Vagheesh Narasimhan
Wellcome Trust Sanger Institute
A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals
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
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 å± 0.05 ÌÑ 10-8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 å± 0.05 ÌÑ 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‰Ûª CCG 3‰Ûª‰Ûä‰ Õ‰Ûä5‰Ûª CTG 3‰Ûª context in the Pakistani population compared to Europeans.
