PT  - JOURNAL ARTICLE
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
TI  - A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals
AID  - 10.1101/059436
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 059436
4099  - http://biorxiv.org/content/early/2016/06/17/059436.short
4100  - http://biorxiv.org/content/early/2016/06/17/059436.full
AB  - 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.