title: Extensive Variation in the Mutation Rate Between and Within Human Genes Associated with Mendelian Disease.
abstract: 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.
authors: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors: Thomas
authors: T
authors: Smith
authors: NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
authors: Gladys
authors: G
authors: Ho
authors: NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.|Disciplines of Paediatrics and Child Health and Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, Australia.
authors: John
authors: J
authors: Christodoulou
authors: Retinoblastoma Genetic Screening Unit, Barts Health NHS Trust, The Royal London Hospital, 80 Newark Street, London, United Kingdom.
authors: Elizabeth Ann
authors: EA
authors: Price
authors: Retinoblastoma Genetic Screening Unit, Barts Health NHS Trust, The Royal London Hospital, 80 Newark Street, London, United Kingdom.
authors: Zerrin
authors: Z
authors: Onadim
authors: Service de Génétique, Institut Curie, Paris, France.
authors: Marion
authors: M
authors: Gauthier-Villars
authors: Service de Génétique, Institut Curie, Paris, France.
authors: Catherine
authors: C
authors: Dehainault
authors: Service de Génétique, Institut Curie, Paris, France.|INSERM U830, centre de recherche de l'Institut Curie, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Claude
authors: C
authors: Houdayer
authors: EA7331, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Service de Biochimie et de Génétique Moléculaire, Hôpital Cochin, AP-HP, Paris, France.
authors: Beatrice
authors: B
authors: Parfait
authors: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands.
authors: Rick
authors: R
authors: van Minkelen
authors: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors: Dietmar
authors: D
authors: Lohman
authors: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors: Adam
authors: A
authors: Eyre-Walker
mesh_terms: D000465:Algorithms; D018389:Codon, Nonsense; D018899:CpG Islands; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D059645:Mutation Rate; D025542:Neurofibromin 1 / Q000235:genetics*; D056286:Retinoblastoma Binding Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D025542:Neurofibromin 1; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases
keywords: CpG; Human mutation; Hypermutation; MECP2; Mendelian disease; NF1; RB1