1932

Abstract

Many traits of interest are highly heritable and genetically complex, meaning that much of the variation they exhibit arises from differences at numerous loci in the genome. Complex traits and their evolution have been studied for more than a century, but only in the last decade have genome-wide association studies (GWASs) in humans begun to reveal their genetic basis. Here, we bring these threads of research together to ask how findings from GWASs can further our understanding of the processes that give rise to heritable variation in complex traits and of the genetic basis of complex trait evolution in response to changing selection pressures (i.e., of polygenic adaptation). Conversely, we ask how evolutionary thinking helps us to interpret findings from GWASs and informs related efforts of practical importance.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-083115-022316
2019-08-31
2024-06-14
Loading full text...

Full text loading...

/deliver/fulltext/genom/20/1/annurev-genom-083115-022316.html?itemId=/content/journals/10.1146/annurev-genom-083115-022316&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Abouchar L, Petkova MD, Steinhardt CR, Gregor T 2014. Fly wing vein patterns have spatial reproducibility of a single cell. J. R. Soc. Interface 11:20140443
    [Google Scholar]
  2. 2.
    Agarwala V, Flannick J, Sunyaev S, GoT2D Consort., Altshuler D 2013. Evaluating empirical bounds on complex disease genetic architecture. Nat. Genet. 45:1418–27
    [Google Scholar]
  3. 3.
    Agrawal AF, Whitlock MC. 2011. Inferences about the distribution of dominance drawn from yeast gene knockout data. Genetics 187:553–66
    [Google Scholar]
  4. 4.
    Andreassen OA, Thompson WK, Schork AJ, Ripke S, Mattingsdal M et al. 2013. Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. PLOS Genet 9:e1003455
    [Google Scholar]
  5. 5.
    Backer LC, McNeel SV, Barber T, Kirkpatrick B, Williams C et al. 2010. Recreational exposure to microcystins during algal blooms in two California lakes. Toxicon 55:909–21
    [Google Scholar]
  6. 6.
    Barghi N, Tobler R, Nolte V, Jaksic AM, Mallard F et al. 2019. Genetic redundancy fuels polygenic adaptation in Drosophila. . PLOS Biol 17:e3000128
    [Google Scholar]
  7. 7.
    Barton NH. 1990. Pleiotropic models of quantitative variation. Genetics 124:773–82Reviews models where the focal trait is neutral, so that variation is shaped by selection on the pleiotropic side effects of alleles.
    [Google Scholar]
  8. 8.
    Barton NH. 2000. Genetic hitchhiking. Philos. Trans. R. Soc. B 355:1553–62
    [Google Scholar]
  9. 9.
    Barton NH, Etheridge AM, Veber A 2017. The infinitesimal model: definition, derivation, and implications. Theor. Popul. Biol. 118:50–73
    [Google Scholar]
  10. 10.
    Barton NH, Hermisson J, Nordborg M 2019. Population genetics: Why structure matters. eLife 8:e45380
    [Google Scholar]
  11. 11.
    Barton NH, Keightley PD. 2002. Understanding quantitative genetic variation. Nat. Rev. Genet. 3:11–21
    [Google Scholar]
  12. 12.
    Beauchamp JP. 2016. Genetic evidence for natural selection in humans in the contemporary United States. PNAS 113:7774–79
    [Google Scholar]
  13. 13.
    Berg JJ, Coop G. 2014. A population genetic signal of polygenic adaptation. PLOS Genet 10:e1004412
    [Google Scholar]
  14. 14.
    Berg JJ, Harpak A, Sinnott-Armstrong N, Joergensen AM, Mostafavi H et al. 2019. Reduced signal for polygenic adaptation of height in UK Biobank. eLife 8:e39725Shows that evidence for selection on polygenic traits (e.g., Refs. 13 and 45) mostly vanishes when using the more homogeneous UK Biobank data (see also Ref. 163).
    [Google Scholar]
  15. 15.
    Berg JJ, Zhang X, Coop G 2017. Polygenic adaptation has impacted multiple anthropometric traits. bioRxiv 167551. https://doi.org/10.1101/167551
    [Crossref]
  16. 16.
    Bourguet D. 1999. The evolution of dominance. Heredity 83:1–4
    [Google Scholar]
  17. 17.
    Boyle EA, Li YI, Pritchard JK 2017. An expanded view of complex traits: from polygenic to omnigenic. Cell 169:1177–86Argues that complex traits are influenced by essentially all expressed loci, via weak interactions that propagate through the regulatory network.
    [Google Scholar]
  18. 18.
    Bulik-Sullivan BK, Finucane HK, Anttila V, Gusev A, Day FR et al. 2015. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47:1236–41
    [Google Scholar]
  19. 19.
    Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J et al. 2015. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47:291–95
    [Google Scholar]
  20. 20.
    Bulmer MG. 1985. The Mathematical Theory of Quantitative Genetics Oxford, UK: Oxford Univ. Press
    [Google Scholar]
  21. 21.
    Burger R. 1991. Moments, cumulants, and polygenic dynamics. J. Math. Biol. 30:199–213
    [Google Scholar]
  22. 22.
    Burger R. 1999. Evolution of genetic variability and the advantage of sex and recombination in changing environments. Genetics 153:1055–69
    [Google Scholar]
  23. 23.
