GC-Biased Gene Conversion in Yeast Is Specifically Associated with Crossovers: Molecular Mechanisms and Evolutionary Significance

GC-biased gene conversion (gBGC) is a process associated with recombination that favors the transmission of GC alleles over AT alleles during meiosis. gBGC plays a major role in genome evolution in many eukaryotes. However, the molecular mechanisms of gBGC are still unknown. Different steps of the recombination process could potentially cause gBGC: the formation of double-strand breaks (DSBs), the invasion of the homologous or sister chromatid, and the repair of mismatches in heteroduplexes. To investigate these models, we analyzed a genome-wide data set of crossovers (COs) and noncrossovers (NCOs) in Saccharomyces cerevisiae. We demonstrate that the overtransmission of GC alleles is specific to COs and that it occurs among conversion tracts in which all alleles are converted from the same donor haplotype. Thus, gBGC results from a process that leads to long-patch repair. We show that gBGC is associated with longer tracts and that it is driven by the nature (GC or AT) of the alleles located at the extremities of the tract. These observations invalidate the hypotheses that gBGC is due to the base excision repair machinery or to a bias in DSB formation and suggest that in S. cerevisiae, gBGC is caused by the mismatch repair (MMR) system. We propose that the presence of nicks on both DNA strands during CO resolution could be the cause of the bias in MMR activity. Our observations are consistent with the hypothesis that gBGC is a nonadaptive consequence of a selective pressure to limit the mutation rate in mitotic cells

The Red Queen Model of Recombination Hotspots Evolution in the Light of Archaic and Modern Human Genomes

International audienceRecombination is an essential process in eukaryotes, which increases diversity by disrupting genetic linkage between loci and ensures the proper segregation of chromosomes during meiosis. In the human genome, recombination events are clustered in hotspots, whose location is determined by the PRDM9 protein. There is evidence that the location of hotspots evolves rapidly, as a consequence of changes in PRDM9 DNA-binding domain. However, the reasons for these changes and the rate at which they occur are not known. In this study, we investigated the evolution of human hotspot loci and of PRDM9 target motifs, both in modern and archaic human lineages (Denisovan) to quantify the dynamic of hotspot turnover during the recent period of human evolution. We show that present-day human hotspots are young: they have been active only during the last 10% of the time since the divergence from chimpanzee, starting to be operating shortly before the split between Denisovans and modern humans. Surprisingly, however, our analyses indicate that Denisovan recombination hotspots did not overlap with modern human ones, despite sharing similar PRDM9 target motifs. We further show that high-affinity PRDM9 target motifs are subject to a strong self-destructive drive, known as biased gene conversion (BGC), which should lead to the loss of the majority of them in the next 3 MYR. This depletion of PRDM9 genomic targets is expected to decrease fitness, and thereby to favor new PRDM9 alleles binding different motifs. Our refined estimates of the age and life expectancy of human hotspots provide empirical evidence in support of the Red Queen hypothesis of recombination hotspots evolution

XACT, a long non-coding transcript coating the active X chromosome in human pluripotent cells

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