Sequence evolution at recombination hotspots

Description

Meiotic recombination is concentrated at recombination hotspots determined in most mammals by the activity of PRDM9, a meiosis-specific, multi-domain protein that regulates recombination hotspots by targeting its DNA recognition sequence for double strand breaks (DSBs). The DNA binding sites of PRDM9 quickly erode and are enriched for polymorphisms. At a coarser scale, regions with high recombination activity are characterized by an increased diversity and divergence. Here, we examined the major processes that drive the sequence evolution at hotspots. By sequencing a large number of single recombinants obtained from human sperm, we showed that recombination is mutagenic and crossovers are enriched for CG to TA mutations, especially at methylated CpG sites, which could be the predominant mutational pattern in processes involving single stranded DNA. Our analysis of crossovers also showed that the transmission of GC- is favored over AT-alleles at polymorphic sites, a phenomenon known as GC-biased gene conversion (gBGC). We observed that gBGC was a stronger driver of sequence evolution than mutagenesis, and given the opposing effects of mutagenesis and gBGC on base composition, it is possible that gBGC is an adaptation to reduce the mutational load of recombination. We have also examined the evolution of short tandem repeats (STR) at hotspots. We observed that a long polymorphic tract of polyAs (A9/A19) located at the center of a hotspot can reduce the overall crossover frequency and potentially shift the crossover distribution. Moreover, we observed an insertion-biased gene conversion (iBGC) at a polymorphic STR site (A6/A7), with longer repeats being transmitted more frequently than shorter ones. The molecular mechanisms driving the observed patterns are not fully clear yet; however, the recurrent repair of double-strand breaks (DSB), required for the initiation of recombination, play an important role in the hotspot sequence evolution.

Period	11 Sept 2016
Event title	European Molecular Biology Organisation (EMBO)
Event type	Conference
Location	GermanyShow on map