Measuring selection for genes that promote long life in a historical human population

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The unusually long lifespans of humans and the persistence of post-reproductive lifespans in women represent evolutionary puzzles because natural selection cannot directly favour continued living in post-menopausal women or elderly men. Suggested sources of indirect selection require genetic correlations between fitness and survival or reproduction at younger ages, reproduction in the opposite sex, or late-life contributions to offspring or grandoffspring fitness. Here we apply quantitative genetic analyses to data from a historical human population to explicitly test these evolutionary genetic hypotheses. Total genetic selection increased the male post-50 lifespans by 0.138 years per generation; 94% of this arose from indirect selection acting to favour early-life fitness in both sexes. These results argue strongly against life-history models of ageing that depend on trade-offs between reproduction and late-life survival. No source of indirect selection for female post-50 lifespan was detected, deepening the mystery of why female post-reproductive survival persists. This result is probably due to recent changes in the genetic architecture of female lifespan, and it highlights the need for similar quantitative genetic analyses of human populations at other points along demographic transitions.

Natural selection favours increased lifespans whenever continued living is expected to yield future reproductive dividends, and this expectation declines with advancing age in humans of both sexes1. In males, the prevailing assumption is that late-life reproduction selects for late-life survival2, but this hypothesis remains untested and males often succeed in living long beyond the last ages of male reproduction3. In females, the late-life attenuation of phenotypic selection is more extreme, as menopause reduces this selective force to zero in middle age. Nevertheless, even women in primitive hunter–gatherer and horticultural populations can live many decades post-menopause4,5,6 in apparent violation of simple evolutionary predictions that late-acting deleterious mutations should accumulate unchecked7 (or even aided8) by natural selection. While there is controversy regarding the precise mechanisms for the genesis of post-reproductive lifespans9,10,11, evolutionary theory requires that its continued persistence must be explained by selection for traits with which it is genetically correlated (indirect selection).

Three evolutionary mechanisms have been suggested to explain the maintenance of post-reproductive lifespans. The ‘inter-age correlation model’ proposes that genes for early-age survival or reproductive function also benefit late-age survival12. The ‘inter-sex correlation model’ proposes that late-life survival genes are shared between the sexes2,13. As males do not experience menopause, selection for these genes in men can favour post-menopausal survival in females. The ‘(grand)maternal models’ suggest that prolonged lifespans of maternal or grandmaternal caregivers convey a fitness advantage to the related recipients of that care. When the same genes affect caregiving and late-life survival, care may generate indirect selection for late-age survival in females7,14,15. To describe this mechanism in quantitative genetic terms, we must invoke the concept of ‘indirect genetic effects’ (IGEs)16; these are the effects that genes have on the phenotypes of social partners. IGEs differ from ‘direct genetic effects’—the influence that one’s own genes has on one’s own phenotype. The (grand)maternal models require a positive genetic correlation between the caregiver-derived IGEs for fitness and the direct genetic effects for lifespan. By predicting an evolutionary response of late-life survival to selection to counter the deleterious effects of new mutations, all three models assume that positive genetic correlations between late-age lifespan and fitness have arisen and are maintained by recurrent mutation. While some studies have demonstrated phenotypic correlations and associations that are consistent with grandmaternal effects4,17, evidence for a positive genetic correlation represents the ‘smoking gun’ necessary to demonstrate the true efficacy of an evolutionary pathway to maintain post-reproductive survival.

We applied ‘animal model’ quantitative genetic analyses18 to estimate genetic correlations between post-reproductive lifespan and sex-specific fitness components. ‘Animal models’ have been used in the past to infer evolution by natural selection of life-history traits in other historical human populations19,20. We used these genetic correlations in conjunction with estimates of phenotypic selection gradients21 to quantitatively compare the importance of candidate evolutionary pathways to explain the persistence of post-50 lifespans in both sexes. We chose 50 years of age as it approximates the age at menopause in humans22 and it has been used previously as a reference age for describing post-reproductive lifespans in humans17. Our human phenotypic and pedigree data came from a subset of the Utah Population Database23,24, which derives from a population of pioneers of the American west that colonized the Utah Territory from 1847. The primary subject cohort comprised all individuals born between 1860 and 1889 and their siblings (n = 128,129). This population was chosen as it was recent enough to present sufficient data to permit powerful statistical analyses while being old enough to exhibit natural fertility and other features of a less-modern environment23. Pre-historical, hunter–gatherer, and modern populations are each lacking in one or more respect.

Each individual was associated with values for relative fitness (w, the relative contribution of an individual to the next generation, which is properly defined in the context of an age-structured population as the individual reproductive value at birth; see Methods) and the following sex-specific traits: the number of years survived beyond 50 (LS50), fitness accumulated before 50 (w1), survival to 50 (P50), and fitness accumulated at 50 and beyond (w2). We took a three-part approach to investigating genetic selection for late-life survival. First, we estimated the genetic covariation between fitness and sex-specific LS50. This predicts a response to selection and provides an estimate of the total selection acting to increase genetic values for late-life lifespan. We then investigated on a finer scale the degree to which specific hypothesized sources of selection act to favour (or disfavour) post-50 survival genes in both sexes. This required a careful articulation of the various evolutionary models put into a quantitative genetic perspective. This was the motivation for the second part of our study, the aim of which was to provide a unified conceptual model for the genetic selection of post-reproductive female lifespan that (1) generalizes across all previous evolutionary genetic hypotheses and (2) parameterizes these hypotheses in terms of estimable quantitative genetic values. To distinguish among these evolutionary models, we then estimated the parameters from this conceptual quantitative genetic model and thus estimated the degree to which selection for post-50 lifespan genes is driven by direct or indirect selection via inter-age, inter-sex or (grand)maternal effects.
Original languageEnglish
Pages (from-to)1773-1781
Number of pages9
JournalNature Ecology & Evolution
Issue number11
Early online date9 Oct 2017
Publication statusPublished - 1 Nov 2017

Keywords / Materials (for Non-textual outputs)

  • Anthropology
  • Evolutionary genetics
  • Evolutionary theory


Dive into the research topics of 'Measuring selection for genes that promote long life in a historical human population'. Together they form a unique fingerprint.

Cite this