Article

Antagonistic pleiotropy and mutation accumulation influence human senescence and disease

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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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Author information

Affiliations

  1. Institute of Evolutionary Biology (UPF-CSIC), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia 08003, Spain

    • Juan Antonio Rodríguez
    • , Urko M. Marigorta
    • , David A. Hughes
    • , Nino Spataro
    • , Elena Bosch
    •  & Arcadi Navarro
  2. School of Biology, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

    • Urko M. Marigorta
  3. Centre de Regulació Genòmica (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Catalonia 08003, Spain

    • Arcadi Navarro
  4. National Institute for Bioinformatics (INB), Barcelona, Catalonia 08003, Spain

    • Arcadi Navarro
  5. Institució Catalana de Recerca i Estudis Avançats (ICREA), Catalonia 08003, Spain

    • Arcadi Navarro

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Contributions

J.A.R., U.M.M., E.B. and A.N. conceived the study. J.A.R. and N.S. performed analyses. J.A.R., U.M.M., D.A.H., N.S., E.B. and A.N. analysed and interpreted the data. J.A.R., D.A.H., N.S., E.B. and A.N. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Elena Bosch or Arcadi Navarro.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Discussion; Supplementary Figures 1–6; Supplementary Tables 1–10

Excel files

  1. 1.

    Supplementary Data 1

    Estimated age of onset for the diseases used in the present study.

  2. 2.

    Supplementary Data 2

    List of the associations SNP-disease retrieved from the GWAS Catalog and used for the present study.

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    Supplementary Data 3

    List of the 266 pleiotropies found in the present study. These include both, the ones involving the same SNP in two diseases and these involving pairs of SNPs with r2 ≥ 0.8.

  4. 4.

    Supplementary Data 4

    Chi square 2×2 tables for number of pleiotropies inside each defined category, considering early–late thresholds from 10 to 60.

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    Supplementary Data 5

    Antagonistic early–late pleiotropies (r2 ≥ 0.8.) (n = 26) for an age threshold of 46 years as transition early–late.

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    Supplementary Data 6

    Pleiotropy and comorbidity overlap.

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    Supplementary Data 7

    Excess of pleiotropy in different gene sets at different levels, compared to genome-wide.

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    Supplementary Data 8

    Genes in the Sousa-Victor et al. ageing gene set28.

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    Supplementary Data 9

    Disease–SNP associations reported after crossing ageing genes from Sousa-Victor et al.28 with the GWAS Catalog used in present study.

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    Supplementary Data 10

    Pleiotropies found in the Sousa-Victor et al. ageing gene set28.

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    Supplementary Data 11

    Genes in the Magalhães et al. ageing gene set29.

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    Supplementary Data 12

    Disease–SNP associations reported after crossing genes from Magalhães et al.29 with the GWAS Catalog used in present study.

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    Supplementary Data 13

    Pleiotropies found in the Magalhães et al. ageing gene set29.

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    Supplementary Data 14

    Genes in the Harries et al. age expression changing gene set30.

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    Supplementary Data 15

    Disease–SNP associations reported after crossing ageing genes from Harries et al.30 with the GWAS Catalog used in the present study.

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    Supplementary Data 16

    Pleiotropies found in the Harries et al. age expression changing gene set30.

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    Supplementary Data 17

    Number of SNPs, diseases and average risk allelic frequency for early and late at each age threshold (10 to 60 years) from Fig. 1a.

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    Supplementary Data 18

    Number of SNPs, diseases and average genetic variance for early and late at each age threshold (10 to 60 years) from Fig. 1b.