The Influence of Recombination on Human Genetic Diversity

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Abstract
In humans, the rate of recombination, as measured on the megabase scale, is positively associated with the level of genetic variation, as measured at the genic scale. Despite considerable debate, it is not clear whether these factors are causally linked or, if they are, whether this is driven by the repeated action of adaptive evolution or molecular processes such as double-strand break formation and mismatch repair. We introduce three innovations to the analysis of recombination and diversity: fine-scale genetic maps estimated from genotype experiments that identify recombination hotspots at the kilobase scale, analysis of an entire human chromosome, and the use of wavelet techniques to identify correlations acting at different scales. We show that recombination influences genetic diversity only at the level of recombination hotspots. Hotspots are also associated with local increases in GC content and the relative frequency of GC-increasing mutations but have no effect on substitution rates. Broad-scale association between recombination and diversity is explained through covariance of both factors with base composition. To our knowledge, these results are the first evidence of a direct and local influence of recombination hotspots on genetic variation and the fate of individual mutations. However, that hotspots have no influence on substitution rates suggests that they are too ephemeral on an evolutionary time scale to have a strong influence on broader scale patterns of base composition and long-term molecular evolution. Patterns of genetic variation in the human genome provide a history of the evolutionary forces that have shaped our species. The role of one factor, recombination, in shaping variation is much debated. The observation is that regions of the genome with high recombination also have high levels of genetic variation, but this pattern can be interpreted as evidence for either repeated, widespread adaptive evolution or correlation through neutral factors such as base composition. To resolve this issue, the authors constructed a genetic map of human Chromosome 20 that has a resolution more than three orders in magnitude greater than previous maps. By comparing the location of recombination hotspots with patterns of genetic variation, evolution, and base composition, the authors show that recombination has only a very local influence on diversity, which suggests that molecular mechanisms, such as mismatch-associated repair or double-strand break formation, not adaptive evolution, drives the association.