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A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals

By Vagheesh M. Narasimhan, Raheleh Rahbari, Aylwyn Scally, Arthur Wuster, Dan Mason, Yali Xue, John Wright, Richard C. Trembath, Eamonn R Maher, David A. van Heel, Adam Auton, Matthew E Hurles, Chris Tyler-Smith, Richard Durbin

Posted 17 Jun 2016
bioRxiv DOI: 10.1101/059436

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations (DNMs) across multiple generations. Using exome sequences from 3,222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10-8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germline mutation rate. We found frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5' CCG 3' → 5' CTG 3' context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

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