Skip to main content

Advertisement

SpringerLink
Log in

Antagonistic Pleiotropy in Human Disease

  • Review
  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

Abstract

Between the 1930s and 1950s, scientists developed key principles of population genetics to try and explain the aging process. Almost a century later, these aging theories, including antagonistic pleiotropy and mutation accumulation, have been experimentally validated in animals. Although the theories have been much harder to test in humans despite research dating back to the 1970s, recent research is closing this evidence gap. Here we examine the strength of evidence for antagonistic pleiotropy in humans, one of the leading evolutionary explanations for the retention of genetic risk variation for non-communicable diseases. We discuss the analytical tools and types of data that are used to test for patterns of antagonistic pleiotropy and provide a primer of evolutionary theory on types of selection as a guide for understanding this mechanism and how it may manifest in other diseases. We find an abundance of non-experimental evidence for antagonistic pleiotropy in many diseases. In some cases, several studies have independently found corroborating evidence for this mechanism in the same or related sets of diseases including cancer and neurodegenerative diseases. Recent studies also suggest antagonistic pleiotropy may be involved in cardiovascular disease and diabetes. There are also compelling examples of disease risk variants that confer fitness benefits ranging from resistance to other diseases or survival in extreme environments. This provides increasingly strong support for the theory that antagonistic pleiotropic variants have enabled improved fitness but have been traded for higher burden of disease later in life. Future research in this field is required to better understand how this mechanism influences contemporary disease and possible consequences for their treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abraham G, Havulinna AS, Bhalala OG, Byars SG, De Livera AM, Yetukuri L, Tikkanen E, Perola M, Schunkert H, Sijbrands EJ, Palotie A, Samani NJ, Salomaa V, Ripatti S, Inouye M (2016) Genomic prediction of coronary heart disease. Eur Heart J 37:3267

    CAS  PubMed  PubMed Central  Google Scholar 

  • Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V (2002) Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 359:1311

    CAS  PubMed  Google Scholar 

  • Alexander DM, Williams LM, Gatt JM, Dobson-Stone C, Kuan SA, Todd EG, Schofield PR, Cooper NJ, Gordon E (2007) The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades. Biol Psychol 75:229

    CAS  PubMed  Google Scholar 

  • Ashur-Fabian O, Avivi A, Trakhtenbrot L, Adamsky K, Cohen M, Kajakaro G, Joel A, Amariglio N, Nevo E, Rechavi G (2004) Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation. Proc Natl Acad Sci USA 101:12236

    CAS  PubMed  PubMed Central  Google Scholar 

  • Austad SN, Hoffman JM (2018) Is antagonistic pleiotropy ubiquitous in aging biology? Evol Med Public Health 1:287–294

    Google Scholar 

  • Babenko VN, Basu MK, Kondrashov FA, Rogozin IB, Koonin EV (2006) Signs of positive selection of somatic mutations in human cancers detected by EST sequence analysis. BMC Cancer 6:36

    PubMed  PubMed Central  Google Scholar 

  • Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, Princen F, Fang DD, Han T, Bailly-Maitre B, Poli V, Varki NM, Wang H, Feng GS (2011) Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell 19:629

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L (2008) Natural selection has driven population differentiation in modern humans. Nat Genet 40:340

    CAS  PubMed  Google Scholar 

  • Bekpen C, Xie C, Nebel A, Tautz D (2018) Involvement of SPATA31 copy number variable genes in human lifespan. Aging 10:674

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN (2004) Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet 74:1111

    CAS  PubMed  PubMed Central  Google Scholar 

  • Billiard S, Faurie C, Raymond M (2005) Maintenance of handedness polymorphism in humans: a frequency-dependent selection model. J Theor Biol 235:85

    PubMed  Google Scholar 

  • Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE, Perry RT, Bassett SS, Chase G, Meyers D, Albert MS, Tanzi R (1997) ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology 48:139

    CAS  PubMed  Google Scholar 

  • Bochdanovits Z, de Jong G (2004) Antagonistic pleiotropy for life-history traits at the gene expression level. Proc R Soc B 271:S75

    CAS  PubMed  Google Scholar 

  • Bochdanovits Z, Gosso FM, van den Berg L, Rizzu P, Polderman TJ, Pardo LM, Houlihan LM, Luciano M, Starr JM, Harris SE, Deary IJ, de Geus EJ, Boomsma DI, Heutink P, Posthuma D (2009) A functional polymorphism under positive evolutionary selection in ADRB2 is associated with human intelligence with opposite effects in the young and the elderly. Behav Genet 39:15

    PubMed  Google Scholar 

  • Booker TR, Jackson BC, Keightley PD (2017) Detecting positive selection in the genome. BMC Biol 15:98

    PubMed  PubMed Central  Google Scholar 

  • Buniello A, MacArthur JAL, Cerezo M, Harris LW, Hayhurst J, Malangone C, McMahon A, Morales J, Mountjoy E, Sollis E, Suveges D, Vrousgou O, Whetzel PL, Amode R, Guillen JA, Riat HS, Trevanion SJ, Hall P, Junkins H, Flicek P, Burdett T, Hindorff LA, Cunningham F, Parkinson H (2019) The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res 47:D1005

    CAS  PubMed  Google Scholar 

  • Butovskaya ML, Lazebny OE, Vasilyev VA, Dronova DA, Karelin DV, Mabulla AZP, Shibalev DV, Shackelford TK, Fink B, Ryskov AP (2015) Androgen receptor gene polymorphism, aggression, and reproduction in Tanzanian foragers and pastoralists. PLoS ONE 10:e0136208

