What factors drive the evolution of human meiotic recombination hotspots?
Sprache des Vortragstitels:
DK SAB meeting 2014, Vetmeduni Vienna
Sprache des Tagungstitel:
Intra- and interspecies comparisons have shown that the base composition at recombination hotspots is rapidly evolving, but it is still highly debated what factors drive this evolution. Meiotic recombination might be mutagenic given that hotspots are recurrently targeted for double strand breaks (DSB), which were shown to be a source of mutations during their repair in mitosis. Yet, it also has been demonstrated that GC-biased gene conversion (gBGC) drives the evolution of recombination hotspots. In order to address the long standing question whether recombination is mutagenic and the role of gBGC in hotspot evolution, we characterized the variation in allelic transmission and frequency of de novo mutations in two human recombination hotspots by screening a large number of single crossover products using sperm typing. Non-recombinant controls were analyzed to obtain a background mutation frequency.
On average we observed 0.0029 new mutations per crossover, which is a 3.5-fold higher frequency of mutations compared to non recombinants. The mutations were predominantly Strong to Weak transitions (S: C or G to W: A or T), with the average mutation frequency for CpG sites 23x higher than for non-CpG sites. CpG sites were shown to be highly methylated in the analyzed regions in sperm DNA. There was no evidence of heterogeneity in the mutation rate among donors, summed over recombinant and non-recombinant types. Additionally, complex crossovers (CCO; conversion events associated with crossovers resulting in haplotype switching within the crossover) were identified at a frequency of 0.0041 (25 CCOs / 6085 mapped crossovers), involving in all cases only one co-converted SNP. Most of the CCOs (56%) lie within 60 bp of another non-converted heterozygous site. In contrast to de novo mutations, these conversion events favored S over W alleles, and could be an important source of GC-biased gene conversion (gBGC).