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Genome Sequencing in The Clinic
Genome Sequencing in The Clinic
Genome Sequencing in The Clinic
Genome sequencing in the clinic: the past, present, and future of genomic
medicine
Jeremy W. Prokop,1,2,3 Thomas May,1,4,5 Kim Strong,1 Stephanie M. Bilinovich,2 Caleb Bupp,2,6
Surender Rajasekaran,2,7 Elizabeth A. Worthey,1 and Jozef Lazar1
1
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama; 2Department of Pediatrics and Human Development,
Michigan State University, East Lansing, Michigan; 3Department of Pharmacology and Toxicology, Michigan State
University, East Lansing, Michigan; 4Institute for Health and Aging, University of California San Francisco, San Francisco,
California; 5Elson S. Floyd College of Medicine, Washington State University, Spokane, Washington; 6Department of
Genetics, Helen DeVos Children’s Hospital, Spectrum Health, Grand Rapids, Michigan; and 7Department of Pediatric
Critical Care Medicine, Helen DeVos Children’s Hospital, Spectrum Health, Grand Rapids, Michigan
THE PAST door to sequence the first genes (78) and genomes (96). The
beginning years of sequencing for clinical impact were
Road to Personalized Medicine
mostly based on targeted gene approaches, with power to
Many books and reviews have highlighted past achieve- resolve only common variants within disease patients.
ments in understanding what DNA and genes are, how to Among these first gene variants to disease associations,
sequence this DNA, and finally into the genomes era of the late found using genetics, were the polymorphisms of beta-
1990s and early 2000s, all culminating into what is now the globin genes for sickle cell disease in 1978 (59), the F508-
“Genomics Era for Medicine” (Fig. 1). From the rediscovery of of CFTR in cystic fibrosis in 1989 (60), CAG repeat length
Mendel defining modes of trait inheritance, the Morgan labo- in the HTT gene in Huntington’s disease in 1993 (71), and
ratory defining trait linkage and mutations, to the identification the 1990 discovery of BRCA1 variants for breast cancer risk
of DNA as the genetic material (5), genetics grew as a field (45). Shortly following the completion of the first human
of biology in the 1900s. The development of sequencing genome in the early 2000s (51, 114), projects were proposed
technologies in the mid to late 1970s (97) opened up the to take genomics into the medical field for personalized
healthcare, such as the Personal Genome Project (19), with
Address for reprint requests and other correspondence: J. W. Prokop,
hopes of identifying genetic events for disease etiology in a
Michigan State Univ., 400 Monroe Ave. NW, Grand Rapids, MI 49503 broad range of diseases. In 2005, publications started solid-
(e-mail: jprokop54@gmail.com). ifying genomics into an understanding of disease at a
1094-8341/18 Copyright © 2018 the American Physiological Society 563
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Copyright © 2018 American Physiological Society. All rights reserved.
564 GENOMICS IN MEDICINE
Fig. 1. Timeline for the discovery of DNA/genes into the genomic era for medicine.
genome level through the development of genome-wide breast cancer, coronary artery disease, and Type 2 diabetes
association studies (GWAS), with the first published study (Fig. 2B). Several chromosomes (chr) such as chr6 and chr19
addressing the genomics of age-related macular degenera- return a higher than average phenotypic activity from GWAS
tion (62). relative to the chromosome size (Fig. 2C). Surprisingly the sex
chr and mitochondrial genome are poorly associated with
Population Genetics and GWAS disease in GWAS, due not to biological association but to
One of the initial GWAS studies contained 116,204 single limited assessment within genome studies. The X-chromosome
nucleotide polymorphisms (SNPs) and only looked at 96 in males is highly associated with hemizygous disease risk and
cases with 50 controls, at the time a ground-breaking paper in females with random X-inactivation, resulting in ~50% of
in Science (62). GWAS continued to advance from that cells with hemizygous loss of function mutations (68, 90). In
initial point, and several reviews of those first few years addition there is suggestions these sex chromosomes, particu-
have previously been published (18, 115). As the cost of larly the Y-chromosome, have high phenotypic impact within
performing the genotyping assays of GWAS decreased, in high-throughput animal phenotyping studies in genetic crosses
combination with increased density of variants on the as- (88, 89).
