The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Evidence for the role of selection for reproductively advantageous alleles in human aging
Published version of a preprint
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 ( PGS R ) have lower survivorships to age 76 ( SV 76 ), and PGS R 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.
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Functional annotation of these variants revealed tissue-specific expression patterns, particularly in the testes and brain, and significant enrichment in regulatory elements.
“Functional annotation of these variants revealed tissue-specific expression patterns, particularly in the testes and brain, and significant enrichment in regulatory elements, as previously shown16.”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [16]
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 [16]
The negative genetic correlation between fertility and longevity supports the AP theory of aging.
“supporting the AP theory of aging7,16,50,51”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [16]
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Cites
The GTEx Consortium atlas of genetic regulatory effects across human tissues
The GTEx Consortium, Aguet, F., Anand, S., Ardlie, K. G., Gabriel, S., Getz, G. A., Graubert, A., Hadley, K., Handsaker, R. E., Huang, K. H., et al. (2020) · Science · doi:10.1126/science.aaz1776 · Cited by 5,547
An atlas of genetic correlations across human diseases and traits
ReproGen Consortium, Bulik-Sullivan, B., Psychiatric Genomics Consortium, Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3, Finucane, H. K., Anttila, V., Gusev, A., Day, F. R., Loh, P.-R., Duncan, L., et al. (2015) · Nature Genetics · doi:10.1038/ng.3406 · Cited by 4,255
Vollset, S. E., Goren, E., Yuan, C.-W., Cao, J., Smith, A. E., Hsiao, T., Bisignano, C., Azhar, G. S., Castro, E., Chalek, J., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30677-2 · Cited by 1,506
arcOGEN Consortium, Tachmazidou, I., Hatzikotoulas, K., Southam, L., Esparza-Gordillo, J., Haberland, V., Zheng, J., Johnson, T., Koprulu, M., Zengini, E., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0327-1 · Cited by 516
Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation
Min, J. L., Hemani, G., Hannon, E., Dekkers, K. F., Castillo-Fernandez, J., Luijk, R., Carnero-Montoro, E., Lawson, D. J., Burrows, K., Suderman, M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00923-x · Cited by 506
Somatic mutation rates scale with lifespan across mammals
Cagan, A., Baez-Ortega, A., Brzozowska, N., Abascal, F., Coorens, T. H. H., Sanders, M. A., Lawson, A. R. J., Harvey, L. M. R., Bhosle, S., Jones, D., et al. (2022) · Nature · doi:10.1038/s41586-022-04618-z · Cited by 481
Selection against variants in the genome associated with educational attainment
Kong, A., Frigge, M. L., Thorleifsson, G., Stefansson, H., Young, A. I., Zink, F., Jonsdottir, G. A., Okbay, A., Sulem, P., Masson, G., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612113114 · Cited by 168 · cited 1×
“For instance, a mutation that negatively affects educational attainment might simultaneously increase reproduction ( 38 ) and reduce longevity ( 39 ).”
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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
Metadata
- Authors
- Long, E., & Zhang, J.
- Affiliations
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
- Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI 48109, USA.
- Venue
- Science Advances
- Published
- 2023-12-08
- Volume
- 9
- Issue
- 49
- ISSN
- 2375-2548
- PMC
- PMC10708185
- Cited by
- 46
- References
- 7
- Language
- en
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