    Burke MK, Dunham JP, Shahrestani P, Thornton KR, Rose MR, Long AD 2010. Genome-wide analysis of a long-term evolution experiment with Drosophila. Nature 467:587–90
    [Google Scholar]
  24. 24.
    Caballero A, Tenesa A, Keightley PD 2015. The nature of genetic variation for complex traits revealed by GWAS and regional heritability mapping analyses. Genetics 201:1601–13
    [Google Scholar]
  25. 25.
    Castro JPL, Yancoskie MN, Marchini M, Belohlavy S, Hiramatsu L et al. 2019. An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice. eLife 8:e42014
    [Google Scholar]
  26. 26.
    Chakravarti A. 1999. Population genetics—making sense out of sequence. Nat. Genet. 21:56–60
    [Google Scholar]
  27. 27.
    Chakravarti A, Turner TN. 2016. Revealing rate-limiting steps in complex disease biology: the crucial importance of studying rare, extreme-phenotype families. BioEssays 38:578–86
    [Google Scholar]
  28. 28.
    Charlesworth B. 1979. Evidence against Fisher's theory of dominance. Nature 278:848–49
    [Google Scholar]
  29. 29.
    Charlesworth B. 1993. Directional selection and the evolution of sex and recombination. Genet. Res. 61:205–24
    [Google Scholar]
  30. 30.
    Charlesworth B. 2015. Causes of natural variation in fitness: evidence from studies of Drosophila populations. PNAS 112:1662–69
    [Google Scholar]
  31. 31.
    Charlesworth B, Charlesworth D. 2010. Elements of Evolutionary Genetics Greenwood Village, CO: Roberts & Co.
    [Google Scholar]
  32. 32.
    Charmantier A, Garant D, Kruuk LEB 2014. Quantitative Genetics in the Wild Oxford, UK: Oxford Univ. Press
    [Google Scholar]
  33. 33.
    Coop G, Pickrell JK, Novembre J, Kudaravalli S, Li J et al. 2009. The role of geography in human adaptation. PLOS Genet 5:e1000500
    [Google Scholar]
  34. 34.
    Cotsapas C, Voight BF, Rossin E, Lage K, Neale BM et al. 2011. Pervasive sharing of genetic effects in autoimmune disease. PLOS Genet 7:e1002254
    [Google Scholar]
  35. 35.
    Coventry A, Bull-Otterson LM, Liu X, Clark AG, Maxwell TJ et al. 2010. Deep resequencing reveals excess rare recent variants consistent with explosive population growth. Nat. Commun. 1:131
    [Google Scholar]
  36. 36.
    Crawford NG, Kelly DE, Hansen MEB, Beltrame MH, Fan S et al. 2017. Loci associated with skin pigmentation identified in African populations. Science 358:867–87
    [Google Scholar]
  37. 37.
    de Vladar HP, Barton NH 2014. Stability and response of polygenic traits to stabilizing selection and mutation. Genetics 197:749–67
    [Google Scholar]
  38. 38.
    Di Rienzo A, Hudson RR 2005. An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet 21:596–601
    [Google Scholar]
  39. 39.
    Edge MD, Coop G. 2019. Reconstructing the history of polygenic scores using coalescent trees. Genetics 211:235–62
    [Google Scholar]
  40. 40.
    Ejsmond MJ, Radwan J. 2015. Red Queen processes drive positive selection on major histocompatibility complex (MHC) genes. PLOS Comput. Biol. 11:e1004627
    [Google Scholar]
  41. 41.
    Ewens WJ. 2004. Mathematical Population Genetics New York: Springer
    [Google Scholar]
  42. 42.
    Eyre-Walker A. 2010. Evolution in health and medicine Sackler colloquium: genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. PNAS 107:Suppl. 11752–56
    [Google Scholar]
  43. 43.
    Falconer DS, Mackay TFC. 1996. Introduction to Quantitative Genetics Harlow, UK: Longman
    [Google Scholar]
  44. 44.
    Felsenstein J. 1988. Phylogenies and quantitative characters. Annu. Rev. Ecol. Syst. 19:445–71
    [Google Scholar]
  45. 45.
    Field Y, Boyle EA, Telis N, Gao Z, Gaulton KJ et al. 2016. Detection of human adaptation during the past 2000 years. Science 354:760–64
    [Google Scholar]
  46. 46.
    Fisher RA. 1918. The correlation between relatives on the supposition of Mendelian inheritance. Trans. R. Soc. Edinb. 52:399–433Reconciled Mendelian genetics with biometry and introduced analysis of trait variance into its components (environmental, additive genetic, dominance, etc.).
    [Google Scholar]
  47. 47.
    Fisher RA. 1930. The Genetical Theory of Natural Selection Oxford, UK: Clarendon
    [Google Scholar]
  48. 48.
    Fraïsse C, Gunnarsson PA, Roze D, Bierne N, Welch JJ 2016. The genetics of speciation: insights from Fisher's geometric model. Evolution 70:1450–64
    [Google Scholar]
  49. 49.
    Fraser HB. 2013. Gene expression drives local adaptation in humans. Genome Res 23:1089–96
    [Google Scholar]
  50. 50.