says, larger cohorts were collected for other indications such As the GWAS database continues to increase in size, it
as neurological (81), cardiovascular (2), metabolic (108), contains an overwhelming number of associations for individ-
renal (63), hepatic (15), and reproductive (85). Studies have uals of European ancestry, at an astonishing ~63% (42,571/
grown to include more than 100,000 individuals, such as the 67,857 as of March 2018) of all associations (Fig. 2D), far
body mass index association studies in 249,796 European exceeding the actual global population composition. This is a
individuals (103) and the 126,559 individuals studied for result of many disease areas having predominantly larger
educational attainment (94). European populations within the studies, therefore increasing
As of the writing this article, nearly 70,000 genetic associ- statistical power for the one ethnicity (Fig. 3). Addressing this
ations have been curated from ~3,000 publications within the lack of diversity to ensure just distribution of benefits from
National Human Genome Research Institute-European Bioin- genomic technologies is one of the leading ELSI (Ethical Legal
formatics Institute GWAS database (116) consisting of ~2,500 and Social Implications of Genetics) concerns for the future of
separate publication-measured traits (https://www.ebi.ac.uk/ genomic research and clinical practice (20). This represents a
gwas/, accessed on March 23, 2018). Following the initial new iteration of a long-existing problem in biomedical re-
growth phase of GWAS from 2005 to 2010, there has been a search, resulting in the National Institutes of Health (NIH)
stable ~300 papers per year with quality GWAS data (Fig. 2A). Revitalization Act of 1993 mandating inclusion of minorities
These studies have revealed the most associations for traits in all NIH-funded research (16). In the past, not only
such as asthma, body mass/obesity/height, schizophrenia, minorities but women and children have been underrepre-
A
400
322 321 331 317
295 285 286
Publications
278
300
196
200
129
100 74
2 5
0
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Year
B
2000
Associations
1500
30 23 22 22
27 26 27 27 24
21 20 19 22 23 23
20 20 17
20 16
13 13
Mb
10 2 0 0
0 MT
16
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
17
18
19
20
21
22
X
Y
Chromosome
D
Associations
60,000
42,571
40,000
20,000
4,664 1,377 1,123 1,073 1,024 959 899 707
0
European African Finnish Han Hispanic Japanese East British Ashkenazi
Asian Jewish
sented in clinical trials, resulting in the need to incentivize experiments have expanded to such a point that meta-analyses
inclusion of more representative populations through the are now being performed on the generated data (69), much like
1997 Food and Drug Administration Modernization Act and those done for GWAS (117). Moreover, as medical health
the 2002 Best Pharmaceuticals for Children Act (74). In record information is more reliable to be data-mined and
short, convenience and ready availability are threatening to correlated to genomic information, phenome-wide association
leave some populations out as the beneficiaries of scientific studies (PheWAS) (25) have been increasing in potential utility
advancement; and at least one policy working group found for genomic medicine (24, 48, 84). Even as the development
that skewed representation in which higher socioeconomic and expansion of these GWAS, EWAS, and PheWAS tools
populations were overrepresented made assessing the risks increase and impact medicine, they still require extensive
of genomic testing difficult, as higher socioeconomic pop- ability to segregate phenotypes, test causality of genotype-to-
ulations may be immune or less vulnerable to many common phenotype, and are underpowered for rare variants. Arguments
concerns about the risks of testing (such as employment or can be made for both rare and common variants in disease
insurance concerns) (21). etiology (39); thus, many of these genomic tools are under-
In the past few years, GWAS approaches have expanded powered for full clinical utility. Other genomic tools such as
into Epigenome-wide association studies (EWAS) (14, 91), an animal models of disease and the expansion of whole exome/
approach where the methylation of cytosines in the DNA are genome sequencing are beginning to overcome these limita-
studied at a genome-wide level for disease association. These tions.
