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Antagonistic pleiotropy and mutation accumulation influence human senescence and disease
Abstract
Senescence has long been a public health challenge as well as a fascinating evolutionary problem. There is neither a universally accepted theory for its ultimate causes, nor a consensus about what may be its impact on human health. Here we test the predictions of two evolutionary explanations of senescence-mutation accumulation and antagonistic pleiotropy-which postulate that genetic variants with harmful effects in old ages can be tolerated, or even favoured, by natural selection at early ages. Using data from genome-wide association studies (GWAS), we study the effects of genetic variants associated with diseases appearing at different periods in life, when they are expected to have different impacts on fitness. Data fit theoretical expectations. Namely, we observe higher risk allele frequencies combined with large effect sizes for late-onset diseases, and detect a significant excess of early-late antagonistically pleiotropic variants that, strikingly, tend to be harboured by genes related to ageing. Beyond providing systematic, genome-wide evidence for evolutionary theories of senescence in our species and contributing to the long-standing question of whether senescence is the result of adaptation, our approach reveals relationships between previously unrelated pathologies, potentially contributing to tackling the problem of an ageing population.
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The association between later onset and stronger negative genetic correlations with longevity is consistent with the evolutionary prediction that genetic variants with post-reproductive effects are more likely to persist across generations.
“consistent with the evolutionary prediction that genetic variants with post-reproductive effects are more likely to persist across generations despite their health-related costs18,22.”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [22]
After age 45, all diseases were linked to higher fertility among diagnosed individuals.
“Notably, after age 45—generally reflecting the end of the reproductive window—all diseases were linked to higher fertility among diagnosed individuals, aligning with established signatures of senescence22.”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [22]
Individuals with high genetic predisposition to late-onset diseases tend to have more children, reduced childlessness and younger ages at first birth.
“Individuals with high genetic predisposition to late-onset diseases tend to have more children, reduced childlessness and younger ages at first birth, suggesting early reproductive advantages of these alleles19,22,75.”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [22]
The evolutionary logic that health-related costs can be tolerated when coupled to reproductive advantage is consistent with previous work.
“This evolutionary logic is consistent with previous work, suggesting that health-related costs can be tolerated when coupled to reproductive advantage16,22,56,57.”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [22]
These alleles have early reproductive advantages.
“suggesting early reproductive advantages of these alleles19,22,75”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [22]
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Brigos-Barril, E., Vasallo, C., Farré, X., Morcillo-Suárez, C., Polo-Alonso, S., Rodríguez-Fernández, B., Valenzuela, A., Sarabia, C., Bosch, E., Laayouni, H., et al. (2026) · Nature Ecology & Evolution · doi:10.1038/s41559-026-03140-z · Cited by 6
Self-citation
Metadata
- Authors
- Rodríguez, J. A., Marigorta, U. M., Hughes, D. A., Spataro, N., Bosch, E., & Navarro, A.
- Venue
- Nature Ecology & Evolution
- Published
- 2017-01-30
- Volume
- 1
- Issue
- 3
- ISSN
- 2397-334X
- Cited by
- 108
- References
- 4
- Language
- en
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