Two Strikes and You're Out: Gene−Gene Mutation Interactions in HCM Gerald W. Dorn II and Elizabeth M. McNally Circ Res. 2014;115:208-210 doi: 10.1161/CIRCRESAHA.114.304383 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/115/2/208
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Editorial Two Strikes and You’re Out Gene–Gene Mutation Interactions in HCM Gerald W. Dorn II, Elizabeth M. McNally While Ockham’s razor is a useful tool in the physical sciences, it can be a very dangerous implement in biology. It is thus very rash to use simplicity and elegance as a guide in biological research. —Francis Crick
G
regor Mendel is credited with first understanding the fundamental characteristics of genetic inheritance through his studies of transgenerational expression of phenotypes in pea plants (Pisum sativum). As every middle schooler knows, through careful cross-breeding he discerned dominant and recessive modes of inheritance for, but not blending of, parental traits. He rightly concluded that inheritance is achieved through vertical transmission of trait-encoding factors that we now call genes.
Article, see p 227 An important underlying assumption to Mendel’s mechanistic view of inheritance is that one inheritance unit (he called them "factors"1; we call them genes) encodes one trait. This relationship holds for the 7 pea phenotypes he cataloged, but is the exception rather than the rule in mammalian biology. For example, stature is an inherited trait, but >50 different genes are thought to contribute to human height.2 Nevertheless, heritable diseases are commonly referred to as Mendelian when they are attributed to mutations in a single gene. The public database Online Mendelian Inheritance in Man (http://www.omim.org) lists >4000 Mendelian disorders with a known molecular basis, plus >1700 others with an unknown molecular basis. Although some of these diseases, such as cystic fibrosis (autosomal recessive mutation of CFTR gene), Huntington disease (autosomal dominant mutation of HTT gene), and hypertrophic cardiomyopathy (HCM; autosomal dominant mutations of the MYH73 and other sarcomeric The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (G.W.D.); and Institute for Cardiovascular Research, Department of Medicine, The University of Chicago, IL (E.M.M.). Correspondence to Elizabeth M. McNally, MD, PhD, A.J. Carlson Professor of Medicine and Human Genetics, Department of Medicine, Division of Cardiovascular Medicine, The University of Chicago, 5841 S Maryland Ave, MC6088, Chicago, IL 60637. E-mail: emcnally@ medicine.bsd.uchicago.edu or Gerald W. Dorn II, MD, Philip and Sima K Needleman Professor, Department of Internal Medicine, Washington University Center for Pharmacogenomics, 660 S Euclid Ave, Campus Box 8220, St. Louis, MO 63110. E-mail [email protected] (Circ Res. 2014;115:208-210.) © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.114.304383
protein genes), are caused by mutations in one gene, even for so-called Mendelian diseases the contribution of additional genetic modifiers is yet to be well modeled. In this issue of Circulation Research, Blankenburg et al4 show how the combinatorial effects of 2 different HCM-associated mutations can be critical determinants of disease phenotype. Humans have an unusual potential to develop genetic diseases because we suffer from an abnormally high prevalence of deleterious mutations. As a species, we have accumulated damaging mutations much faster than we have cleared them.5–7 Here’s why: The rate of nonsynonymous DNA mutations in protein-coding genes is constant, ≈1x105/gene/generation.6 Fitness loss for a mutated protein (ie, the odds that a nonsynonymous mutation will be damaging) is also constant, ≈1%.6 Damaging mutations tend to be cleared from the population through evolutionary suppression for many generations. Thus, in a stable long-term population, negative selection restrains the prevalence of damaging DNA mutations. However, the human population has been anything but stable for a relatively short period of evolutionary time. In 5000 BC, there were ≈5 million Homo sapiens on the planet. The advent of agriculture and transition from nomadic life to urban civilizations prompted an exponential increase in population, resulting in ≈500 million humans by the middle ages, a 100-fold increase. The industrial revolution and modern technologies stimulated a second exponential increase in population, from 1 billion in 1800 to >7 billion now. Thus, in just a few hundred generations, human population has increased by 3 orders of magnitude (doubling just within the authors’ lifetimes!). This represents a tremendous number of new genomes to accumulate damaging mutations with insufficient time to clear them. Accordingly, 73% of