Genotype to Phenotype: from Animal Models to Cells for distantly related to humans, with 7 chr composing ~149 Mb
Human Health with 30,443 proteins (https://www.ncbi.nlm.nih.gov/genome/
?term⫽txid7227[orgn]) compared with the humans’ 23 chr
Human genetic studies have many limitations, mainly result- pairs (22 autosome pairs and 2 sex chromosomes) with ~2,991
ing from the difficulty in deciphering one variant among a
Mb and 79,074 proteins (https://www.ncbi.nlm.nih.gov/
landscape of thousands of other unique variants; therefore,
genome/?term⫽homo⫹sapien). The rat and mouse genomes
connecting a genotype to a phenotype with high confidence is
are more similar to humans and thus provide a more reliable
very difficult in humans. Important questions arise once a
variant is identified, such as does the variant alter the function testing model organism for genotype-to-phenotype relation-
of the gene, does the functional change result in disease or ships. While primate models are even more similar to human,
another phenotype, and is that associated disease or phenotype they have disadvantages ranging from increased time of study,
relevant to the specific clinical condition in the tested individ- expense, and ethical concerns for performing experiments. For
ual? These questions are hard to answer with current scientific the rat we have provided a table of the major milestones for
tools within the index subject. Thus, the dissection of genetic genetic understanding and community resources that have
elements that contribute to traits and diseases has always relevance to understanding genotype-phenotype relationships
needed models within other organisms. Very early in genetics, (Table 1), many of which can also be found within the mouse
animal models served this very function, with the fruit fly community as well.
(Drosophila melanogaster) serving as one of the first and most In the mouse (101) and rat (23), entire chromosomes (con-
successful examples of genotype-to-phenotype relationships somic) can be introgressed from strains of animals that have
(105). This included groundbreaking work by the Morgan disease or particular phenotypes relative to “healthy” con-
laboratory mapping trait inheritance (79), Sturtevant defining trol animals, or vice versa, to determine the chr that con-
trait linkage mapping (106), Muller defining mutation due to tribute to disease. Combining the generation of every chro-
environmental exposures (80), studies of homology between mosome cross between two strains with the measuring of
different genera (107), and finally having complete genomes hundreds of phenotypes one can suggest chr with the highest
from 12 of the Drosophila species (104). Yet the fly is still very impact on phenotypic traits (64, 73). For example, two
complete rat consomic panels were developed by introgress- to illuminate these roles of the sex chr. For example, animal
ing the Brown Norway (BN) to Fawn-Hooded Hypertensive models can be used in explaining the recently reported
(FHH) or the Salt Sensitive (SS) rat genome background. impact of the loss of Y-chromosome (LOY) as a major
Surprisingly, per DNA base, the Y-chr contributes to a disease contributor (30, 35). To resolve the impact of
vastly elevated number of phenotypes relative to all other specific regions of chr on phenotype, researchers utilize F1
chr and also has twice the elevated rate of variation between crosses, heterogeneous stock breeding, and congenic map-
strains (89). As the sex chr where already mentioned to be ping, all of which allow the association of regions/genes on
incredibly underpowered in GWAS (Fig. 2), animal models chr with phenotype. This information can then be used in the
can have power to explain human phenotypes contributed by human to map and test variants that may translate across
sex chr (88) that current techniques used in humans struggle organisms.