    PubMed  PubMed Central  Google Scholar 

  • Byars SG, Voskarides K (2019) Genes that improved fitness also cost modern humans: evidence for genes with antagonistic effects on longevity and disease. Evol Med Public Health 1:4–6

    Google Scholar 

  • Byars SG, Ewbank D, Govindaraju DR, Stearns SC (2010) Colloquium papers: natural selection in a contemporary human population. Proc Natl Acad Sci USA 107(Suppl 1):1787

    CAS  PubMed  Google Scholar 

  • Byars SG, Huang QQ, Gray LA, Bakshi A, Ripatti S, Abraham G, Stearns SC, Inouye M (2017) Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy. PLoS Genet 13:e1006328

    PubMed  PubMed Central  Google Scholar 

  • Cagliani R, Fumagalli M, Pozzoli U, Riva S, Comi GP, Torri F, Macciardi F, Bresolin N, Sironi M (2009) Diverse evolutionary histories for beta-adrenoreceptor genes in humans. Am J Hum Genet 85:64

    CAS  PubMed  PubMed Central  Google Scholar 

  • Capellini TD, Chen H, Cao J, Doxey AC, Kiapour AM, Schoor M, Kingsley DM (2017) Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk. Nat Genet 49:1202

    CAS  PubMed  PubMed Central  Google Scholar 

  • Carter AJ, Nguyen AQ (2011) Antagonistic pleiotropy as a widespread mechanism for the maintenance of polymorphic disease alleles. BMC Med Genet 12:160

    CAS  PubMed  PubMed Central  Google Scholar 

  • Charlesworth B (1993) Evolutionary mechanisms of senescence. Genetica 91:11

    CAS  PubMed  Google Scholar 

  • Charlesworth B (2000) Fisher, Medawar, Hamilton and the evolution of aging. Genetics 156:927

    CAS  PubMed  PubMed Central  Google Scholar 

  • Charlesworth B, Hughes KA (1996) Age-specific inbreeding depression and components of genetic variance in relation to the evolution of senescence. Proc Natl Acad Sci USA 93:6140

    CAS  PubMed  Google Scholar 

  • Cheung CL, Chan V, Kung AW (2008) A differential association of ALOX15 polymorphisms with bone mineral density in pre- and post-menopausal women. Hum Hered 65:1

    PubMed  Google Scholar 

  • Chial H (2008) Huntington’s disease: the discovery of the Huntingtin gene. Nat Educ 1(1):71

    Google Scholar 

  • Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292:104

    CAS  PubMed  Google Scholar 

  • Clark TG, Fry AE, Auburn S, Campino S, Diakite M, Green A, Richardson A, Teo YY, Small K, Wilson J, Jallow M, Sisay-Joof F, Pinder M, Sabeti P, Kwiatkowski DP, Rockett KA (2009) Allelic heterogeneity of G6PD deficiency in West Africa and severe malaria susceptibility. Eur J Hum Genet 17:1080

    CAS  PubMed  PubMed Central  Google Scholar 

  • Connallon T, Chenoweth SF (2019) Dominance reversals and the maintenance of genetic variation for fitness. PLoS Biol 17:e3000118

    PubMed  PubMed Central  Google Scholar 

  • Connallon T, Clark AG (2012) A general population genetic framework for antagonistic selection that accounts for demography and recurrent mutation. Genetics 190:1477

    PubMed  PubMed Central  Google Scholar 

  • Conneally PM (1984) Huntington disease: genetics and epidemiology. Am J Hum Genet 36:506

    CAS  PubMed  PubMed Central  Google Scholar 

  • Corbett S, Courtiol A, Lummaa V, Moorad J, Stearns S (2018) The transition to modernity and chronic disease: mismatch and natural selection. Nat Rev Genet 19:419

    CAS  PubMed  Google Scholar 

  • Corbo RM, Ulizzi L, Scacchi R, Martinez-Labarga C, De Stefano GF (2004) Apolipoprotein E polymorphism and fertility: a study in pre-industrial populations. Mol Hum Reprod 10:617

    CAS  PubMed  Google Scholar 

  • Corona E, Dudley JT, Butte AJ (2010) Extreme evolutionary disparities seen in positive selection across seven complex diseases. PLoS ONE 5:e12236

    PubMed  PubMed Central  Google Scholar 

  • Crespi BJ (2011) The emergence of human-evolutionary medical genomics. Evol Appl 4:292

    PubMed  Google Scholar 

  • Crespi B, Summers K, Dorus S (2007) Adaptive evolution of genes underlying schizophrenia. Proc Biol Sci 274:2801

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cutting GR (2015) Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet 16:45

    CAS  PubMed  Google Scholar 

  • Di Rienzo A (2006) Population genetics models of common diseases. Curr Opin Genet Dev 16:630

    PubMed  Google Scholar 

  • Di Rienzo A, Hudson RR (2005) An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet 21:596

    PubMed  Google Scholar 

  • Ding K, Kullo IJ (2009) Evolutionary genetics of coronary heart disease. Circulation 119:459

    PubMed  Google Scholar 

  • Dowsing AT, Yong EL, Clark M, McLachlan RI, de Kretser DM, Trounson AO (1999) Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. The Lancet 354:640

    CAS  Google Scholar 

  • Drenos F, Kirkwood TB (2010) Selection on alleles affecting human longevity and late-life disease: the example of apolipoprotein E. PLoS ONE 5:e10022

