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


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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Figure 1: Overview of the study design.
Figure 2: Comparison of mutation rate estimates.

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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.

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Authors and Affiliations



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.

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Correspondence to Matthew E Hurles or Philip Awadalla.

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The author declare no competing financial interests.

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

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Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 2–3 and Supplementary Note. (PDF 1320 kb)

Supplementary Table 1

Validation and haplotyping results (XLS 3486 kb)

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the 1000 Genomes Project. Variation in genome-wide mutation rates within and between human families. Nat Genet 43, 712–714 (2011).

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