Why do human diversity levels vary at a megabase scale?

Abstract

Levels of diversity vary across the human genome. This variation is caused by two forces: differences in mutation rates and the differential impact of natural selection. Pertinent to the question of the relative importance of these two forces is the observation that both diversity within species and interspecies divergence increase with recombination rates. This suggests that mutation and recombination are either directly coupled or linked through some third factor. Here, we test these possibilities using the recently generated sequence of the chimpanzee genome and new estimates of human diversity. We find that measures of GC and CpG content, simple-repeat structures, as well as the distance from the centromeres and the telomeres predict diversity as well as divergence. After controlling for these factors, large-scale recombination rates measured from pedigrees are still significant predictors of human diversity and human-chimpanzee divergence. Furthermore, the correlation between human diversity and recombination remains significant even after controlling for human-chimpanzee divergence. Two plausible and non-mutually exclusive explanations are, first, that natural selection has shaped the patterns of diversity seen in humans and, second, that recombination rates across the genome have changed since humans and chimpanzees shared a common ancestor, so that current recombination rates are a better predictor of diversity than of divergence. Because there are indications that recombination rates may have changed rapidly during human evolution, we favor the latter explanation.