    PubMed  PubMed Central  Google Scholar 

  • Elguero E, Delicat-Loembet LM, Rougeron V, Arnathau C, Roche B, Becquart P, Gonzalez JP, Nkoghe D, Sica L, Leroy EM, Durand P, Ayala FJ, Ollomo B, Renaud F, Prugnolle F (2015) Malaria continues to select for sickle cell trait in Central Africa. Proc Natl Acad Sci USA 112:7051

    CAS  PubMed  Google Scholar 

  • Engelhardt SC, Bergeron P, Gagnon A, Dillon L, Pelletier F (2019) Using geographic distance as a potential proxy for help in the assessment of the grandmother hypothesis. Curr Biol 29:651

    CAS  PubMed  Google Scholar 

  • Eskenazi B, Wilson-Rich N, Starks P (2007) A Darwinian approach to Huntington’s disease: subtle health benefits of a neurological disorders. Med Hypotheses 69:1183

    PubMed  Google Scholar 

  • Farrell PM (2008) The prevalence of cystic fibrosis in the European Union. J Cyst Fibros 7:450

    PubMed  Google Scholar 

  • Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278:1349

    CAS  PubMed  Google Scholar 

  • Faurie C, Raymond M (2004) Handedness, homicide and negative frequency-dependent selection. Proc R Soc B 272:25

    Google Scholar 

  • Fisher RA (1930) The genetical theory of natural selection. The Clarendon Press, Oxford

    Google Scholar 

  • Flatt T (2011) Survival costs of reproduction in Drosophila. Exp Gerontol 46:369

    PubMed  Google Scholar 

  • Flatt T, Partridge L (2018) Horizons in the evolution of aging. BMC Biol 16:93

    PubMed  PubMed Central  Google Scholar 

  • Flatt T, Schmidt PS (2009) Integrating evolutionary and molecular genetics of aging. Biochim Biophys Acta 1790:951

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frank JE (2005) Diagnosis and management of G6PD deficiency. Am Fam Physician 72:1277

    PubMed  Google Scholar 

  • Friedman E, Kotsopoulos J, Lubinski J, Lynch HT, Ghadirian P, Neuhausen SL, Isaacs C, Weber B, Foulkes WD, Moller P, Rosen B, Kim-Sing C, Gershoni-Baruch R, Ainsworth P, Daly M, Tung N, Eisen A, Olopade OI, Karlan B, Saal HM, Garber JE, Rennert G, Gilchrist D, Eng C, Offit K, Osborne M, Sun P, Narod SA, Hereditary Breast Cancer Clinical Study Group (2006) Spontaneous and therapeutic abortions and the risk of breast cancer among BRCAmutation carriers. Breast Cancer Res 8:R15

    PubMed  PubMed Central  Google Scholar 

  • Fu W, Akey JM (2013) Selection and adaptation in the human genome. Annu Rev Genomics Hum Genet 14:467

    CAS  PubMed  Google Scholar 

  • Fujito NT, Satta Y, Hane M, Matsui A, Yashima K, Kitajima K, Sato C, Takahata N, Hayakawa T (2018) Positive selection on schizophrenia-associated ST8SIA2 gene in post-glacial Asia. PLoS ONE 13:e0200278

    PubMed  PubMed Central  Google Scholar 

  • Galvani AP, Slatkin M (2003) Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele. Proc Natl Acad Sci USA 100:15276

    CAS  PubMed  Google Scholar 

  • Gavrilets S, Rice WR (2006) Genetic models of homosexuality: generating testable predictions. Proc Biol Sci 273:3031

    PubMed  PubMed Central  Google Scholar 

  • Guindo A, Fairhurst RM, Doumbo OK, Wellems TE, Diallo DA (2007) X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria. PLoS Med 4:e66

    PubMed  PubMed Central  Google Scholar 

  • Haldane JBS (1941) New paths in genetics. Allen & Unwin, London

    Google Scholar 

  • Hamilton WD (1966) The moulding of senescence by natural selection. J Theor Biol 12:12

    CAS  PubMed  Google Scholar 

  • Hay SI, Guerra CA, Tatem AJ, Noor AM, Snow RW (2004) The global distribution and population at risk of malaria: past, present, and future. Lancet Infect Dis 4:327

    PubMed  PubMed Central  Google Scholar 

  • Hedrick PW (1986) Genetic polymorphism in heterogeneous environments: a decade later. Annu Rev Ecol Syst 17:535

    Google Scholar 

  • Hedrick PW (2007) Balancing selection. Curr Biol 17:R230

    CAS  PubMed  Google Scholar 

  • Helgason A, Palsson S, Thorleifsson G, Grant SF, Emilsson V, Gunnarsdottir S, Adeyemo A, Chen Y, Chen G, Reynisdottir I, Benediktsson R, Hinney A, Hansen T, Andersen G, Borch-Johnsen K, Jorgensen T, Schafer H, Faruque M, Doumatey A, Zhou J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Sigurdsson G, Hebebrand J, Pedersen O, Thorsteinsdottir U, Gulcher JR, Kong A, Rotimi C, Stefansson K (2007) Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet 39:218

    CAS  PubMed  Google Scholar 

  • Hillmer AM, Freudenberg J, Myles S, Herms S, Tang K, Hughes DA, Brockschmidt FF, Ruan Y, Stoneking M, Nothen MM (2009) Recent positive selection of a human androgen receptor/ectodysplasin A2 receptor haplotype and its relationship to male pattern baldness. Hum Genet 126:255

    CAS  PubMed  PubMed Central  Google Scholar 

  • Horie K, Takakura K, Imai K, Liao S, Mori T (1992) Immunohistochemical localization of androgen receptor in the human endometrium, decidua, placenta and pathological conditions of the endometrium. Hum Reprod 7:1461