    Galton F. 1877. Typical laws of heredity. Nature 15:492–95 512–14, 532–33 First statement of what became known as the infinitesimal model, where the breeding values of offspring are normally distributed around the mean of the parents.
    [Google Scholar]
  51. 51.
    Gillespie JH. 1991. The Causes of Molecular Evolution Oxford, UK: Oxford Univ. Press
    [Google Scholar]
  52. 52.
    Gillespie JH. 2004. Population Genetics: A Concise Guide Baltimore, MD: Johns Hopkins Univ. Press
    [Google Scholar]
  53. 53.
    Gingerich PD. 1983. Rates of evolution: effects of time and temporal scaling. Science 222:159–61
    [Google Scholar]
  54. 54.
    Grant PR, Grant BR. 2014. 40 Years of Evolution: Darwin's Finches on Daphne Major Island Princeton, NJ: Princeton Univ. Press
    [Google Scholar]
  55. 55.
    Green RE, Krause J, Briggs AW, Maricic T, Stenzel U et al. 2010. A draft sequence of the Neandertal genome. Science 328:710–22
    [Google Scholar]
  56. 56.
    Greenberg R, Crow JF. 1960. A comparison of the effect of lethal and detrimental chromosomes from Drosophila populations. Genetics 45:1153–68
    [Google Scholar]
  57. 57.
    Haldane JBS. 1927. A mathematical theory of natural and artificial selection, part V: selection and mutation. Proc. Camb. Philos. Soc. 23:838–44Showed how deleterious alleles can be maintained by a balance between mutation and selection.
    [Google Scholar]
  58. 58.
    Halligan DL, Keightley PD. 2009. Spontaneous mutation accumulation studies in evolutionary genetics. Annu. Rev. Ecol. Evol. Syst. 40:151–72
    [Google Scholar]
  59. 59.
    Havenstein G, Ferket P, Qureshi M 2003. Growth, livability, and feed conversion of 1957 versus 2001 broilers when fed representative 1957 and 2001 broiler diets. Poult. Sci. 82:1500–8
    [Google Scholar]
  60. 60.
    Hayward L, Sella G. 2019. Polygenic adaptation after a sudden change in environment. Manuscript in preparation
  61. 61.
    Hedrick PW, Whittam TS, Parham P 1991. Heterozygosity at individual amino acid sites: extremely high levels for HLA-A and -B genes. PNAS 88:5897–901
    [Google Scholar]
  62. 62.
    Hellenthal G, Busby GB, Band G, Wilson JF, Capelli C et al. 2014. A genetic atlas of human admixture history. Science 343:747–51
    [Google Scholar]
  63. 63.
    Hernandez RD, Kelley JL, Elyashiv E, Melton SC, Auton A et al. 2011. Classic selective sweeps were rare in recent human evolution. Science 331:920–24
    [Google Scholar]
  64. 64.
    Hill WG. 1982. Rates of change in quantitative traits from fixation of new mutations. PNAS 79:142–45Showed that mutation contributes substantially to genetic variance, consistent with a highly polygenic architecture.
    [Google Scholar]
  65. 65.
    Hill WG. 2014. Applications of population genetics to animal breeding, from Wright, Fisher and Lush to genomic prediction. Genetics 196:1–16
    [Google Scholar]
  66. 66.
    Hill WG. 2016. Is continued genetic improvement of livestock sustainable?. Genetics 202:877–81
    [Google Scholar]
  67. 67.
    Hill WG, Goddard ME, Visscher PM 2008. Data and theory point to mainly additive genetic variance for complex traits. PLOS Genet 4:e1000008
    [Google Scholar]
  68. 68.
    Hill WG, Kirkpatrick M. 2010. What animal breeding has taught us about evolution. Annu. Rev. Ecol. Evol. Syst. 41:1–19
    [Google Scholar]
  69. 69.
    Hill WG, Rasbash J. 1986. Models of long term artificial selection in finite population. Genet. Res. 48:41–50
    [Google Scholar]
  70. 70.
    Hou K, Burch KS, Majumdar A, Shi A, Mancuso N et al. 2019. Accurate estimation of SNP-heritability from biobank-scale data irrespective of genetic architecture. bioRxiv 526855 https://doi.org/10.1101/526855
    [Crossref]
  71. 71.
    Houle D, Bolstad GH, van der Linde K, Hansen TF 2017. Mutation predicts 40 million years of fly wing evolution. Nature 548:447–50
    [Google Scholar]
  72. 72.
    Houle D, Morikawa B, Lynch M 1996. Comparing mutational variabilities. Genetics 143:1467–83
    [Google Scholar]
  73. 73.
    Huang W, Richards S, Carbone MA, Zhu D, Anholt RRH et al. 2012. Epistasis dominates the genetic architecture of Drosophila quantitative traits. PNAS 109:15553–59
    [Google Scholar]
  74. 74.
    Huguet G, Ey E, Bourgeron T 2013. The genetic landscapes of autism spectrum disorders. Annu. Rev. Genom. Hum. Genet. 14:191–213
    [Google Scholar]
  75. 75.
    Jain K, Stephan W. 2017. Rapid adaptation of a polygenic trait after a sudden environmental shift. Genetics 206:389–406
    [Google Scholar]
  76. 76.
