An Evolutionary Perspective on Epistasis and the Missing Heritability
The relative importance between additive and non-additive genetic variance has been widely argued in quantitative genetics. By approaching this question from an evolutionary perspective we show that, while additive variance can be maintained under selection at a low level for some patterns of epistasis, the majority of the genetic variance that will persist is actually non-additive. We propose that one reason that the problem of the “missing heritability” arises is because the additive genetic variation that is estimated to be contributing to the variance of a trait will most likely be an artefact of the non-additive variance that can be maintained over evolutionary time. In addition, it can be shown that even a small reduction in linkage disequilibrium between causal variants and observed SNPs rapidly erodes estimates of epistatic variance, leading to an inflation in the perceived importance of additive effects. We demonstrate that the perception of independent additive effects comprising the majority of the genetic architecture of complex traits is biased upwards and that the search for causal variants in complex traits under selection is potentially underpowered by parameterising for additive effects alone. Given dense SNP panels the detection of causal variants through genome-wide association studies may be improved by searching for epistatic effects explicitly.
Vyšlo v časopise:
An Evolutionary Perspective on Epistasis and the Missing Heritability. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003295
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1003295
Souhrn
The relative importance between additive and non-additive genetic variance has been widely argued in quantitative genetics. By approaching this question from an evolutionary perspective we show that, while additive variance can be maintained under selection at a low level for some patterns of epistasis, the majority of the genetic variance that will persist is actually non-additive. We propose that one reason that the problem of the “missing heritability” arises is because the additive genetic variation that is estimated to be contributing to the variance of a trait will most likely be an artefact of the non-additive variance that can be maintained over evolutionary time. In addition, it can be shown that even a small reduction in linkage disequilibrium between causal variants and observed SNPs rapidly erodes estimates of epistatic variance, leading to an inflation in the perceived importance of additive effects. We demonstrate that the perception of independent additive effects comprising the majority of the genetic architecture of complex traits is biased upwards and that the search for causal variants in complex traits under selection is potentially underpowered by parameterising for additive effects alone. Given dense SNP panels the detection of causal variants through genome-wide association studies may be improved by searching for epistatic effects explicitly.
Zdroje
1. Lynch M, Walsh B (1997) Genetics and analysis of quantitative traits. Sinauer Associates, Inc.
2. BradshawAD (1991) The Croonian Lecture, 1991. Genostasis and the limits to evolution. Philosophical transactions of the Royal Society of London Series B, Biological sciences 333: 289–305.
3. Williams GC (1992) Natural Selection: Domains, Levels, and Challenges. Oxford: Oxford University press.
4. HouleD (1992) Comparing evolvability and variability of quantitative traits. Genetics 130: 195–204.
5. Hansen T, Houle D (2004) Evolvability, stabilizing selection, and the problem of stasis. In: The evolutionary biology of complex phenotypes, Oxford University press. pp. 130–150.
6. HallM, LindholmA, BrooksR (2004) Direct selection on male attractiveness and female preference fails to produce a response. BMC Evolutionary Biology 4: 1–10.
7. McGuiganK, Van HomrighA, BlowsMW (2008) An evolutionary limit to male mating success. Evolution; international journal of organic evolution 62: 1528–37.
8. HansenTF, WagnerGP (2001) Epistasis and the Mutation Load: A Measurement-Theoretical Approach. Genetics 158: 477–485.
9. WalshB, BlowsMW (2009) Abundant Genetic Variation+Strong Selection = Multivariate Genetic Constraints: A Geometric View of Adaptation. Annual Review of Ecology, Evolution, and Systematics 40: 41–59.
10. Gould S (2002) The Structure of Evolutionary Theory. Cambridge, MA: Belknap Press, 880–885 pp.
11. Hindorff LA, Junkins HA, Hall PN, Mehta JP, Manolio TA (2010). A Catalog of Published Genome- Wide Association Studies, available at http://www.genome.gov/gwastudies. Accessed 12/10/2010.
12. MaherB (2008) The case of the missing heritability. Nature 456.
13. Eyre-WalkerA (2010) Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. Proceedings of the National Academy of Sciences of the United States of America 107 Suppl: 1752–6.
14. YangJ, BenyaminB, McEvoyBP, GordonS, HendersAK, et al. (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42: 565–569.
15. LandeR (1975) The maintenance of genetic variability by mutation in a polygenic character with linked loci. Genetical research 26: 221–235.
16. CrowJF (2010) On epistasis: why it is unimportant in polygenic directional selection. Philosophical transactions of the Royal Society of London Series B, Biological sciences 365: 1241–4.
17. CarlborgO, HaleyCS (2004) Epistasis: too often neglected in complex trait studies? Nature reviews Genetics 5: 618–25.
