Abstract
The “heterozygote instability” (HI) hypothesis suggests that gene conversion events focused on heterozygous sites during meiosis locally increase the mutation rate, but this hypothesis remains largely untested. As humans left Africa they lost variability, which, if HI operates, should have reduced the mutation rate in non-Africans. Relative substitution rates were quantified in diverse humans using aligned whole genome sequences from the 1,000 genomes project. Substitution rate is consistently greater in Africans than in non-Africans, but only in diploid regions of the genome, consistent with a role for heterozygosity. Analysing the same data partitioned into a series of non-overlapping 2 Mb windows reveals a strong, non-linear correlation between the amount of heterozygosity lost “out of Africa” and the difference in substitution rate between Africans and non-Africans. Putative recent mutations, derived variants that occur only once among the 80 human chromosomes sampled, occur preferentially at the centre of 2 Kb windows that have elevated heterozygosity compared both with the same region in a closely related population and with an immediately adjacent region in the same population. More than half of all substitutions appear attributable to variation in heterozygosity. This observation provides strong support for HI with implications for many branches of evolutionary biology.
Highlights
Mutations provide the clay on which evolution operates and understanding where and when they occur is critical to many branches of evolutionary biology
One mechanism that might contribute to these heterogeneities in diploid organisms is ‘heterozygote instability’ (HI), a suggestion that mutation rate increases at and near heterozygous sites where the two homologous chromosomes differ in sequence [13]
Two non-overlapping clusters are seen: all Africans have both higher heterozygosity and higher mean relative substitution rate (RSR) compared with all non-Africans
Summary
Mutations provide the clay on which evolution operates and understanding where and when they occur is critical to many branches of evolutionary biology. One mechanism that might contribute to these heterogeneities in diploid organisms is ‘heterozygote instability’ (HI), a suggestion that mutation rate increases at and near heterozygous sites where the two homologous chromosomes differ in sequence [13]. Direct empirical support for HI comes from studies in yeast where, during synapsis, extensive regions of heteroduplex DNA are formed in which heterozygous sites appear as mismatches [14,15]. Such mismatches are recognised by mismatch repair enzymes and these initiate gene conversion-like events [16], where the extra round of DNA replication might be expected to provide opportunities for additional mutations [10,13]. HI is implicated by the way human microsatellite mutation rate increases with population size and with heterozygosity [17,18]
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