title: Inference of Candidate Germline Mutator Loci in Humans from Genome-Wide Haplotype Data.
abstract: The rate of germline mutation varies widely between species but little is known about the extent of variation in the germline mutation rate between individuals of the same species. Here we demonstrate that an allele that increases the rate of germline mutation can result in a distinctive signature in the genomic region linked to the affected locus, characterized by a number of haplotypes with a locally high proportion of derived alleles, against a background of haplotypes carrying a typical proportion of derived alleles. We searched for this signature in human haplotype data from phase 3 of the 1000 Genomes Project and report a number of candidate mutator loci, several of which are located close to or within genes involved in DNA repair or the DNA damage response. To investigate whether mutator alleles remained active at any of these loci, we used de novo mutation counts from human parent-offspring trios in the 1000 Genomes and Genome of the Netherlands cohorts, looking for an elevated number of de novo mutations in the offspring of parents carrying a candidate mutator haplotype at each of these loci. We found some support for two of the candidate loci, including one locus just upstream of the BRSK2 gene, which is expressed in the testis and has been reported to be involved in the response to DNA damage.
authors.affiliation: School of Mathematics, Statistics and Applied Mathematics, NUI Galway, Galway, Ireland.|Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Cathal
authors.identifier: 0000-0003-0496-4029
authors.initials: C
authors.lastname: Seoighe
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Aylwyn
authors.identifier: 0000-0002-0807-1167
authors.initials: A
authors.lastname: Scally
mesh_terms: D004260:DNA Repair / Q000235:genetics; D005787:Gene Frequency; D056426:Genetic Loci; D015894:Genome, Human; D018095:Germ-Line Mutation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D059645:Mutation Rate; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics
chemical_list: C507732:Brsk2 protein, human; D017346:Protein Serine-Threonine Kinases