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Variation in genome-wide mutation rates within and between human families

Nature Genetics volume 43, pages 712714 (2011) | Download Citation


J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline1. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans2,3. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.

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We would like to thank A. Kernytsky, G. McVean, T. Massingham, J. Thorne, J. Hussin, A. Motsinger, Coriell Cell Repositories and members of the 1000 Genomes analysis group for their help and support. D.F.C., S.J.L., Y.Z., C.T. and M.E.H. were funded by the Wellcome Trust (grant number 077014/Z/05/Z). J.E.M.K., F.C., Y.I., M.Z., G.A.R. and P.A. were funded by the Ministry of Development, Exploration and Innovation (grant number PSR-SIIRI-195) in Quebec and a Genome Quebec Award for Population and Medical Genomics to P.A.

Author information


  1. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Donald F Conrad
    • , Sarah J Lindsay
    • , Yujun Zhang
    • , Carlos Torroja
    •  & Matthew E Hurles
  2. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Donald F Conrad
  3. Ste Justine Hospital Research Centre, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

    • Jonathan E M Keebler
    • , Ferran Casals
    • , Youssef Idaghdour
    • , Martine Zilversmit
    •  & Philip Awadalla
  4. Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.

    • Jonathan E M Keebler
    •  & Eric A Stone
  5. Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Mark A DePristo
    • , Chris L Hartl
    • , Kiran V Garimella
    •  & Mark Daly
  6. Department of Genetics, North Carolina State University, Raleigh, North Carolina, USA.

    • Reed Cartwright
    •  & Eric A Stone
  7. Ste Justine Hospital Research Centre, Department of Medicine, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

    • Guy A Rouleau


  1. the 1000 Genomes Project

    A full list of members is provided in the Supplementary Note.



    M.E.H. and P.A. conceived the study. D.F.C., J.E.M.K., M.A.D., M.D., R.C., E.A.S. and P.A. developed statistical methodologies. D.F.C., J.E.M.K., M.A.D., C.L.H., K.V.G., E.A.S., M.E.H. and P.A. analyzed the data. F.C., Y.I., G.A.R., C.T., M.Z., S.J.L. and Y.Z. generated validation data. D.F.C., P.A. and M.E.H. wrote the paper.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Matthew E Hurles or Philip Awadalla.

    Supplementary information

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    1. 1.

      Supplementary Text and Figures

      Supplementary Figures 1–4, Supplementary Tables 2–3 and Supplementary Note.

    Excel files

    1. 1.

      Supplementary Table 1

      Validation and haplotyping results

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