18. PhillipsPC (2008) Epistasis - the essential role of gene interactions in the structure and evolution of genetic systems. Nat Rev Genet 9: 855–867.
19. MooreJ (2003) The Ubiquitous Nature of Epistasis in Determining Susceptibility to Common Human Diseases. Human Heredity 56: 73–82.
20. WrightS (1931) Evolution in Mendelian Populations. Genetics 16: 97–159.
21. ManolioTA, CollinsFS, CoxNJ, GoldsteinDB, Hindor_LA, et al. (2009) Finding the missing heritability of complex diseases. Nature 461: 747–53.
22. FrazerKA, MurraySS, SchorkNJ, TopolEJ (2009) Human genetic variation and its contribution to complex traits. Nature reviews Genetics 10: 241–51.
23. EichlerEE, FlintJ, GibsonG, KongA, LealSM, et al. (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nature reviews Genetics 11: 446–50.
24. ZukO, HechterE, SunyaevSR, LanderES (2012) The mystery of missing heritability: Genetic interactions create phantom heritability. Proceedings of the National Academy of Sciences
25. VisscherPM, HillWG, WrayNR (2008) Heritability in the genomics era - concepts and misconceptions. Nature Reviews Genetics 9: 255–66.
26. MarchiniJ, DonnellyP, CardonLR (2005) Genome-wide strategies for detecting multiple loci that inuence complex diseases. Nat Genet 37: 413–417.
27. EvansDM, MarchiniJ, MorrisAP, CardonLR (2006) Two-Stage Two-Locus Models in Genome-Wide Association. PLoS Genet 2: e157 doi:10.1371/journal.pgen.0020157.
28. HillWG, GoddardME, VisscherPM (2008) Data and Theory Point to Mainly Additive Genetic Variance for Complex Traits. PLoS Genet 4: e1000008 doi:10.1371/journal.pgen.1000008.
29. GreeneCS, PenrodNM, WilliamsSM, MooreJH (2009) Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture. PLoS ONE 4: e5639 doi:10.1371/journal.pone.0005639.
30. EvansDM, GillespieNa, MartinNG (2002) Biometrical genetics. Biological psychology 61: 33–51.
31. ArnoldoA, CurakJ, KittanakomS, ChevelevI, LeeVT, et al. (2008) Identification of small molecule inhibitors of Pseudomonas aeruginosa exoenzyme S using a yeast phenotypic screen. PLoS Genet 4: e1000005 doi:10.1371/journal.pgen.1000005.
32. Waddington CH (1942). Canalization of development and the inheritance of acquired characteristics.
33. MaselJ, SiegalM (2009) Robustness: mechanisms and consequences. Trends in Genetics 25: 395–403.
34. BreenMS, KemenaC, VlasovPK, NotredameC, KondrashovFa (2012) Epistasis as the primary factor in molecular evolution. Nature 490: 535–538.
35. KacserH, BurnsJ (1973) The control of ux. Symp Soc Exp Biol 27: 65–104.
36. FrankelN, DavisGK, VargasD, WangS, PayreF, et al. (2010) Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466: 490–3.
37. SoylemezO, KondrashovFa (2012) Estimating the rate of irreversibility in protein evolution. Genome Biology and Evolution
38. StrangeA, CaponF, SpencerCCa, KnightJ, WealeME, et al. (2010) A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nature genetics 42: 985–90.
39. EvansDM, SpencerCCa, PointonJJ, SuZ, HarveyD, et al. (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature Genetics 43.
40. CarlborgO, JacobssonL, AhgrenP, SiegelP, AnderssonL (2006) Epistasis and the release of genetic variation during long-term selection. Nat Genet 38: 418–420.
41. RutherfordSL, LindquistS (1998) Hsp90 as a capacitor for morphological evolution. Nature 396: 336–342.
42. FraserHB, SchadtEE (2010) The quantitative genetics of phenotypic robustness. PLoS ONE 5: e8635 doi:10.1371/journal.pone.0008635.
43. QueitschC, SangsterTA, LindquistS (2002) Hsp90 as a capacitor of phenotypic variation. Nature 417: 618–624.
44. CulverhouseR, SuarezBK, LinJ, ReichT (2002) A perspective on epistasis: limits of models displaying no main effect. American journal of human genetics 70: 461–71.
45. KimuraM (1956) A Model of a Genetic System which Leads to Closer Linkage by Natural Selection. Evolution 10: 278–287.
46. WeirBS (2008) Linkage disequilibrium and association mapping. Annual review of genomics and human genetics 9: 129–42.
47. HemaniG, TheocharidisA, WeiW, HaleyC (2011) EpiGPU: exhaustive pairwise epistasis scans parallelized on consumer level graphics cards. Bioinformatics (Oxford, England) 27: 1462–5.
