This continues our series of blog posts from PLOS Genetics about our monthly issue images. Author Laurent Duret talks about November’s image from their article, Lesecque et al.
Author: Laurent Duret
Competing interests: Laurent Duret is an author of the article discussed in this blog.
The Red Queen hypothesis proposes that an organism must constantly evolve to allow the species to survive. In this issue of PLOS Genetics, we show that a similar process might account for the very rapid evolution of recombination hotspots within genomes. By analyzing the genome sequence of an archaic human (Denisova), we observed that recombination hotspots have a very short lifespan, caused by a strong process of self-destruction. This suggests that the molecular machinery that determines the location of hotspots must constantly evolve to find new target and thus compensate for the loss of hotspots.
During meiosis, homologous recombination leads to the exchange of genetic information between chromosomes. This process contributes to population genetic diversity and is required for the segregation of chromosomes during meiosis. Recombination is initiated by the formation of double-strand breaks (DSBs), whose repair generates crossover or non-crossover recombination events. In humans and mice, meiotic DSBs occur at specific sites along chromosomes, called hotspots, whose location is primarily determined by the PRDM9 protein [1,2]. In primates and rodents, PRDM9 evolves extremely rapidly and is highly polymorphic, specifically in its DNA binding domain. There is clear evidence that this domain evolves under strong positive selective pressure to change of target , which leads to rapid changes in the location of hotspots. However, the reasons why there is a need for PRDM9 to evolve so rapidly are not known.
The Red Queen hypothesis
In this paper, we test a hypothesis, initially proposed by Myers and colleagues , that the evolution of PRDM9 might be a consequence of a Red Queen process. This model stems of the fact that recombination hotspots are subject to self-destruction, by the phenomenon of biased gene conversion (BGC) . Indeed, the repair of DSBs leads to the conversion of recombination-prone alleles by hotspot-disrupting alleles (we call this form of BGC ‘dBGC’, for DSB-driven BGC). Over generations, the progressive degradation of recombination hotspots through dBGC is expected to lead to a loss of fitness, because the lack recombination can cause a loss of fertility, due to improper chromosome disjunction. Thus, according to this model, the evolution of recombination hotspots would be the consequence of a Red Queen process , in which PRDM9 has to evolve constantly to compensate for the loss of its targets and maintain a sufficient number of recombination hotspots in the genome.
Insights from an archaic human genome
The Red Queen model is a very elegant hypothesis, but up to now has never been tested quantitatively. Is this process of dBGC strong enough to cause a significant depletion of PRDM9 target motifs within the genome in just a few million years (i.e. at the scale of the divergence between human and chimpanzee)? To address this question, we analyzed the genome sequence of an archaic human (Denisova) that diverged from modern humans about 400,000-800,000 years ago . Our results show that human hotspots are younger than previously thought, as the onset of human hotspots activity can be dated to the last 10% of time since the human-chimpanzee split (i.e. 0.7 to 1.3 MYR ago, depending on the estimate of the chimpanzee/human divergence time). Furthermore, multiple lines of evidence reveal that recombination hotspots were not shared between Denisovans and modern humans, indicating that the hotspot turnover can be very fast. We analyzed polymorphism data in human populations to quantify the strength of dBGC on the major PRDM9 target motif (HM). We found that the dBGC process is very strong, and if it remained constant over time (i.e. if PRDM9 alleles remained at the same frequency as in present-day human populations), about 90% of HM motifs located in recombination hotspots would be lost over the next 100,000 generations. In less than 3 MYRs, the dBGC process would therefore lead to a total change in recombination hotspot activity. These observations are fully consistent with the Red Queen hypothesis of recombination hotspot evolution.
1. Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, et al. (2010) PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327: 836–840. doi:10.1126/science.1183439.
2. Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, et al. (2010) Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science 327: 876–879. doi:10.1126/science.1182363.
3. Ponting CP (2011) What are the genomic drivers of the rapid evolution of PRDM9? Trends Genet 27: 165–171. doi:10.1016/j.tig.2011.02.001.
4. Lesecque, Y, Glémin S, Lartillot N, Mouchiroud D., and Duret L (2014) The Red Queen Model of Recombination Hotspots Evolution in the Light of Archaic and Modern Human Genomes. PLoS Genet, 10: e1004790. doi:10.1371/journal.pgen.1004790