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Evidence for the role of selection for reproductively advantageous alleles in human aging.

ABSTRACT: The antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here, we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 U.K. Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and life span. Individuals with higher polygenetic scores for reproduction (PGSR) have lower survivorships to age 76 (SV76), and PGSR increased over birth cohorts from 1940 to 1969. Similar trends are seen from individual genetic variants examined. The antagonistically pleiotropic variants are often associated with cis-regulatory effects across multiple tissues or on multiple target genes. These and other findings support the antagonistic pleiotropy hypothesis of aging in humans and point to potential molecular mechanisms of the reproduction-life-span antagonistic pleiotropy.

SUBMITTER: Long E

PROVIDER: S-EPMC10708185 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Evidence for the role of selection for reproductively advantageous alleles in human aging.

Long Erping E Zhang Jianzhi J

Science advances 20231208 49

The antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here, we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 U.K. Biobank participants. We observe a strong, negative genetic correlat ...[more]

PMID: 38064565

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Project description: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.

Project description:Previous studies have shown that people would like to sacrifice benefits to themselves in order to avoid inequitable outcomes, not only when they receive less than others (disadvantageous inequity aversion) but also when they receive more (advantageous inequity aversion). This feature is captured by the theory of inequity aversion. The present study was inspired by what appears to be asymmetry in the research paradigm toward advantageous inequity aversion. Specifically, studies that supported the existence of advantageous inequity aversion always relied on the paradigm in which participants can determine allocations. Thus, it is interesting to know what would occur if participants could not determine allocations or simply passed judgment on predetermined allocations. To address this, a behavioral experiment (N = 118) and a skin conductance response (SCR) experiment (N = 29) were adopted to compare participants' preferences for advantageous inequity directly when allocations were determined and when allocations were predetermined in an allocating task. In the determined condition, participants could divide by themselves a sum of money between themselves and a matched person, whereas in the predetermined condition, they could simply indicate their satisfaction with an equivalent program-generated allocation. It was found that, compared with those in the determined condition, participants in the predetermined condition behaved as if they liked the advantageous inequity and equity to the same degree (Experiment One) and that the SCRs elicited by advantageous inequity had no differences from those elicited by equity, suggesting that participants did not feel negatively toward advantageous inequity in this situation (Experiment Two). The present study provided mutual corroboration (behavioral and electrophysiological data) to document that advantageous inequity aversion may differ as a function of the individual's role in determining allocations, and it would disappear if individual cannot determine allocations.

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Evidence for the role of selection for reproductively advantageous alleles in human aging.

Publications

Evidence for the role of selection for reproductively advantageous alleles in human aging.

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