48. LiW, ReichJ (2000) A Complete Enumeration and Classification of Two-Locus Disease Models. Human Heredity 50: 334–349.
49. FisherR (1918) The correlation between relatives on the supposition of Mendelian inheritance. Transactions of the Royal Society of Edinburgh 52: 399–433.
50. WolpertD, MacreadyW (1997) No free lunch theorems for optimization. IEEE Transactions on Evolutionary Computation 1: 67–82.
51. ComingsDE, MacMurrayJP (2000) Molecular heterosis: a review. Molecular genetics and metabolism 71: 19–31.
52. LuoLJ, LiZK, MeiHW, ShuQY, TabienR, et al. (2001) Overdominant epistatic loci are the primary genetic basis of inbreeding depression and heterosis in rice. II. Grain yield components. Genetics 158: 1755–71.
53. MollR, LonnquistJ, FortunoJ, JohnsonE (1965) The relationship of heterosis and genetic divergence in maize. Genetics 52: 139.
54. ChenC, RainnieDG, GreeneRW, TonegawaS (1994) Abnormal fear response and aggressive behavior in mutant mice deficient for alpha-calcium-calmodulin kinase II. Science (New York, NY) 266: 291–4.
55. MiskiminsR, EbatoH, SeyfriedTN, YuRK (1986) Molecular basis for heterosis for myelin basic protein content in mice. Proceedings of the National Academy of Sciences of the United States of America 83: 1532–5.
56. Dobzhansky T (1970) Genetics of the Evolutionary Process. Columbia University Press.
57. KondrashovA (1994) Mullers ratchet under epistatic selection. Genetics 136: 1469.
58. ButcherD (1995) Mullers Ratchet, Epistasis and Mutation Effects. Genetics 141: 431.
59. HineE, McGuiganK, BlowsMW (2011) Natural selection stops the evolution of male attractiveness. Proceedings of the National Academy of Sciences of the United States of America 108: 3659–64.
60. CoronaE, DudleyJT, ButteAJ (2010) Extreme evolutionary disparities seen in positive selection across seven complex diseases. PLoS ONE 5: e12236 doi:10.1371/journal.pone.0012236.
61. FrankeA, McGovernDPB, BarrettJC, WangK, Radford-SmithGL, et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 42: 1118–25.
62. BradfieldJP, QuHQ, WangK, ZhangH, SleimanPM, et al. (2011) A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet 7: e1002293 doi:10.1371/journal.pgen.1002293.
63. WanX, YangC, YangQ, XueH, FanX, et al. (2010) BOOST: A Fast Approach to Detecting Gene- Gene Interactions in Genome-wide Case-Control Studies. American journal of human genetics 87: 325–340.
64. ZhangX, HuangS, ZouF, WangW (2010) TEAM: efficient two-locus epistasis tests in human genome-wide association study. Bioinformatics 26: i217–i227.
65. Kam-ThongT, CzamaraD, TsudaK, BorgwardtK, LewisCM, et al. (2010) EPIBLASTERfast exhaustive two-locus epistasis detection strategy using graphical processing units. European Journal of Human Genetics 19: 465–471.
66. HuX, LiuQ, ZhangZ, LiZ, WangS, et al. (2010) SHEsisEpi, a GPU-enhanced genome-wide SNP-SNP interaction scanning algorithm, efficiently reveals the risk genetic epistasis in bipolar disorder. Cell Research 20: 854–857.
67. LewontinR, KojimaK (1960) The Evolutionary Dynamics of Complex Polymorphisms. Evolution 14: 458–472.
68. Ewens WJ (2004) Mathematical Population Genetics. New York, New York, USA: Springer-Verlag, second edition.
69. KojimaK, KelleherT (1961) Changes of mean fitness in random mating populations when epistasis and linkage are present. Genetics 46: 527.
70. KimuraM (1965) Attainment of Quasi Linkage Equilibrium When Gene Frequencies Are Changing by Natural Selection. Genetics 52: 875–90.
71. Alvarez-CastroJMJM, CarlborgO (2007) A Unified Model for Functional and Statistical Epistasis and Its Application in Quantitative Trait Loci Analysis. Genetics 176: 1151–1167.
72. Holland J (1975) Adaptation in natural and artificial systems. Ann Arbor, MI: University of Michigan Press.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2013 Číslo 2
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Complex Inheritance of Melanoma and Pigmentation of Coat and Skin in Grey Horses
- Coordination of Chromatid Separation and Spindle Elongation by Antagonistic Activities of Mitotic and S-Phase CDKs
- Autophagy Induction Is a Tor- and Tp53-Independent Cell Survival Response in a Zebrafish Model of Disrupted Ribosome Biogenesis
- Assembly of the Auditory Circuitry by a Genetic Network in the Mouse Brainstem