Crossovers are associated with mutation and biased gene conversion at human recombination hotspots
Sprache des Vortragstitels:
7th ÖGMBT Annual Meeting ? Salzburg goes Science
Sprache des Tagungstitel:
Meiosis is a potentially important source of germline mutations, as sites where meiotic recombination happens (also referred as recombination hotspots) experience recurrent double-strand breaks (DSBs). However, evidence for a local mutagenic effect of recombination coming from population sequence data has been equivocal, likely because mutation is only one of several forces shaping sequence variation. By sequencing large numbers of single crossover molecules collected from human sperm for two recombination hotspots, we find direct evidence that recombination is mutagenic: Crossovers carry more de novo mutations than non-recombinant DNA molecules analyzed for the same donors and hotspots. The observed mutations were mainly CG to TA transitions, with a higher frequency of transitions at CpG than non-CpGs sites. This enrichment of mutations at CpG sites at recombination hotspots could predominate in methylated regions involving frequent single-stranded DNA processing as part of DSB repair.
In addition, our data set provides evidence that GC alleles are preferentially transmitted during crossing-over, opposing mutation, and shows that GC-biased gene conversion (gBGC) predominates over mutation in the sequence evolution of recombination hotspots. These findings are consistent with the idea that gBGC could be an adaptation to counteract the mutational load of meiotic recombination.