Letter | Published:

Recombination affects accumulation of damaging and disease-associated mutations in human populations

Nature Genetics volume 47, pages 400404 (2015) | Download Citation

Abstract

Many decades of theory have demonstrated that, in non-recombining systems, slightly deleterious mutations accumulate non-reversibly1, potentially driving the extinction of many asexual species. Non-recombining chromosomes in sexual organisms are thought to have degenerated in a similar fashion2; however, it is not clear the extent to which damaging mutations accumulate along chromosomes with highly variable rates of crossing over. Using high-coverage sequencing data from over 1,400 individuals in the 1000 Genomes and CARTaGENE projects, we show that recombination rate modulates the distribution of putatively deleterious variants across the entire human genome. Exons in regions of low recombination are significantly enriched for deleterious and disease-associated variants, a signature varying in strength across worldwide human populations with different demographic histories. Regions with low recombination rates are enriched for highly conserved genes with essential cellular functions and show an excess of mutations with demonstrated effects on health, a phenomenon likely affecting disease susceptibility in humans.

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Acknowledgements

We thank G. Gibson, E. Hatton, G. McVean, J. Novembre, C. Spencer, E. Stone and the anonymous reviewers for insightful comments on the study, and we thank the CARTaGENE participants and team for data collection. We confirm that informed consent was obtained from all subjects. We acknowledge financial support from Fonds de la Recherche en Santé du Québec (FRSQ), Génome Québec, Fonds Québécois de la Recherche sur la Nature et les Technologies (FQRNT) and the Canadian Partnership Against Cancer. J.G.H. is a Human Frontiers Postdoctoral Fellow, A.H. is an FRSQ Research Fellow, and Y.I. is a Banting Postdoctoral Fellow.

Author information

Author notes

    • Julie G Hussin
    •  & Philip Awadalla

    Present addresses: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (J.G.H.) and Ontario Institute of Cancer Research, Toronto, Ontario, Canada (P.A.).

Affiliations

  1. Sainte-Justine University Hospital Research Centre, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

    • Julie G Hussin
    • , Alan Hodgkinson
    • , Youssef Idaghdour
    • , Jean-Christophe Grenier
    • , Elias Gbeha
    • , Elodie Hip-Ki
    •  & Philip Awadalla
  2. CARTaGENE Project, Sainte-Justine University Hospital, Montreal, Quebec, Canada.

    • Julie G Hussin
    • , Alan Hodgkinson
    • , Youssef Idaghdour
    • , Jean-Philippe Goulet
    •  & Philip Awadalla

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Contributions

J.G.H. designed the study, performed quality control on genotyping and sequencing data, performed bioinformatics and statistical analyses and wrote the manuscript. A.H. performed quality control on genotyping and sequencing data and wrote the manuscript. E.G. and E.H.-K. processed samples for sequencing and genotyping. Y.I., J.-C.G. and J.-P.G. preprocessed the genomic data and performed quality control and bioinformatics analyses. P.A. provided samples, designed the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Philip Awadalla.

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DOI

https://doi.org/10.1038/ng.3216