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Estimating the human mutation rate using autozygosity in a founder population



Knowledge of the rate and pattern of new mutation is critical to the understanding of human disease and evolution. We used extensive autozygosity in a genealogically well-defined population of Hutterites to estimate the human sequence mutation rate over multiple generations. We sequenced whole genomes from 5 parent-offspring trios and identified 44 segments of autozygosity. Using the number of meioses separating each pair of autozygous alleles and the 72 validated heterozygous single-nucleotide variants (SNVs) from 512 Mb of autozygous DNA, we obtained an SNV mutation rate of 1.20 × 10−8 (95% confidence interval 0.89–1.43 × 10−8) mutations per base pair per generation. The mutation rate for bases within CpG dinucleotides (9.72 × 10−8) was 9.5-fold that of non-CpG bases, and there was strong evidence (P = 2.67 × 10−4) for a paternal bias in the origin of new mutations (85% paternal). We observed a non-uniform distribution of heterozygous SNVs (both newly identified and known) in the autozygous segments (P = 0.001), which is suggestive of mutational hotspots or sites of long-range gene conversion.

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Figure 1: Relationship of sequenced individuals.
Figure 2: Elevated autozygosity in the Hutterite individuals.
Figure 3: Determination of the MRCA for an autozygous segment.
Figure 4: SNV mutation rate estimates.


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We are grateful to M. Przeworski for thoughtful comments on the manuscript. We thank C. Lee, B. Paeper, J. Smith and M. Rieder for assistance with sequence data generation and J. Huddleston for technical advice. We are grateful to T. Brown for assistance with manuscript preparation. C.D.C. was supported by a US National Institutes of Health (NIH) Ruth L. Kirschstein National Research Service Award (NRSA; F32HG006070). P.H.S. is supported by a Howard Hughes Medical Institute International Student Research Fellowship. This work was supported by an American Asthma Foundation Senior Investigator Award to E.E.E., by US NIH grants R01 HD21244 and R01 HL085197 to C.O. and by US NIH grant R01 HG002899 to M.A. E.E.E. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations



C.D.C., J.X.C., C.O. and E.E.E. designed the study. C.D.C. performed the genome sequencing analysis, molecular inversion probe (MIP)-targeted resequencing analysis and mutation rate calculations. J.X.C. performed analyses to determine the ancestry of the autozygous segments. M.M. performed and analyzed validation experiments, including Sanger sequencing, microarray hybridization and MIP capture. A.K. and P.H.S. performed read-depth copy-number analysis. B.L.D. identified and analyzed the clusters of heterozygous SNVs in the autozygous segments. L.H. and M.A. performed autozygosity analysis with SNP microarray data. L.V. and B.J.O. created the sequencing libraries. B.J.O. designed the MIP oligonucleotides. L.V., along with M.M., performed MIP capture. E.E.E., C.O., M.A. and J.S. supervised the project. C.D.C. and E.E.E. wrote the manuscript with input and approval from all coauthors.

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Correspondence to Evan E Eichler.

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Competing interests

E.E.E. is on the scientific advisory boards for Pacific Biosciences, SynapDx and DNAnexus.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–4 and 6, Supplementary Figures 1–5 and Supplementary Note (PDF 2790 kb)

Supplementary Table 5

Summary of Sanger sequencing validations performed (XLSX 29 kb)

Supplementary Table 7

Summary of putative de novo mutations and validation (XLSX 59 kb)

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Campbell, C., Chong, J., Malig, M. et al. Estimating the human mutation rate using autozygosity in a founder population. Nat Genet 44, 1277–1281 (2012).

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