%0 Journal Article %A Vagheesh M Narasimhan %A Raheleh Rahbari %A Aylwyn Scally %A Arthur Wuster %A Dan Mason %A Yali Xue %A John Wright %A Richard C Trembath %A Eamonn R Maher %A David A van Heel %A Adam Auton %A Matthew E Hurles %A Chris Tyler-Smith %A Richard Durbin %T A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals %D 2016 %R 10.1101/059436 %J bioRxiv %P 059436 %X 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 noncrossover 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. %U https://www.biorxiv.org/content/biorxiv/early/2016/06/17/059436.full.pdf