The development of technologies such as Zn fingers, including multiple ethnicities from the 1000 Genomes Project
TALENs, and now CRISPR/Cas9 has revolutionized our abil- (1), new approaches [whole exome sequencing (WES)] were
ity to characterize clinical variants found from whole genome designed to sequence just those regions of the genome that
sequencing in human (29, 33). As these technologies can be code for proteins (~1% of the genome), opening the door for
applied to nearly any species, particularly those that have had identifying potential pathogenic variants without spending the
their genomes sequenced, it is possible to study a gene or vast resources needed for the entire genome (6, 17). Some of
variant in diverse species such as the fruit fly, Caenorhabditis the first large-scale sequencing projects, such as those done in
elegans, zebrafish, mouse and rat. An easier approach, and cancer and the National Heart, Lung, and Blood Institute Gene
what most groups have used to date, for characterization is Ontology (NHLBI GO) Exome Sequencing Project (111),
either the deletion or insertion of an entire gene of interest. Yet began to highlight the full spectrum of variation using whole
these are based on all or none impacts, limiting the scope for exome sequencing, showing a large number of rare variants
potential gain of function or gene dosage contribution to that might influence disease. Around this same time, studies
disease. Utilizing these genome editing technologies, one of began to be published that showed discovery of rare diseases
the growing approaches in animals is the generation of human- caused by rare variants (55). Among these first cases was a
ized species, such that the model organism is susceptible to young boy whose life was saved through the identification of a
human disease when it normally is not; therefore, opening the C203Y variant in XIAP causing his inflammatory bowel dis-
door for studies such as viral/bacterial infections and human ease. The variant was linked to a phenotype that primarily was
tumor growth (26, 28, 32, 54). With more advanced humanized an immunologic defect associated with a X-linked inhibitor of
species, ethical concerns raised in the past from chimaera apoptosis deficiency. Based on this finding the clinicians caring
research return, and the NIH has only recently sought public for this patient applied a bone marrow transplant to prevent the
feedback concerning plans to lift a moratorium forbidding development of life-threatening hemophagocytic lymphohis-
federal funding, which is currently pending review by ethics tiocytosis. Here, WES not only provided the diagnosis but also
panels (50, 58). More recently groups have begun to insert suggested the previously unconsidered treatment option of a
variants using donor sequence after cutting the genome with bone marrow transplant, bringing precision genomic medicine
CRISPR/Cas9, thus generating single variants of interest. into the public spotlight for the first time (118).
While these approaches are still difficult, they should continue With WES becoming more established in the clinic, the
to grow in the future and become more common practice for number of patients benefitting from these tools has rapidly
variant-to-phenotype associations. grown (40, 120). It is estimated that the use of WES allows
While animal studies have significant scientific promise, ~25% of rare disease cases to reach a molecular diagnosis (56,
they do result in multiple practical issues in addition to the 119). With the robust yield and the continual decrease in cost
ethical issues identified above. Primarily, their genomes are not of sequencing, many groups have begun the transition to whole
the same as the human genome, and not all traits are shared genome sequencing (WGS) from exome (123). WGS can
between species. Therefore, many groups have moved into resolve protein-coding variants at a similar or higher rate as
human cell culture characterization, using either isolated dis- WES (72, 98) while also allowing for better coverage of the
ease tissue from a patient, primary or stable cell lines, or exons and identification of variants that might alter gene
generating organoids in culture. Moreover, human cells can be expression, gene splicing, and chromosome replication. With a
manipulated in many ways to define the biology of disease limited knowledge of noncoding regions of the genome, inves-
progression. Tumor biopsies can be sequenced and grown in tigators still interpret many variants with ambiguity, but with
culture, or they can be delivered to humanized models of mice future research the role for noncoding regions may be better
and rats to study drug responses based on genetic variability of understood. Sequencing an entire genome just once allows for
the specific tumor (43, 112). Germline cells can be obtained, additional bioinformatics analysis to interpret future knowl-
sequenced, and then converted into inducible pluripotent stem edge that whole exome does not provide, allowing for reas-
cells (83, 109, 121). These cells can be manipulated with sessment of variants instead of resequencing of the patient with
genome editing tools such as CRISPR/Cas9 (124) and then new technology. Genome sequencing is still in its infancy, and
differentiated to many linages including neural (27), liver identification of variants that are rare (such as n ⫽ 1 cases)
(102), fat (87), and heart (36, 125) to characterize phenotypic does create issues that arise and warrant caution in reporting,
changes with the hope of potentially being used to treat with defined standards now becoming available (41). Con-
disease. The question remains whether current research tools straints also exist as only some health insurance providers have
and costs can keep pace with the ever-growing number of started reimbursing the ordering institution for WES but few do
human variants identified from clinical sequencing, or whether for WGS.
new methods are necessary.
THE PRESENT
within genes. Tools such as MyGene2 (https:// a wide range of vertebrate species, suggesting they greatly
www.mygene2.org) even expand this idea directly into the affect cell function and are highly conserved, yet we have
patient’s hands, connecting researchers, clinicians, and patients minimal knowledge about their biology. This highlights the
on the basis of genes and phenotypes. Identifying a large fact that many variants falling within the poorly defined re-
number of similar patients combined with some basic biochem- gions of the genome will be missed from current bioinformat-
ical, molecular, and animal experimentation can further resolve ics, not because of limitations of bioinformatics but because of
a variant’s role in disease etiology (Fig. 4). limited studies of these genes.
