Crossovers are associated with mutation and biased gene conversion at recombination hotspots
Sprache des Vortragstitels:
5th Central European Genome Stability and Dynamics Meeting
Sprache des Tagungstitel:
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 ~50-fold higher frequency of transitions at CpG than non CpGs sites. This enrichment of mutations at CpG sites in hotspots is not representative of genome-wide mutation averages, but could dominate in 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.