that dramatically shorten lives, involve
that assist primary care and other physicians in
great pain in those afflicted, or impose large-scale
interpreting the results of genetic and genomic
economic burdens on society? We will not presume to
tests and guide clinical decision making.
guess how such issues will be resolved, but it is clear
• Physicians may simply be expected to adapt and that they are presenting and will require addressing.
to educate themselves regarding genomics simi-
lar to how they have to access information on new Since germline editing impacts our evolution as a
drugs and new practice procedures. Education species, it is a particularly contentious issue, and
here would occur via continuing professional it needs to be globally addressed. Currently, more
education courses, through visits by company than 40 countries ban germline editing, but there
representatives, and other traditional pathways. are 195 countries in the world.169 Somatic gene
editing holds significant promise for helping peo-
• Genetics and genomics counselors may become ple who are sick and presents less of an ethical
increasingly embedded in large clinical prac- challenge (although there are still issues relating
tices as a localized resource, working to keep to the potential for unforeseen consequences
pace with expanding genetics and genomics in editing a not fully understood genome).
advancements and to provide consultation
with physicians and other clinical providers. The widespread collection of individual genetic
data also presents privacy issues and potential for
Because the field is moving quite fast, there will be a
genetic discrimination (for example, the risk of a
need to not only relay new discoveries and advance-
person being treated differently by their employer or
ments to clinicians, but also to revise their knowledge
insurance company because they have a gene vari-
since it is likely that reinterpretation of variant results
ant that causes or increases the risk of an inherited
will occur under evolving evidence and study.
disorder). The NHGRI sought to identify potential
ethical and legal issues pertaining to human genet-
More widespread use of testing for predisposition
ics as a component of the original Human Genome
for disease, and the growth in polygenic risk score
Project, establishing the Ethical, Legal, and Social
systems and other tools, will require physicians to
Implications of Human Genetics Research (ELSI)
become comfortable in working with patients to in-
program to “examine these issues and assist in
terpret results and develop preventive care regimens.
the development of policy recommendations and

169 Center for Genetics and Society. “Other Countries.” www.geneticsandsociety.org/topics/other-countries. Accessed 12 May 2021.

71
guidelines to ensure that genetic information is used sub-populations with multiple large-scale genome
appropriately.” 170
The ELSI program continues to study sequencing projects taking place in areas of the globe
and address these issues, and NHGRI notes that: whose populations have been underrepresented
in current genomic data. Increasing diversity in the
As the ELSI program has evolved, four high pri- data is important to advancing equitable research
ority areas have emerged from its work that and, ultimately, for equity in the clinical applica-
serve to categorize domains of ethical, legal, tions of genetic and genomic medical innovations
public policy, and societal education that will that can benefit the full spectrum of humanity.
need to be further addressed. These include:

1. Privacy and Fairness in the Use and

E. Conclusion
Interpretation of Genetic Information What is absolutely clear is that human genetics
• Privacy and genomics will be in the vanguard in terms of
• Discrimination/Stigmatization contributing to advancements in medical science
• Philosophical/Conceptual Assumptions and enhancing the practice of clinical medicine.
• Public Policy Issues Expanding understanding of the human genome,
variations in genomes, external factors that interface
2. Clinical Integration of Genetic Technologies with the genome, and genetic relationships to health
• Clinical Ethical Issues and disease will provide improved health, quality of
• Genetic Testing/Counseling life, and large-scale benefits to society (both economic
• Professional Issues and Standards and social). Indeed, as this report finds, it already has.

3. Issues Surrounding Genetics Research

It is heartening to note that a survey of the general
• Informed Consent
public in the U.S. found that people generally share
• Other Philosophical and Ethical Issues
an optimistic view of genetics and genomics and
• Legal Issues
the promise it holds for a better future. A study re-
• Ethnocultural Issues
leased by the American Society of Human Genetics
• Other
in partnership with Research!America found that
4. Education the “large majority of Americans agree that genetic
• Professional-Health knowledge will be important to their own health
• Professional-Other and their families’ health.” 171 The study also found
• Public-K through 12 that “a strong majority of Americans (77%) indicate
• Public-College positive feelings about human genetic research”.
• Public-Consumer Figure 6 summarizes other topline survey findings.
• Combination Professional/Public.

Equitable access to the benefits of modern human

genetics and genomics advancements also rep-
resents a challenge to be addressed. As noted in
this report, there are concerted efforts underway
to increase the diversity of sequencing human

170 National Human Genome Research Institute. “Review of the Ethical, Legal and Social Implications Research Program and Related Activities
(1990-1995).” www.genome.gov/ 10001747/elsi-program-review-19901995#:~:text=The%20original%20issues% 20identified %20
in,impact%20of%20genetic%20information%20on. Accessed 12 May 2021.
171 ASHG Survey Finds Americans Strongly Support Human Genetics Research. Research!America and American Society of Human Genetics, 29
Jan. 2020.

72
Figure 6: U.S. Adults Attitudes Regarding Human Genetics Research – Survey Findings

Source: American Society of Human Genetics and Research!America 2019. “ASHG Survey Finds Americans Strongly Support Human Genetics Research.”