To speed up these analyses, detailed knowledge of every While projects such as the Encyclopedia of DNA Elements
gene within the genome provides tools to interpret variants (ENCODE) (31a) and RoadMap Epigenomics (95) have begun
with higher resolution at a faster pace; however, we are elucidating noncoding regions within the genome, significant
currently far from understanding every gene. For example, progress must still be made. It is likely that many of the
querying annotated publications for the 20,120 high-confi- disease-causing variants remaining unidentified fall within
dence proteins or 2,030 transcription factors from the UniProt these noncoding regions. From GWAS, it is suggested that the
database (Fig. 5) shows a clear skew to our knowledge of majority of variants identified for trait association are noncod-
proteins throughout the genome. A few proteins represent a ing and likely expression quantitative trait loci (eQTLs) (82),
very large amount of the curated work within UniProt. Around meaning the variant does not alter the function of the protein
15% of human proteins currently have 0 publications curated, but more likely changes the expression of the protein. GWAS
which we refer to as the “Unknown Proteome.” Data sets such has not resolved the causal variant for the majority of identified
as the Human Protein Atlas (113) show the expression profile loci, so additional tools and detailed analysis of GWAS mech-
for the genes of the Unknown Proteome is 8% ubiquitously anism to disease will be needed to address rare variants. In
expressed and 17% tissue specific (primarily from the testis). addition, the field of EvoDevo hypothesizes that speciation
Of the ubiquitously expressed genes, most of these are found in events often happen through changes in gene regulation timing
A
25
% of Proteins
through alteration in the noncoding DNA (12, 13). Therefore, information can be seen as even more of a risk. The genome by
evolutionary conservation is also not able to resolve many its nature is difficult to deidentify due to its uniqueness, making
potential impactful noncoding variants within the genome. it more difficult to keep genotype-to-phenotype associations
Future tools are needed to resolve the role of noncoding stored within datacenters and necessitating a delicate approach
variants at a cellular level if we want to fully understand all the as genomic medicine advances. Technologies will continue
genetic contribution to disease development and progression. advancing in the coming years as well, with technologies
moving the cost of whole genome sequencing potentially to a
THE FUTURE few hundred dollars with shorter turn-around time, opening the
Where Can Sequencing Go? possibility for a human to be routinely sequenced or even
building multicellular human genomes, yielding even more
As these large-scale projects that involve millions of ge- data per individual.
nomes return results, we expect to gain a clearer view of what Even as WGS becomes the standard method for researchers
regions within the genome have variation and those that do not, in the USA, GWAS studies need to continue around the world,
including noncoding control regions. As we perform cell-level particularly in areas such as Africa, Asia and South America
ENCODE-style experiments at higher resolution, we can also where populations are underrepresented and understudied.
correlate these conserved sites with functional enhancers and From functional studies, many groups will continue to break
promoters. With pharmaceutical companies analyzing large down the linkage disequilibrium block of GWAS to resolve the
numbers of WES, we expect pharmacogenomics to expand functional units and define transcription factor networks in-
continually. With the number of genomes being sequenced volved in disease progression, which may unlock new tools for
ever growing, and with integration of other data sets such as deciphering the role of rare variants in the noncoding portion of
medical health records, imaging, expression profiles, and mo- the genome. To decrease the time needed for classification of
bile health data (such as Fitbit), the field is moving into the big every protein-coding variant associated with disease, we need
data age. Each individual could be represented by terabytes of to develop fuller databases for protein knowledge. A larger
information sitting in datacenters, which need to be secured for focus and more resources need to be applied to characterizing
patient protection while being available for analysis for corre- poorly studied proteins if we want to understand the impor-
lations among other patients by research centers. This level of tance of clinical variants anywhere within the genome at a
data will require massive datacenters with fast data transfer speed compatible with real-time clinical care.