all protein-coding variants and 86% of all deleterious single-nucleotide poylmorphisms are only 5000 to 10 000 years old.7 Mathematically, every person currently alive is carrying ≥1 severely damaging DNA mutations, and every protein-coding gene is represented by someone carrying a dysfunctional variant, most of which are rare or private. Mutations in MYH7 and MYBPC3, which encode β myosin heavy chain and myosin binding protein C, respectively, account for approximately half of inherited HCM. Clinical genetic testing for HCM has become more commonplace and revealed marked interindividual variability in disease, that is, the same gene mutation is present in individuals with a spectrum of HCM, even within the same family. Differences in disease phenotype (ie, symmetrical versus asymmetrical hypertrophy and the occurrence of arrhythmias), variable disease severity, and different patterns of onset all suggest a role for modifiers that may be genetic or environmental. Blankenburg et al4 examined 3 MYH7 mutations, V606M, R453C, and R719W, mapping to unique regions of the
Downloaded from http://circres.ahajournals.org/ at208 CONS CALIFORNIA DIG LIB on September 2, 2014
Dorn and McNally Additive HCM Gene Effects 209 β-myosin heavy chain (MHC) head domain. V606M has been characterized as a mild HCM-associated mutation in humans associated with late-onset disease and less severe hypertrophy.8 V606 lies in the 50-kDa portion of the myosin S1 head, where it contributes to the actin-binding site.9 R453C has been associated with more severe human HCM and is located within the γ-phosphate sensing domain of the myosin ATPase.10 When engineered in vitro into human β myosin, the R453C mutation has reduced actin-activated ATPase and directs slower in vitro sliding of actin filaments.11 The final mutation, R719W, is also associated with more severe human HCM, is located within the myosin converter domain, and has been linked to increased elastic distortion of individual myosin heads.12 To better evaluate their individual and combined phenotypes on identical genetic backgrounds, Blankenburg et al4 introduced these 3 human MYH7 HCM mutations into the respective positions of the mouse Myh6 gene (encoding αMHC, the major myosin heavy chain protein found in the murine heart). Somewhat recapitulating the human genotype–phenotype spectrum, R453C caused hypertrophy by 26 weeks of age in mice, whereas V606M had no significant effect on left ventricular hypertrophy at that same time. Even when homozygous, the V606M mutation was insufficient to produce cardiac hypertrophy. However, when the V606M mutant mice were crossed with the R453C mutant mice, the dual heterozygous mutant progeny mice developed more hypertrophy than either of the parent mutant strains, demonstrating additive phenotypic effects of these 2 mutations. Functionally, these allelic combinations offer the potential for fresh molecular insight. The V606M mutation with its ability to modify actin binding is insufficient to produce HCM, even when homozygous (ie, in the absence of any normal MHC). However, altered actin binding plus reduced ATPase evoked significantly more hypertrophy, suggesting a disease model wherein the cardiac sarcomeres contain a mixture of myosin heads, some with different actin binding and others with reduced ATPase. These mixed mutations may or may not reflect a situation where each allele produces half the total MHC protein, because V606M and R719W may not be expressed at equal levels to the normal allele.10 It is also possible that some mutations may alter mRNA stability and splicing, provoking reduced expression of the mutant protein relative to normal MHC, thereby leading to less hypertrophy. This work demonstrates that a seemingly innocuous secondary mutation may, in some cases, evoke more severe HCM. As a caveat, an inbred murine genome and heart differ markedly from the human HCM condition. Nonetheless, the findings suggest that multiple mutations are likely to elicit a more severe phenotype. To translate this finding to the human condition requires estimating the frequency of MYH7 genetic variation in the population at large, including DNA variations not yet linked to HCM phenotypes. Where it has been studied, the frequency of potentially pathogenic MYH7 mutations in the general population is much higher than would be predicted from the prevalence of HCM.13,14 HCM occurs in ≈1 in 500 individuals, but DNA variants thought to predispose to HCM are present at 5- to 10-fold higher frequency. Taken together,
Figure. Schematic depiction of variable genetic and nongenetic influences on individual phenotype. Left, Different forms of secondary mutations. Right, Role of secondary mutations in context of other modifying influences.
