Seoighe Cathal, Scally Aylwyn
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.
PLoS Genet. 2017 Jan 17;13(1):e1006549. doi: 10.1371/journal.pgen.1006549. eCollection 2017 Jan.
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.
种系突变率在不同物种间差异很大，但对于同一物种个体之间种系突变率的变化程度却知之甚少。在此，我们证明，一个增加种系突变率的等位基因可在与受影响位点相连的基因组区域产生独特的特征，其特点是在携带典型比例衍生等位基因的单倍型背景下，有许多单倍型具有局部高比例的衍生等位基因。我们在千人基因组计划第3阶段的人类单倍型数据中寻找这一特征，并报告了一些候选突变基因座，其中几个位于参与DNA修复或DNA损伤反应的基因附近或内部。为了研究这些基因座上是否有任何突变等位基因仍处于活跃状态，我们利用了千人基因组计划和荷兰基因组队列中人类亲子三人组的新生突变计数，寻找在这些基因座上携带候选突变单倍型的父母所生后代中新生突变数量增加的情况。我们发现其中两个候选基因座有一定证据支持，包括一个位于BRSK2基因上游的基因座，该基因在睾丸中表达，并且据报道参与DNA损伤反应。
