The Impact of Recombination on Nucleotide Substitutions in the Human Genome

Abstract

Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major issue for detecting selection within sequences. Mammalian genomes show large-scale regional variations of GC-content (the isochores), but the substitution processes at the origin of this structure are poorly understood. We analyzed the pattern of neutral substitutions in 1 Gb of primate non-coding regions. We show that the GC-content toward which sequences are evolving is strongly negatively correlated to the distance to telomeres and positively correlated to the rate of crossovers (R ² = 47%). This demonstrates that recombination has a major impact on substitution patterns in human, driving the evolution of GC-content. The evolution of GC-content correlates much more strongly with male than with female crossover rate, which rules out selectionist models for the evolution of isochores. This effect of recombination is most probably a consequence of the neutral process of biased gene conversion (BGC) occurring within recombination hotspots. We show that the predictions of this model fit very well with the observed substitution patterns in the human genome. This model notably explains the positive correlation between substitution rate and recombination rate. Theoretical calculations indicate that variations in population size or density in recombination hotspots can have a very strong impact on the evolution of base composition. Furthermore, recombination hotspots can create strong substitution hotspots. This molecular drive affects both coding and non-coding regions. We therefore conclude that along with mutation, selection and drift, BGC is one of the major factors driving genome evolution. Our results also shed light on variations in the rate of crossover relative to non-crossover events, along chromosomes and according to sex, and also on the conservation of hotspot density between human and chimp.

Author Summary

Mammalian genomes show a very strong heterogeneity of base composition along chromosomes (the so-called isochores). The functional significance of these peculiar genomic landscapes is highly debated: do isochores confer some selective advantage, or are they simply the by-product of neutral evolutionary processes? To resolve this issue, we analyzed the pattern of substitution in the human genome by comparison with chimpanzee and macaque. We show that the evolution of base composition (GC-content) is essentially determined by the rate of recombination. This effect appears to be much stronger in male than in female germline, which rules out selective explanations for the evolution of isochores. We show that this impact of recombination is most probably a consequence of the process of biased gene conversion (BGC). This neutral process mimics the action of selection and can induce strong substitution hotspots within recombination hotspots, sometimes leading to the fixation of deleterious mutations. BGC appears to be one of the major factors driving genome evolution. It is therefore essential to take this process into account if we want to be able to interpret genome sequences.