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Estimating the human mutation rate using autozygosity in a founder population.

  • Author(s): Campbell, Catarina D;
  • Chong, Jessica X;
  • Malig, Maika;
  • Ko, Arthur;
  • Dumont, Beth L;
  • Han, Lide;
  • Vives, Laura;
  • O'Roak, Brian J;
  • Sudmant, Peter H;
  • Shendure, Jay;
  • Abney, Mark;
  • Ober, Carole;
  • Eichler, Evan E
  • et al.

Published Web Location

https://doi.org/10.1038/ng.2418
Abstract

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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