these population-based estimates and the current findings in mice show how individual DNA variants that contribute little or nothing to cardiac phenotypes in otherwise normal individuals may lead to more severe disease in the context of a more pathogenic HCM mutation. Although these analyses focused on the MYH7 gene, the second genetic hit principle is certainly not restricted to this gene; functional significance of other sarcomere gene DNA variants is likely to be revealed in the context of a pathogenic MYH7 HCM mutation. For this reason, Blankenburg et al4 advocate more broad-based genetic screening to help identify those at highest risk for faster progression. A markedly increased potential for gene–gene interactions is one of the consequences of a human genetic landscape replete with mutations that are both rare and predicted to be damaging. If a given mutation is causal, other functionally significant DNA variants can almost certainly act as phenotypic modifiers. Depending on genetic context, DNA variants may therefore be categorized as primary or driver, associated, or comorbid mutations and may exhibit variable expression or reduced penetrance. This genetic reality not only provokes interindividual variability in phenotype but also blurs the distinction between monogenic, bigenic, and polygenic or complex inheritance. It is likely that the genetic component of phenotype can only be explained by the cumulative functional consequences of all coding and noncoding DNA sequence variants in the same gene, in other genes of the same pathway, and finally in all genes that impact the affected organ system (Figure). And, this approach still fails to incorporate epigenetic and environmental influences. Serious attempts at this type of systems-level genetic integration will need to be both comprehensive and unbiased. Accordingly, the initial discovery of a genetic disease might be accomplished using conventional genetic linkage of the suspected primary mutation in a relatively few affected subjects, but to understand fully how the spectrum of personal genotypes help determine individual phenotype will require identifying all genomic DNA variants in large cohorts of subjects presenting with the disease phenotype, regardless of primary mutation.
Acknowledgments This work was supported by National Institutes of Health grant U54 AR052646.
Downloaded from http://circres.ahajournals.org/ at CONS CALIFORNIA DIG LIB on September 2, 2014
210 Circulation Research July 7, 2014
Disclosures None.
References 1. Mendel G. Versuche über Pflanzen-Hybriden. Verh. Naturforsch. Ver. Brünn. 1866;4:3–47. 2. Lanktree MB, Guo Y, Murtaza M, et al.; Hugh Watkins on behalf of PROCARDIS; Meena Kumari on behalf of the Whitehall II Study and the WHII 50K Group. Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height. Am J Hum Genet. 2011;88:6–18. 3. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006. 4. Blankenburg R, Hackert K, Wurster S, Deenen R, Seidman JG, Seidman CE, Lohse MJ, Schmitt JP. β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations. Circ Res. 2014;115:227–237. 5. Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA. Clan genomics and the complex architecture of human disease. Cell. 2011;147:32–43. 6. Kiezun A, Garimella K, Do R, et al. Exome sequencing and the genetic basis of complex traits. Nat Genet. 2012;44:623–630. 7. Fu W, O’Connor TD, Jun G, Kang HM, Abecasis G, Leal SM, Gabriel S, Rieder MJ, Altshuler D, Shendure J, Nickerson DA, Bamshad MJ, Akey JM; NHLBI Exome Sequencing Project. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature. 2013;493:216–220.
8. Van Driest SL, Ackerman MJ, Ommen SR, Shakur R, Will ML, Nishimura RA, Tajik AJ, Gersh BJ. Prevalence and severity of “benign” mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy. Circulation. 2002;106:3085–3090. 9. Fisher AJ, Smith CA, Thoden J, Smith R, Sutoh K, Holden HM, Rayment I. Structural studies of myosin:nucleotide complexes: a revised model for the molecular basis of muscle contraction. Biophys J. 1995;68:19S–26S, discussion 27S. 10. Tripathi S, Schultz I, Becker E, Montag J, Borchert B, Francino A, Navarro-Lopez F, Perrot A, Özcelik C, Osterziel KJ, McKenna WJ, Brenner B, Kraft T. Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy. Basic Res Cardiol. 2011;106:1041–1055. 11. Sommese RF, Sung J, Nag S, Sutton S, Deacon JC, Choe E, Leinwand LA, Ruppel K, Spudich JA. Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function. Proc Natl Acad Sci U S A. 2013;110:12607–12612. 12. Seebohm B, Matinmehr F, Köhler J, Francino A, Navarro-Lopéz F, Perrot A, Ozcelik C, McKenna WJ, Brenner B, Kraft T. Cardiomyopathy mutations reveal variable region of myosin converter as major element of cross-bridge compliance. Biophys J. 2009;97:806–824. 13. Golbus JR, Puckelwartz MJ, Fahrenbach JP, Dellefave-Castillo LM, Wolfgeher D, McNally EM. Population-based variation in cardiomyopathy genes. Circ Cardiovasc Genet. 2012;5:391–399. 14. Pan S, Caleshu CA, Dunn KE, Foti MJ, Moran MK, Soyinka O, Ashley EA. Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation. Circ Cardiovasc Genet. 2012;5:602–610. Key Words: Editorials
■
genetics
■
models, animal
Downloaded from http://circres.ahajournals.org/ at CONS CALIFORNIA DIG LIB on September 2, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/115/2/208
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ at CONS CALIFORNIA DIG LIB on September 2, 2014
Editorial Two Strikes and You’re Out Gene–Gene Mutation Interactions in HCM Gerald W. Dorn II, Elizabeth M. McNally While Ockham’s razor is a useful tool in the physical sciences, it can be a very dangerous implement in biology. It is thus very rash to use simplicity and elegance as a guide in biological research. —Francis Crick
G
regor Mendel is credited with first understanding the fundamental characteristics of genetic inheritance through his studies of transgenerational expression of phenotypes in pea plants (Pisum sativum). As every middle schooler knows, through careful cross-breeding he discerned dominant and recessive modes of inheritance for, but not blending of, parental traits. He rightly concluded that inheritance is achieved through vertical transmission of trait-encoding factors that we now call genes.