speeds as well as high security to protect private patient
information. Research databases will continue increasing in Potential Issues and Conclusions for the Future
size, such that maintaining NIH-funded data sets in multiple
locations will not be feasible, but cloud storage and computing Moving genomic medicine into the science of individuals,
must increase to disseminate the information into the hands of known as n of 1 science, we must make clearer associations of
many scientists. If social media data can be leveraged in variants that are either common or rare with changes and
marketing and even politics, the power of medical and genomic mechanisms of biology. As the databases of sequenced ge-
nomes continue to grow, we will better understand the dynam- Evans DS, Post WS, Waggott D, Lyytikäinen L-P, Hicks AA, Eisele
ics of the human genome, the acceptability of variation at any L, Ellinghaus D, Hayward C, Navarro P, Ulivi S, Tanaka T, Tester
DJ, Chatel S, Gustafsson S, Kumari M, Morris RW, Naluai ÅT,
one site within it, and the degree of structural changes in the Padmanabhan S, Kluttig A, Strohmer B, Panayiotou AG, Torres M,
genome. Yet resources need to be put into the functional Knoflach M, Hubacek JA, Slowikowski K, Raychaudhuri S, Kumar
outcome of genetic variants, developing cheaper and quicker RD, Harris TB, Launer LJ, Shuldiner AR, Alonso A, Bader JS,
tools for variant characterization. With continual identification Ehret G, Huang H, Kao WHL, Strait JB, Macfarlane PW, Brown M,
Caulfield MJ, Samani NJ, Kronenberg F, Willeit J, CARe Consor-
of VUS and GUDS, time and money will be needed to test and
tium, COGENT Consortium, Smith JG, Greiser KH, Meyer Zu
reclassify variants. Much of the future for genomic medicine Schwabedissen H, Werdan K, Carella M, Zelante L, Heckbert SR,
relies more on phenotype associations and knowledge of genes Psaty BM, Rotter JI, Kolcic I, Polašek O, Wright AF, Griffin M, Daly
and the proteins those genes code and less on further advance- MJ, DCCT/EDIC, Arnar DO, Hólm H, Thorsteinsdottir U,
ments of sequencing technologies. As we try to understand the eMERGE Consortium; Denny JC, Roden DM, Zuvich RL, Emilsson
V, Plump AS, Larson MG, O’Donnell CJ, Yin X, Bobbo M,
functional effects of the genome, a better understanding of the D’Adamo AP, Iorio A, Sinagra G, Carracedo A, Cummings SR,
interactions with the metabolome and microbiome will further Nalls MA, Jula A, Kontula KK, Marjamaa A, Oikarinen L, Perola
those goals in humans. The use of animal models, cell culture, M, Porthan K, Erbel R, Hoffmann P, Jöckel KH, Kälsch H, Nöthen
microdevices mimicking organs, and even basic biochemistry MM, HRGEN Consortium, den Hoed M, Loos RJ, Thelle DS, Gieger
of proteins will facilitate these advances. We must begin C, Meitinger T, Perz S, Peters A, Prucha H, Sinner MF, Walden-
berger M, de Boer RA, Franke L, van der Vleuten PA, Beckmann
addressing our knowledge of proteins in the genome, starting BM, Martens E, Bardai A, Hofman N, Wilde AA, Behr ER, Dala-
with elimination of the Unknown Proteome. We need to start georgou C, Giudicessi JR, Medeiros-Domingo A, Barc J, Kyndt F,
paying more attention to the sex chromosomes (X and Y) and Probst V, Ghidoni A, Insolia R, Hamilton RM, Scherer SW,
also the mitochondria for phenotype association in humans, as Brandimarto J, Margulies K, Moravec CE, del Greco MF, Fuchs-
animal models have suggested these regions to be drivers for berger C, O’Connell JR, Lee WK, Watt GC, Campbell H, Wild SH,
El Mokhtari NE, Frey N, Asselbergs FW, Mateo Leach I, Navis G,
phenotypic diversity. The role of noncoding variants need to be van den Berg MP, van Veldhuisen DJ, Kellis M, Krijthe BP, Franco