    CAS  PubMed  Google Scholar 

  • Hughes KA, Reynolds RM (2005) Evolutionary and mechanistic theories of aging. Annu Rev Entomol 50:421

    CAS  PubMed  Google Scholar 

  • Hughes KA, Alipaz JA, Drnevich JM, Reynolds RM (2002) A test of evolutionary theories of aging. Proc Natl Acad Sci USA 99:14286

    CAS  PubMed  Google Scholar 

  • Hunt B, Geddes DM (1985) Newly diagnosed cystic fibrosis in middle and later life. Thorax 40:23

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ingles SA, Ross RK, Yu MC, Irvine RA, La Pera G, Haile RW, Coetzee GA (1997) Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 89:166

    CAS  PubMed  Google Scholar 

  • Itan Y, Powell A, Beaumont MA, Burger J, Thomas MG (2009) The origins of lactase persistence in Europe. PLoS Comput Biol 5:e1000491

    PubMed  PubMed Central  Google Scholar 

  • Ito R, Nakayama H, Yoshida K, Kuraoka K, Motoshita J, Oda N, Oue N, Yasui W (2003) Expression of osteoprotegerin correlates with aggressiveness and poor prognosis of gastric carcinoma. Virchows Arch 443:146

    CAS  PubMed  Google Scholar 

  • Jasienska G, Ellison PT, Galbarczyk A, Jasienski M, Kalemba-Drozdz M, Kapiszewska M, Nenko I, Thune I, Ziomkiewicz A (2015) Apolipoprotein E (ApoE) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy? Proc Biol Sci 282:20142395

    PubMed  PubMed Central  Google Scholar 

  • Kang HJ, Feng Z, Sun Y, Atwal G, Murphy ME, Rebbeck TR, Rosenwaks Z, Levine AJ, Hu W (2009) Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci USA 106:9761

    CAS  PubMed  Google Scholar 

  • Kenyon C (2001) A conserved regulatory system for aging. Cell 105:165

    CAS  PubMed  Google Scholar 

  • Knight CG, Zitzmann S, Prabhakar S, Antrobus R, Dwek R, Hebestreit H, Rainey PB (2006) Unraveling adaptive evolution: how a single point mutation affects the protein coregulation network. Nat Genet 38:1015

    CAS  PubMed  Google Scholar 

  • Knudson AG Jr, Wayne L, Hallett WY (1967) On the selective advantage of cystic fibrosis heterozygotes. Am J Hum Genet 19:388

    PubMed  PubMed Central  Google Scholar 

  • Koh XH, Liu X, Teo YY (2014) Can evidence from genome-wide association studies and positive natural selection surveys be used to evaluate the thrifty gene hypothesis in East Asians? PLoS ONE 9:e110974

    PubMed  PubMed Central  Google Scholar 

  • Kosova G, Pickrell JK, Kelley JL, McArdle PF, Shuldiner AR, Abney M, Ober C (2010) The CFTR Met 470 allele is associated with lower birth rates in fertile men from a population isolate. PLoS Genet 6:e1000974

    PubMed  PubMed Central  Google Scholar 

  • Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, Jervis S, van Leeuwen FE, Milne RL, Andrieu N, Goldgar DE, Terry MB, Rookus MA, Easton DF, Antoniou AC, BRCA1 and BRCA2 Cohort Consortium, McGuffog L, Evans DG, Barrowdale D, Frost D, Adlard J, Ong KR, Izatt L, Tischkowitz M, Eeles R, Davidson R, Hodgson S, Ellis S, Nogues C, Lasset C, Stoppa-Lyonnet D, Fricker JP, Faivre L, Berthet P, Hooning MJ, van der Kolk LE, Kets CM, Adank MA, John EM, Chung WK, Andrulis IL, Southey M, Daly MB, Buys SS, Osorio A, Engel C, Kast K, Schmutzler RK, Caldes T, Jakubowska A, Simard J, Friedlander ML, McLachlan SA, Machackova E, Foretova L, Tan YY, Singer CF, Olah E, Gerdes AM, Arver B, Olsson H (2017) Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317:2402

    CAS  PubMed  Google Scholar 

  • Kudaravalli S, Veyrieras JB, Stranger BE, Dermitzakis ET, Pritchard JK (2009) Gene expression levels are a target of recent natural selection in the human genome. Mol Biol Evol 26:649

    CAS  PubMed  Google Scholar 

  • Kulminski AM, Culminskaya I, Ukraintseva SV, Arbeev KG, Land KC, Yashin AI (2010) Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context. Mech Ageing Dev 131:338

    CAS  PubMed  PubMed Central  Google Scholar 

  • La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77

    PubMed  Google Scholar 

  • Lappalainen T, Salmela E, Andersen PM, Dahlman-Wright K, Sistonen P, Savontaus M-L, Schreiber S, Lahermo P, Kere J (2010) Genomic landscape of positive natural selection in Northern European populations. Eur J Hum Genet (EJHG) 18:471

    Google Scholar 

  • Lemaitre JF, Berger V, Bonenfant C, Douhard M, Gamelon M, Plard F, Gaillard JM (2015) Early-late life trade-offs and the evolution of ageing in the wild. Proc Biol Sci 282:20150209

    PubMed  PubMed Central  Google Scholar 

  • Levine DA, Boyd J (2001) The androgen receptor and genetic susceptibility to ovarian cancer: results from a case series. Cancer Res 61:908