Article, see p 227 An important underlying assumption to Mendel’s mechanistic view of inheritance is that one inheritance unit (he called them "factors"1; we call them genes) encodes one trait. This relationship holds for the 7 pea phenotypes he cataloged, but is the exception rather than the rule in mammalian biology. For example, stature is an inherited trait, but >50 different genes are thought to contribute to human height.2 Nevertheless, heritable diseases are commonly referred to as Mendelian when they are attributed to mutations in a single gene. The public database Online Mendelian Inheritance in Man (http://www.omim.org) lists >4000 Mendelian disorders with a known molecular basis, plus >1700 others with an unknown molecular basis. Although some of these diseases, such as cystic fibrosis (autosomal recessive mutation of CFTR gene), Huntington disease (autosomal dominant mutation of HTT gene), and hypertrophic cardiomyopathy (HCM; autosomal dominant mutations of the MYH73 and other sarcomeric The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (G.W.D.); and Institute for Cardiovascular Research, Department of Medicine, The University of Chicago, IL (E.M.M.). Correspondence to Elizabeth M. McNally, MD, PhD, A.J. Carlson Professor of Medicine and Human Genetics, Department of Medicine, Division of Cardiovascular Medicine, The University of Chicago, 5841 S Maryland Ave, MC6088, Chicago, IL 60637. E-mail: emcnally@ medicine.bsd.uchicago.edu or Gerald W. Dorn II, MD, Philip and Sima K Needleman Professor, Department of Internal Medicine, Washington University Center for Pharmacogenomics, 660 S Euclid Ave, Campus Box 8220, St. Louis, MO 63110. E-mail [email protected] (Circ Res. 2014;115:208-210.) © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.114.304383
protein genes), are caused by mutations in one gene, even for so-called Mendelian diseases the contribution of additional genetic modifiers is yet to be well modeled. In this issue of Circulation Research, Blankenburg et al4 show how the combinatorial effects of 2 different HCM-associated mutations can be critical determinants of disease phenotype. Humans have an unusual potential to develop genetic diseases because we suffer from an abnormally high prevalence of deleterious mutations. As a species, we have accumulated damaging mutations much faster than we have cleared them.5–7 Here’s why: The rate of nonsynonymous DNA mutations in protein-coding genes is constant, ≈1x105/gene/generation.6 Fitness loss for a mutated protein (ie, the odds that a nonsynonymous mutation will be damaging) is also constant, ≈1%.6 Damaging mutations tend to be cleared from the population through evolutionary suppression for many generations. Thus, in a stable long-term population, negative selection restrains the prevalence of damaging DNA mutations. However, the human population has been anything but stable for a relatively short period of evolutionary time. In 5000 BC, there were ≈5 million Homo sapiens on the planet. The advent of agriculture and transition from nomadic life to urban civilizations prompted an exponential increase in population, resulting in ≈500 million humans by the middle ages, a 100-fold increase. The industrial revolution and modern technologies stimulated a second exponential increase in population, from 1 billion in 1800 to >7 billion now. Thus, in just a few hundred generations, human population has increased by 3 orders of magnitude (doubling just within the authors’ lifetimes!). This represents a tremendous number of new genomes to accumulate damaging mutations with insufficient time to clear them. Accordingly, 73% of all protein-coding variants and 86% of all deleterious single-nucleotide poylmorphisms are only 5000 to 10 000 years old.7 Mathematically, every person currently alive is carrying ≥1 severely damaging DNA mutations, and every protein-coding gene is represented by someone carrying a dysfunctional variant, most of which are rare or private. Mutations in MYH7 and MYBPC3, which encode β myosin heavy chain and myosin binding protein C, respectively, account for approximately half of inherited HCM. Clinical genetic testing for HCM has become more commonplace and revealed marked interindividual variability in disease, that is, the same gene mutation is present in individuals with a spectrum of HCM, even within the same family. Differences in disease phenotype (ie, symmetrical versus asymmetrical hypertrophy and the occurrence of arrhythmias), variable disease severity, and different patterns of onset all suggest a role for modifiers that may be genetic or environmental. Blankenburg et al4 examined 3 MYH7 mutations, V606M, R453C, and R719W, mapping to unique regions of the