    Johnson T, Barton NH. 2005. Theoretical models of selection and mutation on quantitative traits. Philos. Trans. R. Soc. B 360:1411–25
    [Google Scholar]
  77. 77.
    Jones FC, Grabherr MG, Chan YF, Russell P, Mauceli E et al. 2012. The genomic basis of adaptive evolution in threespine sticklebacks. Nature 484:55–61
    [Google Scholar]
  78. 78.
    Kaplan NL, Hudson RR, Langley CH 1989. The “hitchhiking effect” revisited. Genetics 123:887–99
    [Google Scholar]
  79. 79.
    Keightley PD, Hill WG. 1988. Quantitative genetic variability maintained by mutation-stabilizing selection balance in finite populations. Genet. Res. 52:33–43
    [Google Scholar]
  80. 80.
    Keightley PD, Hill WG. 1990. Variation maintained in quantitative traits with mutation–selection balance: pleiotropic side-effects on fitness traits. Proc. R. Soc. B 242: 19900110
    [Google Scholar]
  81. 81.
    Kelly JK, Hughes KA. 2019. An examination of the evolve-and-resequence method using Drosophila simulani. . Genetics 211:943–61
    [Google Scholar]
  82. 82.
    Kiezun A, Pulit SL, Francioli LC, van Dijk F, Swertz M et al. 2013. Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency. PLOS Genet 9:e1003301
    [Google Scholar]
  83. 83.
    Kimura M. 1965. A stochastic model concerning the maintenance of genetic variability in quantitative characters. PNAS 54:731–36
    [Google Scholar]
  84. 84.
    Kingsolver JG, Hoekstra HE, Hoekstra JM, Berrigan D, Vignieri SN et al. 2001. The strength of phenotypic selection in natural populations. Am. Nat 157245–61Reviews the many estimates of selection in nature made using the Pearson–Lande–Arnold method.
    [Google Scholar]
  85. 85.
    Kinnison MT, Hendry AP. 2001. The pace of modern life II: from rates of contemporary microevolution to pattern and process. Genetica 112–113:145–64
    [Google Scholar]
  86. 86.
    Kirkpatrick M, Barton NH. 2006. Chromosome inversions, local adaptation and speciation. Genetics 173:419–34
    [Google Scholar]
  87. 87.
    Kondrashov AS, Turelli M. 1992. Deleterious mutations, apparent stabilizing selection and the maintenance of quantitative variation. Genetics 132:603–18
    [Google Scholar]
  88. 88.
    Kong A, Frigge ML, Thorleifsson G, Stefansson H, Young AI et al. 2017. Selection against variants in the genome associated with educational attainment. PNAS 114:E727–32
    [Google Scholar]
  89. 89.
    Kopp M, Hermisson J. 2007. Adaptation of a quantitative trait to a moving optimum. Genetics 176:715–19
    [Google Scholar]
  90. 90.
    Kopp M, Hermisson J. 2009. The genetic basis of phenotypic adaptation I: fixation of beneficial mutations in the moving optimum model. Genetics 182:233–49
    [Google Scholar]
  91. 91.
    Kruuk EB, Slate J, Pemberton JM, Brotherstone S, Guinness F, Clutton-Brock T 2002. Antler size in red deer: heritability and selection but no evolution. Evolution 56:1683–95
    [Google Scholar]
  92. 92.
    Lande R. 1975. The maintenance of genetic variability by mutation in a polygenic character with linked loci. Genet. Res. 26:221–35
    [Google Scholar]
  93. 93.
    Lande R. 1976. Natural-selection and random genetic drift in phenotypic evolution. Evolution 30:314–34
    [Google Scholar]
  94. 94.
    Lande R, Arnold SJ. 1983. The measurement of selection on correlated characters. Evolution 371210–26Revived and extended Pearson's methods for estimating selection on multiple traits.
    [Google Scholar]
  95. 95.
    Lee SH, Yang J, Goddard ME, Visscher PM, Wray NR 2012. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood. Bioinformatics 28:2540–42
    [Google Scholar]
  96. 96.
    Lello L, Avery SG, Tellier L, Vazquez AI, de Los Campos G, Hsu SDH 2018. Accurate genomic prediction of human height. Genetics 210:477–97
    [Google Scholar]
  97. 97.
    Lenz TL, Spirin V, Jordan DM, Sunyaev SR 2016. Excess of deleterious mutations around HLA genes reveals evolutionary cost of balancing selection. Mol. Biol. Evol. 33:2555–64
    [Google Scholar]
  98. 98.
    Lewontin RC. 2000. The Triple Helix: Gene, Organism, and Environment Cambridge, MA: Harvard Univ. Press
    [Google Scholar]
  99. 99.
    Li Y, Huang Y, Bergelson J, Nordborg M, Borevitz JO 2010. Association mapping of local climate-sensitive quantitative trait loci in Arabidopsis thaliana. . PNAS 107:21199–204
    [Google Scholar]
  100. 100.
    Liu X, Li YI, Pritchard JK 2019. Trans effects on gene expression can drive omnigenic inheritance. Cell 177:1022–34.e6
    [Google Scholar]
  101. 101.
    Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH et al. 2015. Genetic studies of body mass index yield new insights for obesity biology. Nature 518:197–206
    [Google Scholar]
  102. 102.
    Loh PR, Bhatia G, Gusev A, Finucane HK, Bulik-Sullivan BK et al. 2015. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis. Nat. Genet. 47:1385–92
    [Google Scholar]
  103. 103.
    Lohmueller KE. 2014. The impact of population demography and selection on the genetic architecture of complex traits. PLOS Genet 10:e1004379
    [Google Scholar]
  104. 104.
    Lush JL. 1937. Animal Breeding Plans Ames, IA: Coll. Press
    [Google Scholar]
  105. 105.
    Lynch M, Hill WG. 1986. Phenotypic evolution by neutral mutation. Evolution 40:915–35
    [Google Scholar]
  106. 106.
    Lynch M, Walsh B. 1998. Genetics and Analysis of Quantitative Traits Sunderland, MA: Sinauer
    [Google Scholar]
  107. 107.
    Maki-Tanila A, Hill WG. 2014. Influence of gene interaction on complex trait variation with multilocus models. Genetics 198:355–67
    [Google Scholar]
  108. 108.
    Mancuso N, Rohland N, Rand KA, Tandon A, Allen A et al. 2016. The contribution of rare variation to prostate cancer heritability. Nat. Genet. 48:30–35
    [Google Scholar]
  109. 109.
    Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA et al. 2009. Finding the missing heritability of complex diseases. Nature 461:747–53
    [Google Scholar]
  110. 110.
    Martin G, Lenormand T. 2006. A general multivariate extension of Fisher's geometrical model and the distribution of mutation fitness effects across species. Evolution 60:893–907
    [Google Scholar]
  111. 111.
    Mathieson I, Lazaridis I, Rohland N, Mallick S, Patterson N et al. 2015. Genome-wide patterns of selection in 230 ancient Eurasians. Nature 528:499–503
    [Google Scholar]
  112. 112.
    Matuszewski S, Hermisson J, Kopp M 2014. Fisher's geometric model with a moving optimum. Evolution 68:2571–88
    [Google Scholar]
  113. 113.
    Matuszewski S, Hermisson J, Kopp M 2015. Catch me if you can: adaptation from standing genetic variation to a moving phenotypic optimum. Genetics 200:1255–74
    [Google Scholar]
  114. 114.
    Maynard Smith JM, Haigh J 1974. The hitch-hiking effect of a favourable gene. Genet. Res. 23:23–35
    [Google Scholar]
  115. 115.
    McGuigan K, Aguirre JD, Blows MW 2015. Simultaneous estimation of additive and mutational genetic variance in an outbred population of Drosophila serrata. . Genetics 201:1239–51
    [Google Scholar]
  116. 116.
    Mitchell KJ. 2012. What is complex about complex disorders?. Genome Biol 13:237
    [Google Scholar]
  117. 117.
    Moose SP, Dudley JW, Rocheford TR 2004. Maize selection passes the century mark: a unique resource for 21st century genomics. Trends Plant Sci 9:358–64
    [Google Scholar]
  118. 118.
    Mostafavi H, Berisa T, Day FR, Perry JRB, Przeworski M, Pickrell JK 2017. Identifying genetic variants that affect viability in large cohorts. PLOS Biol 15:e2002458
    [Google Scholar]
  119. 119.
    Mousseau TA, Roff DA. 1987. Natural selection and the heritability of fitness components. Heredity 59:Part 2181–97
    [Google Scholar]
  120. 120.
    Nielsen R, Williamson S, Kim Y, Hubisz MJ, Clark AG, Bustamante C 2005. Genomic scans for selective sweeps using SNP data. Genome Res 15:1566–75
    [Google Scholar]
  121. 121.
    Novembre J, Barton NH. 2018. Tread lightly interpreting polygenic tests of selection. Genetics 208:1351–55
    [Google Scholar]
  122. 122.
    O'Connor LJ, Schoech AP, Hormozdiari F, Gazal S, Patterson N, Price AL 2018. Polygenicity of complex traits is explained by negative selection. bioRxiv 420497. https://doi.org/10.1101/420497
    [Crossref]
  123. 123.
    Orr HA. 1998. Testing natural selection versus genetic drift in phenotypic evolution using quantitative trait locus data. Genetics 149:2099–104
    [Google Scholar]
  124. 124.
    Ovaskainen O, Karhunen M, Zheng C, Arias JM, Merila J 2011. A new method to uncover signatures of divergent and stabilizing selection in quantitative traits. Genetics 189:621–32
    [Google Scholar]
  125. 125.
    Pearson K. 1903. I. Mathematical contributions to the theory of evolution.—XI. On the influence of natural selection on the variability and correlation of organs. Philos. Trans. R. Soc. A 200:1–66
    [Google Scholar]
  126. 126.
    Perry JRB, Day F, Elks CE, Sulem P, Thompson DJ et al. 2014. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 514:92–97
    [Google Scholar]
  127. 127.
    Phadnis N, Fry JD. 2005. Widespread correlations between dominance and homozygous effects of mutations: implications for theories of dominance. Genetics 171:385–92
    [Google Scholar]
  128. 128.