    CAS  PubMed  Google Scholar 

  • Li J, Wen WX, Eklund M, Kvist A, Eriksson M, Christensen HN, Torstensson A, Bajalica-Lagercrantz S, Dunning AM, Decker B, Allen J, Luccarini C, Pooley K, Simard J, Dorling L, Easton DF, Teo SH, Hall P, Borg A, Gronberg H, Czene K (2019) Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort. Int J Cancer 144:1195

    CAS  PubMed  Google Scholar 

  • Liu X, Ong Rick T-H, Pillai Esakimuthu N, Elzein Abier M, Small Kerrin S, Clark Taane G, Kwiatkowski Dominic P, Teo Y-Y (2013) Detecting and characterizing genomic signatures of positive selection in global populations. Am J Hum Genet 92:866

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lo W-S, Xu Z, Yu Z, Pun FW, Ng S-K, Chen J, Tong K-L, Zhao C, Xu X, Tsang S-Y, Harano M, Stöber G, Nimgaonkar VL, Xue H (2007) Positive selection within the schizophrenia-associated GABAA receptor β2 gene. PLoS ONE 2:e462

    PubMed  PubMed Central  Google Scholar 

  • Long E, Zhang J (2019) Retesting the influences of mutation accumulation and antagonistic pleiotropy on human senescence and disease. Nat Ecol Evol 3:992

    PubMed  Google Scholar 

  • MacDonald HR, Wilson A, Radtke F (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971

    Google Scholar 

  • Maehle BO, Vatten LJ, Tretli S (2010) Birth length and weight as predictors of breast cancer prognosis. BMC Cancer 10:115

    PubMed  PubMed Central  Google Scholar 

  • Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F, Hall MWJ, Cagan A, Murai K, Mahbubani K, Stratton MR, Fitzgerald RC, Handford PA, Campbell PJ, Saeb-Parsy K, Jones PH (2018) Somatic mutant clones colonize the human esophagus with age. Science 362:911

    CAS  PubMed  PubMed Central  Google Scholar 

  • Marx RN (1973) Huntington's chorea in Minnesota. Adv Neurol 1:237

    Google Scholar 

  • Mayeux R, Stern Y (2012) Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med 2(8):a006239

    PubMed  PubMed Central  Google Scholar 

  • McNulty P, Pilcher R, Ramesh R, Necuiniate R, Hughes A, Farewell D, Holmans P, Jones L (2018) Reduced Cancer incidence in Huntington's disease: analysis in the registry study. J Huntingtons Dis 7:209

    PubMed  Google Scholar 

  • Medawar PB (1946) Old age and natural death. Mod Q 2:30

    Google Scholar 

  • Medawar PB (1952) An unsolved problem of biology. H.K. Lewis, London

    Google Scholar 

  • Medina-Gómez C, Chesi A, Heppe DHM, Zemel BS, Yin J-L, Kalkwarf HJ, Hofman A, Lappe JM, Kelly A, Kayser M, Oberfield SE, Gilsanz V, Uitterlinden AG, Shepherd JA, Jaddoe VWV, Grant SFA, Lao O, Rivadeneira F (2015) BMD loci contribute to ethnic and developmental differences in skeletal fragility across populations: assessment of evolutionary selection pressures. Mol Biol Evol 32:2961

    PubMed  PubMed Central  Google Scholar 

  • Modugno F (2004) Ovarian cancer and polymorphisms in the androgen and progesterone receptor genes: a HuGE review. Am J Epidemiol 159:319

    PubMed  Google Scholar 

  • Mokkonen M, Crespi BJ (2015) Genomic conflicts and sexual antagonism in human health: insights from oxytocin and testosterone. Evol Appl 8:307

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moncke-Buchner E, Reich S, Mucke S, Reuter M, Messer W, Wanker EE, Kruger D (2002) Counting CAG repeats in the Huntington’s disease gene by restriction endonuclease EcoP15I cleavage. Nucleic Acid Res 30:e83

    PubMed  Google Scholar 

  • Morrow EH, Connallon T (2013) Implications of sex-specific selection for the genetic basis of disease. Evol Appl 6:1208

    PubMed  PubMed Central  Google Scholar 

  • Moslehi R, Singh R, Lessner L, Friedman JM (2010) Impact of BRCA mutations on female fertility and offspring sex ratio. Am J Hum Biol 22:201

    PubMed  PubMed Central  Google Scholar 

  • Mummidi S, Ahuja SS, Gonzalez E, Anderson SA, Santiago EN, Stephan KT, Craig FE, O'Connell P, Tryon V, Clark RA, Dolan MJ, Ahuja SK (1998) Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Nat Med 4:786

    CAS  PubMed  Google Scholar 

  • Muntane G, Farre X, Rodriguez JA, Pegueroles C, Hughes DA, de Magalhaes JP, Gabaldon T, Navarro A (2018) Biological processes modulating longevity across primates: a phylogenetic genome-phenome analysis. Mol Biol Evol 35:1990

    CAS  PubMed  PubMed Central  Google Scholar 

  • Myers RH (2004) Huntington’s disease genetics. NeuroRx 1:255

    PubMed  PubMed Central  Google Scholar 

  • Myles S, Davison D, Barrett J, Stoneking M, Timpson N (2008) Worldwide population differentiation at disease-associated SNPs. BMC Med Genomics 1:22

    PubMed  PubMed Central  Google Scholar 

  • Nielsen R, Bustamante C, Clark AG, Glanowski S, Sackton TB, Hubisz MJ, Fledel-Alon A, Tanenbaum DM, Civello D, White TJ, Sninsky JJ, Adams MD, Cargill M (2005) A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol 3:e170

