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Estimating the human mutation rate from autozygous segments reveals population differences in human mutational processes

Published version
Peer-reviewed

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Article

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Authors

Narasimhan, VM 
Maher, ER 

Abstract

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 find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5’ CCG 3’ to 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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Keywords

Exome, Genetics, Population, Genome, Human, Germ-Line Mutation, Heterozygote, Homozygote, Humans, Mutation, Mutation Rate, Polymorphism, Genetic

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

8

Publisher

Springer Nature
Sponsorship
The study was funded by the Wellcome Trust (WT102627 & WT098051). This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber. Core support for Born in Bradford is also provided by the Wellcome Trust (WT101597).