Downloaded from http://circres.ahajournals.org/ at208 CONS CALIFORNIA DIG LIB on September 2, 2014
Dorn and McNally Additive HCM Gene Effects 209 β-myosin heavy chain (MHC) head domain. V606M has been characterized as a mild HCM-associated mutation in humans associated with late-onset disease and less severe hypertrophy.8 V606 lies in the 50-kDa portion of the myosin S1 head, where it contributes to the actin-binding site.9 R453C has been associated with more severe human HCM and is located within the γ-phosphate sensing domain of the myosin ATPase.10 When engineered in vitro into human β myosin, the R453C mutation has reduced actin-activated ATPase and directs slower in vitro sliding of actin filaments.11 The final mutation, R719W, is also associated with more severe human HCM, is located within the myosin converter domain, and has been linked to increased elastic distortion of individual myosin heads.12 To better evaluate their individual and combined phenotypes on identical genetic backgrounds, Blankenburg et al4 introduced these 3 human MYH7 HCM mutations into the respective positions of the mouse Myh6 gene (encoding αMHC, the major myosin heavy chain protein found in the murine heart). Somewhat recapitulating the human genotype–phenotype spectrum, R453C caused hypertrophy by 26 weeks of age in mice, whereas V606M had no significant effect on left ventricular hypertrophy at that same time. Even when homozygous, the V606M mutation was insufficient to produce cardiac hypertrophy. However, when the V606M mutant mice were crossed with the R453C mutant mice, the dual heterozygous mutant progeny mice developed more hypertrophy than either of the parent mutant strains, demonstrating additive phenotypic effects of these 2 mutations. Functionally, these allelic combinations offer the potential for fresh molecular insight. The V606M mutation with its ability to modify actin binding is insufficient to produce HCM, even when homozygous (ie, in the absence of any normal MHC). However, altered actin binding plus reduced ATPase evoked significantly more hypertrophy, suggesting a disease model wherein the cardiac sarcomeres contain a mixture of myosin heads, some with different actin binding and others with reduced ATPase. These mixed mutations may or may not reflect a situation where each allele produces half the total MHC protein, because V606M and R719W may not be expressed at equal levels to the normal allele.10 It is also possible that some mutations may alter mRNA stability and splicing, provoking reduced expression of the mutant protein relative to normal MHC, thereby leading to less hypertrophy. This work demonstrates that a seemingly innocuous secondary mutation may, in some cases, evoke more severe HCM. As a caveat, an inbred murine genome and heart differ markedly from the human HCM condition. Nonetheless, the findings suggest that multiple mutations are likely to elicit a more severe phenotype. To translate this finding to the human condition requires estimating the frequency of MYH7 genetic variation in the population at large, including DNA variations not yet linked to HCM phenotypes. Where it has been studied, the frequency of potentially pathogenic MYH7 mutations in the general population is much higher than would be predicted from the prevalence of HCM.13,14 HCM occurs in ≈1 in 500 individuals, but DNA variants thought to predispose to HCM are present at 5- to 10-fold higher frequency. Taken together,
Figure. Schematic depiction of variable genetic and nongenetic influences on individual phenotype. Left, Different forms of secondary mutations. Right, Role of secondary mutations in context of other modifying influences.
