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Extensive variation in the mutation rate between and within human genes associated with Mendelian disease

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posted on 2023-06-09, 00:36 authored by Thomas Smith, Gladys Ho, John Christodoulou, Elizabeth Ann Price, Zerrin Onadim, Marion Gauthier-Villars, Catherine Dehainault, Claude Houdayer, Beatrice Parfait, Rick van Minkelen, Dietmar Lohman, Adam Eyre-WalkerAdam Eyre-Walker
We have investigated whether the mutation rate varies between genes and sites using de novo mutations (DNMs) from three genes associated with Mendelian diseases (RB1, NF1, and MECP2). We show that the relative frequency of mutations at CpG dinucleotides relative to non-CpG sites varies between genes and relative to the genomic average. In particular we show that the rate of transition mutation at CpG sites relative to the rate of non-CpG transversion is substantially higher in our disease genes than amongst DNMs in general; the rate of CpG transition can be several hundred-fold greater than the rate of non-CpG transversion. We also show that the mutation rate varies significantly between sites of a particular mutational type, such as non-CpG transversion, within a gene. We estimate that for all categories of sites, except CpG transitions, there is at least a 30-fold difference in the mutation rate between the 10% of sites with the highest and lowest mutation rates. However, our best estimate is that the mutation rate varies by several hundred-fold variation. We suggest that the presence of hypermutable sites may be one reason certain genes are associated with disease.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Human Mutation

ISSN

1059-7794

Publisher

Wiley

Issue

5

Volume

37

Page range

488-494

Department affiliated with

  • Evolution, Behaviour and Environment Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-03-18

First Open Access (FOA) Date

2017-03-14

First Compliant Deposit (FCD) Date

2016-03-18

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