    PubMed  PubMed Central  Google Scholar 

  • Nielsen R, Hellmann I, Hubisz M, Bustamante C, Clark AG (2007) Recent and ongoing selection in the human genome. Nat Rev Genet 8:857

    CAS  PubMed  PubMed Central  Google Scholar 

  • Niu W, Qi Y, Qian Y, Gao P, Zhu D (2009) The relationship between apolipoprotein E epsilon2/epsilon3/epsilon4 polymorphisms and hypertension: a meta-analysis of six studies comprising 1812 cases and 1762 controls. Hypertens Res 32:1060

    CAS  PubMed  Google Scholar 

  • Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2:a001008

    PubMed  PubMed Central  Google Scholar 

  • O'Malley CA (2009) Infection control in cystic fibrosis: cohorting, cross-contamination, and the respiratory therapist. Respir Care 54:641

    PubMed  Google Scholar 

  • Orsted DD, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG (2007) Tumor suppressor p53 Arg72Pro polymorphism and longevity, cancer survival, and risk of cancer in the general population. J Exp Med 204:1295

    PubMed  PubMed Central  Google Scholar 

  • Ostrow SL, Barshir R, DeGregori J, Yeger-Lotem E, Hershberg R (2014) Cancer evolution is associated with pervasive positive selection on globally expressed genes. PLoS Genet 10:e1004239

    PubMed  PubMed Central  Google Scholar 

  • Paaby AB, Schmidt PS (2008) Functional significance of allelic variation at methuselah, an aging gene in Drosophila. PLoS ONE 3(4):e1987

    PubMed  PubMed Central  Google Scholar 

  • Paaby AB, Bergland AO, Behrman EL, Schmidt PS (2014) A highly pleiotropic amino acid polymorphism in the Drosophila insulin receptor contributes to life-history adaptation. Evolution 68:3395

    PubMed  PubMed Central  Google Scholar 

  • Pal T, Keefe D, Sun P, Narod SA, Hereditary Breast Cancer Clinical Study Group (2010) Fertility in women with BRCA mutations: a case-control study. Fertil Steril 93:1805

    CAS  PubMed  Google Scholar 

  • Partridge L, Barton NH (1993) Evolution of aging—testing the theory using Drosophila. Genetica 91:89

    CAS  PubMed  Google Scholar 

  • Partridge L, Gems D (2002) Mechanisms of ageing: public or private? Nat Rev Genet 3:165

    CAS  PubMed  Google Scholar 

  • Pavard S, Metcalf CJ (2007) Negative selection on BRCA1 susceptibility alleles sheds light on the population genetics of late-onset diseases and aging theory. PLoS ONE 2:e1206

    PubMed  PubMed Central  Google Scholar 

  • Pavlicek A, Noskov VN, Kouprina N, Barrett JC, Jurka J, Larionov V (2004) Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. Hum Mol Genet 13:2737

    CAS  PubMed  Google Scholar 

  • Peng J, Redman CM, Wu X, Song X, Walker RH, Westhoff CM, Lee S (2007) Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases. Gene 392:142

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pritchard JK, Pickrell JK, Coop G (2010) The genetics of human adaptation: hard sweeps, soft sweeps, and polygenic adaptation. Curr Biol 20:R208

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ralser M, Heeren G, Breitenbach M, Lehrach H, Krobitsch S (2006) Triose phosphate isomerase deficiency is caused by altered dimerization—not catalytic inactivity—of the mutant enzymes. PLoS ONE 1:e30

    PubMed  PubMed Central  Google Scholar 

  • Rawlins MD, Wexler NS, Wexler AR, Tabrizi SJ, Douglas I, Evans SJ, Smeeth L (2016) The prevalence of Huntington's disease. Neuroepidemiology 46:144

    PubMed  Google Scholar 

  • Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, Godwin AK, Daly MB, Narod SA, Garber JE, Lynch HT, Weber BL, Brown M (1999) Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet 64:1371

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reed TE, Neel JV (1959) Huntington's chorea in Michigan. 2. Selection and mutation. Am J Hum Genet 11:107

    CAS  PubMed  PubMed Central  Google Scholar 

  • Refoyo-Martinez A, da Fonseca RR, Halldorsdottir K, Arnason E, Mailund T, Racimo F (2019) Identifying loci under positive selection in complex population histories. Genome Res 29:1506

    CAS  PubMed  Google Scholar 

  • Rodriguez JA, Marigorta UM, Hughes DA, Spataro N, Bosch E, Navarro A (2017) Antagonistic pleiotropy and mutation accumulation influence human senescence and disease. Nat Ecol Evol 1:55

    PubMed  Google Scholar 

  • Rodríguez JA, Farré X, Muntané G, Marigorta UM, Hughes DA, Spataro N, Bosch E, Navarro A (2019) Reply to: Retesting the influences of mutation accumulation and antagonistic pleiotropy on human senescence and disease. Nat Ecol Evol 3:994

    PubMed  Google Scholar 

  • Roff DA (1992) The evolution of life histories: theory and analysis. Chapman & Hall, New York

    Google Scholar 

  • Roff DA (2007) Contributions of genomics to life-history theory. Nat Rev Genet 8:116

    CAS  PubMed  Google Scholar 

  • Roff DA, Fairbairn DJ (2007) The evolution of trade-offs: where are we? J Evol Biol 20:433

    CAS  PubMed  Google Scholar 

  • Romero IG, Ruvinsky I, Gilad Y (2012) Comparative studies of gene expression and the evolution of gene regulation. Nat Rev Genet 13:505

