Center for Rett Syndrome Research Western Sydney Genetics Program Childrens Hospital at Westmead Sydney Australia

Australia

Center for Rett Syndrome Research Western Sydney Genetics Program Childrens Hospital at Westmead Sydney Australia

Australia

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Smith T.,University of Sussex | Ho G.,Center for Rett Syndrome Research Western Sydney Genetics Program Childrens Hospital at Westmead Sydney Australia | Christodoulou J.,University of Sydney | Price E.A.,Retinoblastoma Genetic Screening Unit Barts Health NHS Trust The Royal London Hospital 80 Newark Street London United Kingdom | And 8 more authors.
Human Mutation | Year: 2016

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. © 2016 Wiley Periodicals, Inc.

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