Based on the economic and functional impacts the advancement of human genetics and genomics,
of human genetics and genomics detailed herein, the fields have also had the very positive spillover
the public is right to feel optimistic about human effect of building a powerful science- and technol-
genetics research. The fields of human genetics ogy-based economic sector for the U.S.—a sector
and genomics are having profound positive impacts that supports 850,263 jobs across the nation and
both in terms of biomedical discovery as well as generates $265.4 billion in economic output. Human
within the clinical practice of medicine—working genetics and genomics innovation is expanding
to improve outcomes for millions of patients and the stock of knowledge upon which the nation’s
demonstrating great promise for future highly continued advancement depends and shows great
positive contributions to human health and well-be- promise to continue to do so long into the future.
ing worldwide. While generating these positive
functional impacts is the raison d’etre for pursuing

73
74
Glossary of Terms
Term Definition

A variant of a gene inherited from one parent. An allele’s frequency in a population

Allele can change due to four forces: mutation, natural selection, random genetic drift,
and gene flow.

Any substance, structure, or process that can be measured in the body or its
Biomarker
products that influence or predict the incidence of outcome or disease

The study of the DNA sequence and gene expression in tumor cells as they compare
Cancer Genomics
to normal host cells.

The observation and treatment of actual patients rather than theoretical or

Clinical
laboratory studies.

Deoxyribonucleic acid, the molecule that carries genetic instructions in all living
things. The DNA molecule consists of two strands that wind around one another
to form a double helix. Each strand has a backbone made of alternating sugar
DNA (deoxyribose) and phosphate groups. Attached to each sugar is one of four bases:
adenine (A), cytosine (C), guanine (G), and thymine (T). The sequence of the bases
along the backbones serves as instructions for assembling protein and RNA
molecules.

Functional Genomics The study of how elements in the genome contribute to biological processes.

The basic physical and functional unit of heredity. Technically a distinct sequence
of nucleotides forming part of a chromosome, the order of which determines the
Gene
order of monomers in a polypeptide or nucleic acid molecule which a cell (or virus)
may synthesize.

Genotype The genetic constitution of an individual organism.

Germline cells pass on their genetic material to the progeny. These include sperm
Germline Cells
and egg cells.

The collective genomes of the microbes (composed of bacteria, bacteriophage,

Microbiome
fungi, protozoa, and viruses) that live inside and on the human body

Mosaicism is when a person has two or more genetically different sets of cells in his
Mosaicism
or her body

The study of the role of the genome, or multiple genes, in predicting drug
Pharmacogenomics
metabolism and response.

75
Term Definition

A molecule made up of amino acids. Proteins are needed for the body to function
Protein properly. They are the basis of body structures and of other substances such as
enzymes, cytokines, and antibodies.

Somatic Cells All cells in the body that are not germline cells

An interdisciplinary field that involves the application of engineering principles to

Synthetic Biology biology. It aims at the (re-)design and fabrication of biological components and
systems that do not already exist in the natural world.

The holistic study of the interactions and behavior of the components of biological
Systems Biology
entities, including molecules, cells, organs, and organisms.

Whole Exome Identification of the sequence of base-pairs in the protein-coding regions of the
Sequencing (WES) genome.

Whole Genome Identification of the sequence of base-pairs across the full genome, including
Sequencing protein-coding and regulatory regions.

76
Appendix—
Additional Economic Impact Information
Table 11: Listing of NIH Genetic and Genomic-Related Proposal Review Study Sections

• Behavioral Genetics and Epidemiology Study Section [BGES]

• Cancer Genetics Study Section [CG]
• Gene and Drug Delivery Systems Study Section [GDD]
• Genes, Genomes, and Genetics [F08]
• Genetic Variation and Evolution Study Section [GVE]
• Genetics of Health and Disease Study Section [GHD]
• Genomics, Computational Biology and Technology Study Section [GCAT]
• Molecular Genetics A Study Section [MGA]
• Molecular Genetics B Study Section [MGB]
• Molecular Neurogenetics Study Section [MNG]
• Therapeutic Approaches to Genetic Diseases Study Section [TAG]

Table 12: Economic (Expenditure) Impacts—

Additional Expanded NIH Funding Scenario ($7.018 billion)

State/
Labor Value Federal
Output Local Tax
Impact Type Employment Income Added Tax Reve-
($B) Revenues
($B) ($B) nues ($B)
($B)

Direct Effect 181,595 $23.31 $54.78 $112.04 $2.95 $5.48

Indirect Effect 303,139 $25.83 $45.15 $89.86 $3.00 $5.59

Induced Effect 418,167 $23.69 $41.71 $74.18 $3.88 $5.23

Total Effect 902,902 $72.84 $141.64 $276.08 $9.83 $16.31

Multiplier 4.97 3.12 2.59 2.46

Source: TEConomy Partners analysis of Human Genetics and Genomics Input Dataset; IMPLAN 2019 U.S. Impact Model

77
Table 13: Economic (Expenditure) Impacts—
Additional Use as Tool NIH Funding Scenario ($14.202 billion)

State/
Labor Value Federal
Output Local Tax
Impact Type Employment Income Added Tax Reve-
($B) Revenues
($B) ($B) nues ($B)
($B)

Direct Effect 210,493 $26.37 $58.85 $119.23 $3.05 $6.04

Indirect Effect 329,541 $27.72 $48.03 $95.07 $3.16 $5.98

Induced Effect 460,234 $26.07 $45.91 $81.64 $4.27 $5.76

Total Effect 1,000,268 $80.16 $152.78 $295.93 $10.48 $17.78

Multiplier 4.75 3.04 2.60 2.48

Source: TEConomy Partners analysis of Human Genetics and Genomics Input Dataset; IMPLAN 2019 U.S. Impact Model

78
ASHG and the project authors wish to thank the following organizations
for their generous support of this study.