    Pickrell JK, Berisa T, Liu JZ, Segurel L, Tung JY, Hinds DA 2016. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48:709–17
    [Google Scholar]
  129. 129.
    Pickrell JK, Reich D. 2014. Toward a new history and geography of human genes informed by ancient DNA. Trends Genet 30:377–89
    [Google Scholar]
  130. 130.
    Polderman TJC, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A et al. 2015. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat. Genet. 47:702–9
    [Google Scholar]
  131. 131.
    Price GR. 1970. Selection and covariance. Nature 227:520–21
    [Google Scholar]
  132. 132.
    Price TD, Grant PR, Gibbs HL, Boag PT 1984. Recurrent patterns of natural selection in a population of Darwin's finches. Nature 309:787–89
    [Google Scholar]
  133. 133.
    Pritchard JK. 2001. Are rare variants responsible for susceptibility to complex diseases. ? Am. J. Hum. Genet. 69:124–37
    [Google Scholar]
  134. 134.
    Pritchard JK, Di Rienzo A 2010. Adaptation – not by sweeps alone. Nat. Rev. Genet. 11:665–67
    [Google Scholar]
  135. 135.
    Pritchard JK, Pickrell JK, Coop G 2010. The genetics of human adaptation: hard sweeps, soft sweeps, and polygenic adaptation. Curr. Biol. 20:R208–15
    [Google Scholar]
  136. 136.
    Racimo F, Berg JJ, Pickrell JK 2018. Detecting polygenic adaptation in admixture graphs. Genetics 208:1565–84
    [Google Scholar]
  137. 137.
    Rands CM, Meader S, Ponting CP, Lunter G 2014. 8.2% of the human genome is constrained: variation in rates of turnover across functional element classes in the human lineage. PLOS Genet 10:e1004525
    [Google Scholar]
  138. 138.
    Reich DE, Lander ES. 2001. On the allelic spectrum of human disease. Trends Genet 17:502–10
    [Google Scholar]
  139. 139.
    Risch N. 1990. Linkage strategies for genetically complex traits. I. Multilocus models. Am. J. Hum. Genet. 46:222–28
    [Google Scholar]
  140. 140.
    Risch N, Merikangas K. 1996. The future of genetic studies of complex human diseases. Science 273:1516–17
    [Google Scholar]
  141. 141.
    Robertson A. 1956. The effect of selection against extreme deviants based on deviation or on homozygosis. J. Genet. 54:236–48
    [Google Scholar]
  142. 142.
    Robertson A. 1960. A theory of limits in artificial selection. Proc. R. Soc. B 153:234–49
    [Google Scholar]
  143. 143.
    Robertson A. 1966. A mathematical model of the culling process in dairy cattle. Anim. Sci. 8:95–108
    [Google Scholar]
  144. 144.
    Robinson MR, Hemani G, Medina-Gomez C, Mezzavilla M, Esko T et al. 2015. Population genetic differentiation of height and body mass index across Europe. Nat. Genet. 47:1357–62
    [Google Scholar]
  145. 145.
    Roff DA. 1996. The evolution of genetic correlations: an analysis of patterns. Evolution 50:1392–403
    [Google Scholar]
  146. 146.
    Sabeti PC, Reich DE, Higgins JM, Levine HZP, Richter DJ et al. 2002. Detecting recent positive selection in the human genome from haplotype structure. Nature 419:832–37
    [Google Scholar]
  147. 147.
    Sanjak JS, Sidorenko J, Robinson MR, Thornton KR, Visscher PM 2018. Evidence of directional and stabilizing selection in contemporary humans. PNAS 115:151–56
    [Google Scholar]
  148. 148.
    Schaid DJ, Chen W, Larson NB 2018. From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat. Rev. Genet. 19:491–504
    [Google Scholar]
  149. 149.
    Schiffels S, Durbin R. 2014. Inferring human population size and separation history from multiple genome sequences. Nat. Genet. 46:919–25
    [Google Scholar]
  150. 150.
    Schiffman JS, Ralph PL. 2018. System drift and speciation. bioRxiv 231209. https://doi.org/10.1101/231209
    [Crossref]
  151. 151.
    Schoech AP, Jordan DM, Loh P-R, Gazal S, O'Connor LJ et al. 2019. Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection. Nat. Commun. 10:790
    [Google Scholar]
  152. 152.
    Scott RA, Lagou V, Welch RP, Wheeler E, Montasser ME et al. 2012. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat. Genet. 44:991–1005
    [Google Scholar]
  153. 153.
    Segre D, Deluna A, Church GM, Kishony R 2005. Modular epistasis in yeast metabolism. Nat. Genet. 37:77–83
    [Google Scholar]
  154. 154.
    Sham PC, Purcell SM. 2014. Statistical power and significance testing in large-scale genetic studies. Nat. Rev. Genet. 15:335–46
    [Google Scholar]
  155. 155.
    Shi H, Kichaev G, Pasaniuc B 2016. Contrasting the genetic architecture of 30 complex traits from summary association data. Am. J. Hum. Genet. 99:139–53
    [Google Scholar]
  156. 156.
    Simon A, Bierne N, Welch JJ 2018. Coadapted genomes and selection on hybrids: Fisher's geometric model explains a variety of empirical patterns. Evol. Lett. 2:472–98
    [Google Scholar]
  157. 157.