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rowntree RK, Harris A (2003) The Phenotypic consequences of CFTR mutations. Ann Hum Genet 67:471

    CAS  PubMed  Google Scholar 

  • Sabeti PC, Schaffner SF, Fry B, Lohmueller J, Varilly P, Shamovsky O, Palma A, Mikkelsen TS, Altshuler D, Lander ES (2006) Positive natural selection in the human lineage. Science 312:1614

    CAS  PubMed  Google Scholar 

  • Samelson EJ, Broe KE, Demissie S, Beck TJ, Karasik D, Kathiresan S, Kiel DP (2008) Increased plasma osteoprotegerin concentrations are associated with indices of bone strength of the hip. J Clin Endocrinol Metab 93:1789

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sanchis-Gomar F, Perez-Quilis C, Leischik R, Lucia A (2016) Epidemiology of coronary heart disease and acute coronary syndrome. Ann Transl Med 4:256

    PubMed  PubMed Central  Google Scholar 

  • Saunders MA, Slatkin M, Garner C, Hammer MF, Nachman MW (2005) The extent of linkage disequilibrium caused by selection on G6PD in humans. Genetics 171:1219

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scriver CR, Byck S, Prevost L, Hoang L (1996) The phenylalanine hydroxylase locus: a marker for the history of phenylketonuria and human genetic diversity. PAH Mutation Analysis Consortium. Ciba Found Symp 197:73

    CAS  PubMed  Google Scholar 

  • Sgro CM (1999) A delayed wave of death from reproduction in Drosophila. Science 286:2521

    CAS  PubMed  Google Scholar 

  • Shokeir MHK (1975) Investigation on Huntington’s disease in the Canadian Prairies II. Fecundity and fitness. Clin Genet 7:349

    CAS  PubMed  Google Scholar 

  • Smith KR, Hanson HA, Mineau GP, Buys SS (2012) Effects of BRCA1 and BRCA2 mutations on female fertility. Proc Biol Sci 279:1389

    CAS  PubMed  Google Scholar 

  • Song Y, Stampfer MJ, Liu S (2004) Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med 141:137

    PubMed  Google Scholar 

  • Sorenson SA, Fenger K, Olsen J (1999) Significantly lower incidence of cancer among patients with Huntington’s disease. Cancer 6:1342

    Google Scholar 

  • Speakman JR (2006) Thrifty genes for obesity and the metabolic syndrome—time to call off the search? Diab Vasc Dis Res 3:7

    PubMed  Google Scholar 

  • Spyropoulos B (1988) Tay–Sachs carriers and tuberculosis resistance. Nature 331:666

    CAS  PubMed  Google Scholar 

  • Srinivasan TN, Padmavati R (1997) Fertility and schizophrenia: evidence for increased fertility in the relatives of schizophrenic patients. Acta Psychiatr Scand 96:260

    CAS  PubMed  Google Scholar 

  • Stearns SC (1992) The evolution of life histories. Oxford University Press, Oxford, New York

    Google Scholar 

  • Stearns SC, Partridge L (2001) The genetics of aging in Drosophila. In: Masoro E, Austad S (eds) Handbook of the biology of aging. Academic Press, Cambridge, pp 353–368

    Google Scholar 

  • Stearns SC, Byars SG, Govindaraju DR, Ewbank D (2010) Measuring selection in contemporary human populations. Nat Rev Genet 11:611

    CAS  PubMed  Google Scholar 

  • Stearns SC, Govindaraju DR, Ewbank D, Byars SG (2012) Constraints on the coevolution of contemporary human males and females. Proc Biol Sci 279:4836

    PubMed  PubMed Central  Google Scholar 

  • Takeda M, Martinez R, Kudo T, Tanaka T, Okochi M, Tagami S, Morihara T, Hashimoto R, Cacabelos R (2010) Apolipoprotein E and central nervous system disorders: reviews of clinical findings. Psychiatry Clin Neurosci 64:592

    CAS  PubMed  Google Scholar 

  • Taplin ME, Balk SP (2004) Androgen receptor: a key molecule in the progression of prostate cancer to hormone independence. J Cell Biochem 91:483

    CAS  PubMed  Google Scholar 

  • Vallender EJ, Lahn BT (2004) Positive selection on the human genome. Hum Mol Genet 13(2):R245

    CAS  PubMed  Google Scholar 

  • Vamathevan JJ, Hasan S, Emes RD, Amrine-Madsen H, Rajagopalan D, Topp SD, Kumar V, Word M, Simmons MD, Foord SM, Sanseau P, Yang Z, Holbrook JD (2008) The role of positive selection in determining the molecular cause of species differences in disease. BMC Evol Biol 8:273

    PubMed  PubMed Central  Google Scholar 

  • van Exel E, Koopman JJE, Bodegom DV, Meij JJ, Knijff P, Ziem JB, Finch CE, Westendorp RGJ (2017) Effect of APOE epsilon4 allele on survival and fertility in an adverse environment. PLoS ONE 12:e0179497

    PubMed  PubMed Central  Google Scholar 

  • Vasseur E, Quintana-Murci L (2013) The impact of natural selection on health and disease: uses of the population genetics approach in humans. Evol Appl 6:596

    PubMed  PubMed Central  Google Scholar 

  • Vaupel JW (2010) Biodemography of human ageing. Nature 464:536

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vicens A, Posada D (2018) Selective pressures on human cancer genes along the evolution of mammals. Genes 9:582

    PubMed Central  Google Scholar 

  • Vitti JJ, Grossman SR, Sabeti PC (2013) Detecting natural selection in genomic data. Annu Rev Genet 47:97