moved out of standard cell lines and human tissues and into OH, Hofman A, Kors JA, Uitterlinden AG, Witteman JC, Kedenko
individual cells of the human tissues to understand normal L, Lamina C, Oostra BA, Abecasis GR, Lakatta EG, Mulas A, Orrú
cellular control and the diversity of cell types within any M, Schlessinger D, Uda M, Markus MR, Völker U, Snieder H,
Spector TD, Ärnlöv J, Lind L, Sundström J, Syvänen AC, Kivimaki
human tissue. Any one variant may not act alone, further M, Kähönen M, Mononen N, Raitakari OT, Viikari JS, Adamkova
complicating our understanding of biology; therefore, we must V, Kiechl S, Brion M, Nicolaides AN, Paulweber B, Haerting J,
also consider how to model and test the role of epistasis and Dominiczak AF, Nyberg F, Whincup PH, Hingorani AD, Schott JJ,
gene modifiers within the genome. Above all, for genomic Bezzina CR, Ingelsson E, Ferrucci L, Gasparini P, Wilson JF, Rudan
medicine to become a major factor in the future, we must I, Franke A, Mühleisen TW, Pramstaller PP, Lehtimäki TJ, Paterson
AD, Parsa A, Liu Y, van Duijn CM, Siscovick DS, Gudnason V,
remember that genomics, as powerful as it is, cannot explain all Jamshidi Y, Salomaa V, Felix SB, Sanna S, Ritchie MD, Stricker BH,
disease risk, including those risks that are passed from gener- Stefansson K, Boyer LA, Cappola TP, Olsen JV, Lage K, Schwartz
ation to generation. Lifestyle choices, environmental expo- PJ, Kääb S, Chakravarti A, Ackerman MJ, Pfeufer A, de Bakker PI,
sures, the microbiome, and cultural upbringing need to be Newton-Cheh C. Genetic association study of QT interval highlights
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human biology. These integrations will move our genomic 3. Atanur SS, Birol I, Guryev V, Hirst M, Hummel O, Morrissey C,
understanding to phenotypic outcomes through precision med- Behmoaras J, Fernandez-Suarez XM, Johnson MD, McLaren WM,
icine and revolutionize health care. Patone G, Petretto E, Plessy C, Rockland KS, Rockland C, Saar K,
Zhao Y, Carninci P, Flicek P, Kurtz T, Cuppen E, Pravenec M,
GRANTS Hubner N, Jones SJM, Birney E, Aitman TJ. The genome sequence of
the spontaneously hypertensive rat: Analysis and functional significance.
Supported by National Institute of Environmental Health Sciences Grant Genome Res 20: 791–803, 2010. doi:10.1101/gr.103499.109.
K01ES-025435 (to J. W. Prokop). 4. Atanur SS, Diaz AG, Maratou K, Sarkis A, Rotival M, Game L,
Tschannen MR, Kaisaki PJ, Otto GW, Ma MCJ, Keane TM, Hum-
DISCLOSURES mel O, Saar K, Chen W, Guryev V, Gopalakrishnan K, Garrett MR,
Joe B, Citterio L, Bianchi G, McBride M, Dominiczak A, Adams DJ,
No conflicts of interest, financial or otherwise, are declared by the authors.
Serikawa T, Flicek P, Cuppen E, Hubner N, Petretto E, Gauguier D,
Kwitek A, Jacob H, Aitman TJ. Genome sequencing reveals loci under
AUTHOR CONTRIBUTIONS artificial selection that underlie disease phenotypes in the laboratory rat.
J.W.P. analyzed data; J.W.P. and J.L. prepared figures; J.W.P., T.M., K.S., Cell 154: 691–703, 2013. doi:10.1016/j.cell.2013.06.040.
S.M.B., C.B., S.R., E.A.W., and J.L. drafted manuscript; J.W.P., T.M., K.S., 5. Avery OT, Macleod CM, McCarty M. Studies on the Chemical Nature
S.M.B., C.B., S.R., E.A.W., and J.L. edited and revised manuscript; J.W.P., of the Substance Inducing Transformation of Pneumococcal Types:
T.M., K.S., S.M.B., C.B., S.R., E.A.W., and J.L. approved final version of Induction of Transformation by a Desoxyribonucleic Acid Fraction
manuscript. Isolated from Pneumococcus Type III. J Exp Med 79: 137–158, 1944.
doi:10.1084/jem.79.2.137.
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