these population-based estimates and the current findings in mice show how individual DNA variants that contribute little or nothing to cardiac phenotypes in otherwise normal individuals may lead to more severe disease in the context of a more pathogenic HCM mutation. Although these analyses focused on the MYH7 gene, the second genetic hit principle is certainly not restricted to this gene; functional significance of other sarcomere gene DNA variants is likely to be revealed in the context of a pathogenic MYH7 HCM mutation. For this reason, Blankenburg et al4 advocate more broad-based genetic screening to help identify those at highest risk for faster progression. A markedly increased potential for gene–gene interactions is one of the consequences of a human genetic landscape replete with mutations that are both rare and predicted to be damaging. If a given mutation is causal, other functionally significant DNA variants can almost certainly act as phenotypic modifiers. Depending on genetic context, DNA variants may therefore be categorized as primary or driver, associated, or comorbid mutations and may exhibit variable expression or reduced penetrance. This genetic reality not only provokes interindividual variability in phenotype but also blurs the distinction between monogenic, bigenic, and polygenic or complex inheritance. It is likely that the genetic component of phenotype can only be explained by the cumulative functional consequences of all coding and noncoding DNA sequence variants in the same gene, in other genes of the same pathway, and finally in all genes that impact the affected organ system (Figure). And, this approach still fails to incorporate epigenetic and environmental influences. Serious attempts at this type of systems-level genetic integration will need to be both comprehensive and unbiased. Accordingly, the initial discovery of a genetic disease might be accomplished using conventional genetic linkage of the suspected primary mutation in a relatively few affected subjects, but to understand fully how the spectrum of personal genotypes help determine individual phenotype will require identifying all genomic DNA variants in large cohorts of subjects presenting with the disease phenotype, regardless of primary mutation.
Acknowledgments This work was supported by National Institutes of Health grant U54 AR052646.
Downloaded from http://circres.ahajournals.org/ at CONS CALIFORNIA DIG LIB on September 2, 2014
210 Circulation Research July 7, 2014
Disclosures None.
References 1. Mendel G. Versuche über Pflanzen-Hybriden. Verh. Naturforsch. Ver. Brünn. 1866;4:3–47. 2. Lanktree MB, Guo Y, Murtaza M, et al.; Hugh Watkins on behalf of PROCARDIS; Meena Kumari on behalf of the Whitehall II Study and the WHII 50K Group. Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height. Am J Hum Genet. 2011;88:6–18. 3. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006. 4. Blankenburg R, Hackert K, Wurster S, Deenen R, Seidman JG, Seidman CE, Lohse MJ, Schmitt JP. β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations. Circ Res. 2014;115:227–237. 5. Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA. Clan genomics and the complex architecture of human disease. Cell. 2011;147:32–43. 6. Kiezun A, Garimella K, Do R, et al. Exome sequencing and the genetic basis of complex traits. Nat Genet. 2012;44:623–630. 7. Fu W, O’Connor TD, Jun G, Kang HM, Abecasis G, Leal SM, Gabriel S, Rieder MJ, Altshuler D, Shendure J, Nickerson DA, Bamshad MJ, Akey JM; NHLBI Exome Sequencing Project. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature. 2013;493:216–220.
8. Van Driest SL, Ackerman MJ, Ommen SR, Shakur R, Will ML, Nishimura RA, Tajik AJ, Gersh BJ. Prevalence and severity of “benign” mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy. Circulation. 2002;106:3085–3090. 9. Fisher AJ, Smith CA, Thoden J, Smith R, Sutoh K, Holden HM, Rayment I. Structural studies of myosin:nucleotide complexes: a revised model for the molecular basis of muscle contraction. Biophys J. 1995;68:19S–26S, discussion 27S. 10. Tripathi S, Schultz I, Becker E, Montag J, Borchert B, Francino A, Navarro-Lopez F, Perrot A, Özcelik C, Osterziel KJ, McKenna WJ, Brenner B, Kraft T. Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy. Basic Res Cardiol. 2011;106:1041–1055. 11. Sommese RF, Sung J, Nag S, Sutton S, Deacon JC, Choe E, Leinwand LA, Ruppel K, Spudich JA. Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function. Proc Natl Acad Sci U S A. 2013;110:12607–12612. 12. Seebohm B, Matinmehr F, Köhler J, Francino A, Navarro-Lopéz F, Perrot A, Ozcelik C, McKenna WJ, Brenner B, Kraft T. Cardiomyopathy mutations reveal variable region of myosin converter as major element of cross-bridge compliance. Biophys J. 2009;97:806–824. 13. Golbus JR, Puckelwartz MJ, Fahrenbach JP, Dellefave-Castillo LM, Wolfgeher D, McNally EM. Population-based variation in cardiomyopathy genes. Circ Cardiovasc Genet. 2012;5:391–399. 14. Pan S, Caleshu CA, Dunn KE, Foti MJ, Moran MK, Soyinka O, Ashley EA. Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation. Circ Cardiovasc Genet. 2012;5:602–610. Key Words: Editorials
■
genetics
■
models, animal
Downloaded from http://circres.ahajournals.org/ at CONS CALIFORNIA DIG LIB on September 2, 2014
