TY - JOUR T1 - A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals JF - bioRxiv DO - 10.1101/059436 SP - 059436 AU - Vagheesh M Narasimhan AU - Raheleh Rahbari AU - Aylwyn Scally AU - Arthur Wuster AU - Dan Mason AU - Yali Xue AU - John Wright AU - Richard C Trembath AU - Eamonn R Maher AU - David A van Heel AU - Adam Auton AU - Matthew E Hurles AU - Chris Tyler-Smith AU - Richard Durbin Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/06/17/059436.abstract N2 - 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. ER -