title: Protein molecular function influences mutation rates in human genetic diseases with allelic heterogeneity.
abstract: Molecular epidemiology studies have used the counts of different mutational types like transitions, transversions, etc. to identify putative mutagens, with little reference to gene organization and structure-function of the translated product. Moreover, geographical variation in the mutational spectrum is not limited to the mutational types at the nucleotide level but also have a bearing at the functional level. Here, we developed a novel measure to estimate the rate of spontaneous detrimental mutations called "mutation index" for comparing the mutational spectra consisting of all single base, missense, and non-missense changes. We have analyzed 1609 mutations occurring in 38 exons in 24 populations in three diseases viz. hemophilia B (F9 gene - 420 mutations in 9 populations across 8 exons), hemophilia A (F8 gene - 650, 8 and 26, respectively) and ovarian carcinoma (TP53 gene - 539, 7 and 4, respectively). We considered exons as units of evolution instead of the entire gene and observed feeble differences among populations implying lack of a mutagen-specific effect and the possibility of mutation causing endogenous factors. In all the three genes we observed elevated rates of detrimental mutations in exons encoding regions of significance for the molecular function of the protein. We propose that this can be extended to the entire exome with implications in exon-shuffling and complex human diseases.
authors.affiliation: Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, CSIR, Delhi, India. sreenivaschavali@gmail.com
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Chavali
authors.forename: Anubha
authors.initials: A
authors.lastname: Mahajan
authors.forename: Saurabh
authors.initials: S
authors.lastname: Ghosh
authors.forename: Bappaditya
authors.initials: B
authors.lastname: Mondal
authors.forename: Dwaipayan
authors.initials: D
authors.lastname: Bharadwaj
mesh_terms: D000483:Alleles; D002277:Carcinoma / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005164:Factor IX / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005169:Factor VIII / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006467:Hemophilia A / Q000235:genetics*; D002836:Hemophilia B / Q000235:genetics*; D006801:Humans; D016296:Mutagenesis; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D005169:Factor VIII; D005164:Factor IX