    Simons YB, Bullaughey K, Hudson RR, Sella G 2018. A population genetic interpretation of GWAS findings for human quantitative traits. PLOS Biol 16:e2002985Models stabilizing selection on multiple traits to show that the distribution of the contributions of a SNP to trait variance takes a characteristic form.
    [Google Scholar]
  158. 158.
    Simons YB, Stella G. 2016. The impact of recent population history on the deleterious mutation load in humans and close evolutionary relatives. Curr. Opin. Genet. Dev. 41:150–58
    [Google Scholar]
  159. 159.
    Simons YB, Turchin MC, Pritchard JK, Sella G 2014. The deleterious mutation load is insensitive to recent population history. Nat. Genet. 46:220–24
    [Google Scholar]
  160. 160.
    Sivakumaran S, Agakov F, Theodoratou E, Prendergast JG, Zgaga L et al. 2011. Abundant pleiotropy in human complex diseases and traits. Am. J. Hum. Genet. 89:607–18
    [Google Scholar]
  161. 161.
    Slatkin M. 2008. Exchangeable models of complex inherited diseases. Genetics 179:2253–61
    [Google Scholar]
  162. 162.
    Sniegowski PD, Gerrish PJ, Johnson T, Shaver A 2000. The evolution of mutation rates: separating causes from consequences. BioEssays 22:1057–66
    [Google Scholar]
  163. 163.
    Sohail M, Maier RM, Ganna A, Bloemendal A, Martin AR et al. 2019. Polygenic adaptation on height is overestimated due to uncorrected stratification in genome-wide association studies. eLife 8:e39702Shows that evidence for selection on polygenic traits (e.g., Refs. 13 and 45) mostly vanishes when using the more homogeneous UK Biobank data (see also Ref. 14).
    [Google Scholar]
  164. 164.
    Solovieff N, Cotsapas C, Lee PH, Purcell SM, Smoller JW 2013. Pleiotropy in complex traits: challenges and strategies. Nat. Rev. Genet. 14:483–95
    [Google Scholar]
  165. 165.
    Speed D, Hemani G, Johnson MR, Balding DJ 2012. Improved heritability estimation from genome-wide SNPs. Am. J. Hum. Genet. 91:1011–21
    [Google Scholar]
  166. 166.
    Speidel L, Forest M, Shi S, Myers S 2019. A method for genome-wide genealogy estimation for thousands of samples. bioRxiv 550558. https://doi.org/10.1101/550558
    [Crossref]
  167. 167.
    Spurgin LG, Richardson DS. 2010. How pathogens drive genetic diversity: MHC, mechanisms and misunderstandings. Proc. R. Soc. B 277:979–88
    [Google Scholar]
  168. 168.
    Sudlow C, Gallacher J, Allen N, Beral V, Burton P et al. 2015. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLOS Med 12:e1001779
    [Google Scholar]
  169. 169.
    Thornton KR. 2018. Polygenic adaptation to an environmental shift: temporal dynamics of variation under Gaussian stabilizing selection and additive effects on a single trait. bioRxiv 505750. https://doi.org/10.1101/505750
    [Crossref]
  170. 170.
    Tobler R, Franssen SU, Kofler R, Orozco-terWengel P, Nolte V et al. 2014. Massive habitat-specific genomic response in D. melanogaster populations during experimental evolution in hot and cold environments. Mol. Biol. Evol. 31:364–75
    [Google Scholar]
  171. 171.
    Trowsdale J. 2011. The MHC, disease and selection. Immunol. Lett. 137:1–8
    [Google Scholar]
  172. 172.
    Trowsdale J, Knight JC. 2013. Major histocompatibility complex genomics and human disease. Annu. Rev. Genom. Hum. Genet. 14:301–23
    [Google Scholar]
  173. 173.
    Turchin MC, Chiang CW, Palmer CD, Sankararaman S, Reich D et al. 2012. Evidence of widespread selection on standing variation in Europe at height-associated SNPs. Nat. Genet. 44:1015–19
    [Google Scholar]
  174. 174.
    Turelli M. 1984. Heritable genetic variation via mutation-selection balance: Lerch's zeta meets the abdominal bristle. Theor. Popul. Biol. 25:138–93Reviews evidence that variation is maintained by a mutation–selection balance and argues (contra Ref. 93) that rare alleles are responsible.
    [Google Scholar]
  175. 175.
    Turelli M, Barton NH. 1990. Dynamics of polygenic characters under selection. Theor. Popul. Biol. 38:1–57
    [Google Scholar]
  176. 176.
    Turner TL, Stewart AD, Fields AT, Rice WR, Tarone AM 2011. Population-based resequencing of experimentally evolved populations reveals the genetic basis of body size variation in Drosophila melanogaster. . PLOS Genet 7:e1001336
    [Google Scholar]
  177. 177.
    Visscher PM, Brown MA, McCarthy MI, Yang J 2012. Five years of GWAS discovery. Am. J. Hum. Genet. 90:7–24
    [Google Scholar]
  178. 178.
    Visscher PM, Hill WG, Wray NR 2008. Heritability in the genomics era—concepts and misconceptions. Nat. Rev. Genet. 9:255–66
    [Google Scholar]
  179. 179.
