Mutagenesis at recombination hotspots

Description

Meiosis could be a potentially important source of germline mutations, as sites of meiotic recombination experience recurrent double-strand breaks (DSBs). However, evidence for a local mutagenic effect of recombination in population sequence data has been equivocal,likely because mutation is only one of several forces shaping sequence variation. By sequencing a large number of single crossover molecules obtained from human sperm for two recombination hotspots, we find direct evidence that recombination is mutagenic. Crossovers carry more de novo mutations than the respective non-recombinant DNA molecules. The observed mutations were primarily CG to TA transitions with a 30-40-fold higher frequency of transitions at CpG than non CpGs sites. This enrichment of mutations at CpG sites could dominate in methylated regions involving frequent single stranded DNA processing, as part of DSB repair. In addition to mutations, our large data set also provides new evidence that transmission of GC alleles is favored during crossing over and shows that GC-biased gene conversion (gBGC) is a strong driver of hotspot sequence evolution opposing mutation. Our findings are consistent with the idea that gBGC might be an adaptation to counteract the mutational load of recombination.

Period	26 Feb 2015
Event title	The Human Mutation Rate Meeting (THMR2015)
Event type	Conference
Location	GermanyShow on map