    CAS  PubMed  Google Scholar 

  • Voskarides K (2018) Combination of 247 genome-wide association studies reveals high cancer risk as a result of evolutionary adaptation. Mol Biol Evol 35:473

    CAS  PubMed  Google Scholar 

  • Voskarides K (2019) The “cancer-cold” hypothesis and possible extensions for the Nordic populations. Scand J Public Health 47(5):477–481. https://doi.org/10.1177/1403494819831905

    PubMed  Google Scholar 

  • Walker DA, Harper PS, Newcombe RG, Davies K (1983) Huntington's chorea in South Wales: mutation, fertility, and genetic fitness. J Med Genet 20:12

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wallace DC (1967) The inevitability of growing old. J Chronic Dis 20:475

    CAS  PubMed  Google Scholar 

  • Wallace DC, Parker N (1973) Huntington's chorea in Queensland: the most recent story. Adv Neurol 1:223

    Google Scholar 

  • Wang G, Speakman JR (2016) Analysis of positive selection at single nucleotide polymorphisms associated with body mass index does not support the “thrifty gene” hypothesis. Cell Metab 24:531

    PubMed  Google Scholar 

  • Wang K, Baldassano R, Zhang H, Qu HQ, Imielinski M, Kugathasan S, Annese V, Dubinsky M, Rotter JI, Russell RK, Bradfield JP, Sleiman PM, Glessner JT, Walters T, Hou C, Kim C, Frackelton EC, Garris M, Doran J, Romano C, Catassi C, Van Limbergen J, Guthery SL, Denson L, Piccoli D, Silverberg MS, Stanley CA, Monos D, Wilson DC, Griffiths A, Grant SF, Satsangi J, Polychronakos C, Hakonarson H (2010) Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects. Hum Mol Genet 19:2059

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Byars SG, Stearns SC (2013) Genetic links between post-reproductive lifespan and family size in Framingham. Evol Med Public Health 2013:241

    PubMed  PubMed Central  Google Scholar 

  • Wei X, Nielsen R (2019) CCR5-∆32 is deleterious in the homozygous state in humans. Nat Med 25:909

    CAS  PubMed  PubMed Central  Google Scholar 

  • Weinberg ED (2008) Survival advantage of the hemochromatosis C282Y mutation. Perspect Biol Med 51:98

    PubMed  Google Scholar 

  • Williams GC (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398

    Google Scholar 

  • Wilmoth JR (2000) Demography of longevity: past, present, and future trends. Exp Gerontol 35:1111

    CAS  PubMed  Google Scholar 

  • Woolf LI (1986) The heterozygote advantage in phenylketonuria. Am J Hum Genet 38:773

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu D-D, Li G-M, Jin W, Li Y, Zhang Y-P (2012) Positive selection on the osteoarthritis-risk and decreased-height associated variants at the GDF5 gene in East Asians. PLoS ONE 7:e42553

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ye K, Cao C, Lin X, O'Brien KO, Gu Z (2015) Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption. BMC Genet 16:61

    PubMed  PubMed Central  Google Scholar 

  • Yokoyama A, Kakiuchi N, Yoshizato T, Nannya Y, Suzuki H, Takeuchi Y, Shiozawa Y, Sato Y, Aoki K, Kim SK, Fujii Y, Yoshida K, Kataoka K, Nakagawa MM, Inoue Y, Hirano T, Shiraishi Y, Chiba K, Tanaka H, Sanada M, Nishikawa Y, Amanuma Y, Ohashi S, Aoyama I, Horimatsu T, Miyamoto S, Tsunoda S, Sakai Y, Narahara M, Brown JB, Sato Y, Sawada G, Mimori K, Minamiguchi S, Haga H, Seno H, Miyano S, Makishima H, Muto M, Ogawa S (2019) Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565:312

    CAS  PubMed  Google Scholar 

  • Young JH, Chang YP, Kim JD, Chretien JP, Klag MJ, Levine MA, Ruff CB, Wang NY, Chakravarti A (2005) Differential susceptibility to hypertension is due to selection during the out-of-Africa expansion. PLoS Genet 1:e82

    PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Ren JL, Wang MY, Zhang ST, Liu Y, Li M, Cao YB, Zu HY, Chen XC, Wu CI, Nevo E, Chen XQ, Du JZ (2013) Codon 104 variation of p53 gene provides adaptive apoptotic responses to extreme environments in mammals of the Tibet plateau. Proc Natl Acad Sci USA 110:20639

    CAS  PubMed  Google Scholar 

  • Zink N, Bensmann W, Arning L, Beste C, Stock AK (2019) Apolipoprotein epsilon4 is associated with better cognitive control allocation in healthy young adults. Neuroimage 185:274

    CAS  PubMed  Google Scholar 

  • Zwaan B, Bijlsma R, Hoekstra RF (1995) Direct selection on life span in Drosophila. Evolution 49:649

    PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank several reviewers and Professor Stephen Stearns for reading and commenting on this review.

Author information

Authors and Affiliations

  1. Melbourne School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia

    Sean G. Byars

  2. Medical School, University of Cyprus, Nicosia, Cyprus

    Konstantinos Voskarides

Authors
  1. Sean G. Byars
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Konstantinos Voskarides
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sean G. Byars or Konstantinos Voskarides.

Additional information

Handling Editor: David Liberles.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Byars, S.G., Voskarides, K. Antagonistic Pleiotropy in Human Disease. J Mol Evol 88, 12–25 (2020). https://doi.org/10.1007/s00239-019-09923-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00239-019-09923-2

Keywords

Search

Navigation