    Voight BF, Kudaravalli S, Wen X, Pritchard JK 2006. A map of recent positive selection in the human genome. PLOS Biol 4:e72
    [Google Scholar]
  180. 180.
    Wagner GP, Zhang J. 2011. The pleiotropic structure of the genotype-phenotype map: the evolvability of complex organisms. Nat. Rev. Genet. 12:204–13
    [Google Scholar]
  181. 181.
    Wall JD, Przeworski M. 2000. When did the human population size start increasing?. Genetics 155:1865–74
    [Google Scholar]
  182. 182.
    Walsh B, Lynch M. 2018. Evolution and Selection of Quantitative Traits Oxford, UK: Oxford Univ. Press
    [Google Scholar]
  183. 183.
    Weber KE. 1990. Selection on wing allometry in Drosophila melanogaster. . Genetics 126:975–89
    [Google Scholar]
  184. 184.
    Weber KE. 1996. Large genetic change at small fitness cost in large populations of Drosophila melanogaster selected for wind tunnel flight: rethinking fitness surfaces. Genetics 144:205–13
    [Google Scholar]
  185. 185.
    Weber KE, Diggins LT. 1990. Increased selection response in larger populations. II. Selection for ethanol vapor resistance in Drosophila melanogaster at two population sizes. Genetics 125:585–97
    [Google Scholar]
  186. 186.
    Weber KE, Eisman R, Morey L, Patty A, Sparks J et al. 1999. An analysis of polygenes affecting wing shape on chromosome 3 in Drosophila melanogaster. . Genetics 153:773–86
    [Google Scholar]
  187. 187.
    Wei WH, Hemani G, Haley CS 2014. Detecting epistasis in human complex traits. Nat. Rev. Genet. 15:722–33
    [Google Scholar]
  188. 188.
    Wellcome Trust Case Control Consort 2007. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–78
    [Google Scholar]
  189. 189.
    Wood AR, Esko T, Yang J, Vedantam S, Pers TH et al. 2014. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46:1173–86
    [Google Scholar]
  190. 190.
    Wray NR, Goddard ME. 2010. Multi-locus models of genetic risk of disease. Genome Med 2:10
    [Google Scholar]
  191. 191.
    Wright S. 1929. Fisher's theory of dominance. Am. Nat. 63:274–79
    [Google Scholar]
  192. 192.
    Wright S. 1931. Evolution in Mendelian populations. Genetics 16:97–159
    [Google Scholar]
  193. 193.
    Wright S. 1931. On the genetics of number of digits of the guinea pig. Anat. Rec. 51:115
    [Google Scholar]
  194. 194.
    Wright S. 1935. The analysis of variance and the correlations between relatives with respect to deviations from an optimum. J. Genet. 30:243–56
    [Google Scholar]
  195. 195.
    Wright S. 1937. The distribution of gene frequencies in populations. PNAS 23:307–20
    [Google Scholar]
  196. 196.
    Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK et al. 2010. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42:565–69
    [Google Scholar]
  197. 197.
    Yeaman S. 2013. Genomic rearrangements and the evolution of clusters of locally adaptive loci. PNAS 110:E1743–51
    [Google Scholar]
  198. 198.
    Yeaman S, Otto SP. 2011. Establishment and maintenance of adaptive genetic divergence under migration, selection, and drift. Evolution 65:2123–29
    [Google Scholar]
  199. 199.
    Yeaman S, Whitlock MC. 2011. The genetic architecture of adaptation under migration-selection balance. Evolution 65:1897–911
    [Google Scholar]
  200. 200.
    Yoo BH. 1980. Long-term selection for a quantitative character in large replicate populations of Drosophila melanogaster: 1. Response to selection. Genet. Res. 35:1–17
    [Google Scholar]
  201. 201.
    Young AI, Frigge ML, Gudbjartsson DF, Thorleifsson G, Bjornsdottir G et al. 2018. Relatedness disequilibrium regression estimates heritability without environmental bias. Nat. Genet. 50:1304–10
    [Google Scholar]
  202. 202.
    Young AI, Wauthier FL, Donnelly P 2018. Identifying loci affecting trait variability and detecting interactions in genome-wide association studies. Nat. Genet. 50:1608–14
    [Google Scholar]
  203. 203.
    Zaitlen N, Kraft P, Patterson N, Pasaniuc B, Bhatia G et al. 2013. Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits. PLOS Genet 9:e1003520
    [Google Scholar]
  204. 204.
    Zhang XS, Hill WG. 2005. Predictions of patterns of response to artificial selection in lines derived from natural populations. Genetics 169:411–25
    [Google Scholar]
  205. 205.
    Zhu Z, Bakshi A, Vinkhuyzen AA, Hemani G, Lee SH et al. 2015. Dominance genetic variation contributes little to the missing heritability for human complex traits. Am. J. Hum. Genet. 96:377–85
    [Google Scholar]
  206. 206.
    Zuk O, Hechter E, Sunyaev SR, Lander ES 2012. The mystery of missing heritability: Genetic interactions create phantom heritability. PNAS 109:1193–98
    [Google Scholar]
/content/journals/10.1146/annurev-genom-083115-022316
Loading

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error