Differences in the rare variant spectrum among human populations

Mutations occur at vastly different rates across the genome, and populations, leading to differences in the spectrum of segregating polymorphisms. Here, we investigate variation in the rare variant spectrum in a sample of human genomes representing all major world populations. We find at least two distinct signatures of variation. One, consistent with a previously reported signature is characterized by an increased rate of TCC>TTC mutations in people from Western Eurasia and South Asia, likely related to differences in the rate, or efficiency of repair, of damage due to deamination of methylated guanine. We describe the geographic extent of this signature and show that it is detectable in the genomes of ancient, but not archaic humans. The second signature is private to certain Native American populations, and is concentrated at CpG sites. We show that this signature is not driven by differences in the CpG mutation rate, but is a result of the fact that highly mutable CpG sites are more likely to undergo multiple independent mutations across human populations, and the spectrum of such mutations is highly sensitive to recent demography. Both of these effects dramatically affect the spectrum of rare variants across human populations, and should be taken into account when using mutational clocks to make inference about demography.Author summary: Genetic variation among humans is built up by a constant stream of new mutations. New mutations appear every generation because of unrepaired DNA damage, or copying errors in DNA replication. Differences between populations in the rate or types of mutations that appear are one of several factors that affect patterns of genetic variation. Here, we examined genomes from all major world populations, looking at patterns of variation to see whether different types of rare variant were more common in different parts of the world. We found two types of variant that had this property. The first is more common in Western Eurasia than in other parts of the world and seems to be related to an historical increase in the rate of a specific kind of mutation. The second type of variant–C>T changes at CpG sites–is more common in Native Americans, not because mutation rates are different, but because these mutations occur at a very high rate, and this kind of variation is very sensitive to differences in demographic history between populations. These results demonstrate the importance of considering both mutation and demography in the interpretation of genetic variation.