The magnitude of negative selection on alleles involved in age-specific mortality decreases with age. This is the foundation of the evolutionary theory of senescence. Because of this decrease in negative selection with age, and because of the absence of reproduction after menopause, alleles involved in women's late-onset diseases are generally considered evolutionarily neutral. Recently, genetic and epidemiological data on alleles involved in late onset-diseases have become available. It is therefore timely to estimate selection on these alleles. Here, we estimate selection on BRCA1 alleles leading to susceptibility to late-onset breast and ovarian cancer. For this, we integrate estimates of the risk of developing a cancer for BRCA1-carriers into population genetics frameworks, and calculate selection coefficients on BRCA1 alleles for different demographic scenarios varying across the extent of human demography. We then explore the magnitude of negative selection on alleles leading to a diverse range of risk patterns, to capture a variety of late-onset diseases. We show that BRCA1 alleles may have been under significant negative selection during human history. Although the mean age of onset of the disease is long after menopause, variance in age of onset means that there are always enough cases occurring before the end of reproductive life to compromise the selective value of women carrying a susceptibility allele in BRCA1. This seems to be the case for an extended range of risk of onset functions varying both in mean and variance. This finding may explain the distribution of BRCA1 alleles' frequency, and also why alleles for many late-onset diseases, like certain familial forms of cancer, coronary artery diseases and Alzheimer dementia, are typically recent and rare. Finally, we discuss why the two most popular evolutionary theories of aging, mutation accumulation and antagonistic pleiotropy, may underestimate the effect of selection on survival at old ages.
References
[1]
Hamilton WD (1966) The moulding of senescence by natural selection. J Theor Biol 12: 12–45.
[2]
Abrams PA (1993) Does increased mortality favor the evolution of more rapid senescence? Evolution 47: 877–887.
[3]
Charlesworth B (1994) Evolution in age-structured populations. Cambridge: Cambridge University Press.
[4]
Charlesworth B (2001) Patterns of age-specific means and genetic variances of mortality rates predicted by the mutation-accumulation theory of ageing. J Theor Biol 210: 47–65.
[5]
Steinsaltz D, Evans SN, Wachter KW (2005) A generalized model of mutation–selection balance with applications to aging. Adv Appl Math 35: 16–33.
[6]
Christensen K, Johnson TE, Vaupel J (2006) The quest for genetic determinants of human longevity: challenges and insights. Nature Rev Genet 7: 436–448.
[7]
Claus EB, Risch NJ, Thompson WD (1991) Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet 48: 232–242.
[8]
Szabo CI, King MC (1997) Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60: 1013–1033.
[9]
Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, et al. (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 2003: 1117–1130.
[10]
Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, et al. (1995) The frequency of BRCA1 185delAG mutation is approximately 1% in Ashkenazi Jewish individuals. Nature Genet 11: 198–200.
[11]
Wright A, Charlesworth B, Rudan I, Carothers A, Campbell H (2003) A polygenic basis for late-onset disease. Trends Genet 19: 97–106.
[12]
Charbonneau H, Guillemette A, Légaré J, Desjardin B, Landry Y, et al. (1987) Naissance d'une population, Les Fran？ais établis au Canada au XVIIe siècle. Montréal, Canada: Presses de l'université de Montréal.
[13]
Hill K, Hurtado AM (1996) Ache life history: the ecology and demography of a foraging people. New York, USA: De Gruyter.
[14]
Coale AJ, Demeny P (1966) Regional model life table and stable populations. Princeton, USA: Princeton University Press.
[15]
Hadwiger H (1940) Eine analytische reproductions-funktion für biologische gesamtheiten. Skandinavisk Aktuarietidskrift 23: 101–113.
Knudson AG (1971) Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823.
[18]
Whitlock MC, Bürger R (2004) Fixation of new mutations in small populations. In: Ferrière R, Dieckmann U, Couvet D, editors. Evolutionary conservation biology. Cambridge: Cambridge Univ. Press. pp. 155–170. chapter 9.
[19]
Austerlitz F, Heyer E (1998) Social transmission of reproductive behavior increases frequency of inherited disorders in a young-expanding population. Proc Natl Acad Sci USA 95: 15140–15144.
[20]
Morton NE (1982) Outline of Genetic Epidemiology. Basel, Switzerland: S. Karger.
[21]
Pavard S, Sibert A, Heyer E (2007) Mother's death and child's survival: a demographic, genetics and evolutionary perspective. Evolution. 61: 1153–1161.
[22]
Kovacs BW, Shahbahrami B, Comings D (1990) Quantitation and characterization of human germinal mutations at hypervariable loci. Biology of Mammalian Germ Cell Mutagenesis. New York, USA: Cold Spring Harbor Laboratory Press. pp. 351–362. Banbury Report 34,.
[23]
Neuhausen SL, Mazoyer S, Friedman L, Stratton M, Offit K, et al. (1996) Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: Results of an international study. Am J Hum Genet 58: 271–280.
[24]
Zhong Q, Chen CF, Li S, Chen Y, Wang CC, et al. (1999) Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science 285: 747–750.
[25]
Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, et al. (2001) Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68: 700–710.
[26]
Rahman N, Stratton MR (1998) The genetics of breast cancer susceptibility. Annu Rev Genet 32: 95–121.
[27]
Goldstein AM, Falk RT, Korczak JF, Lubin JH (1997) Detecting gene-environment interactions using a case-control design. Genet Epidemiol 14: 1085–1089.
[28]
Levy-Lahad E, Catane R, Eisenberg S, Kaufman B, Hornreich G, et al. (1997) Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet 60: 1059–1067.
[29]
Eaton SB, Pike MC, Short RV, Lee NC, Trussell J, et al. (1994) Women's reproductive cancers in evolutionary context. Q Rev Biol 69(3): 353–367.
[30]
Charmantier A, Perrins C, McCleery RH, Sheldon BC (2006) Quantitative genetics of age at reproduction in wild swans: support for antagonistic pleiotropy models of senescence. Proc Natl Acad Sci USA 103: 6587–6592.
[31]
Lee RD (2003) Rethinking the evolutionary theory of aging: transfers, not births, shape senescence in social species. Proc Natl Acad Sci USA 100: 9637–9642.
[32]
Tuljapurkar SD, Puleston CO, Gurven MD (2007) Why men matter: mating patterns drive evolution of human lifespan. PLoS ONE 2: e785.
