Cryptic variation in the human mutation rate

Abstract

The mutation rate is known to vary between adjacent sites within the human genome as a consequence of context, the most well-studied example being the influence of CpG dinucelotides. We investigated whether there is additional variation by testing whether there is an excess of sites at which both humans and chimpanzees have a single-nucleotide polymorphism (SNP). We found a highly significant excess of such sites, and we demonstrated that this excess is not due to neighbouring nucleotide effects, ancestral polymorphism, or natural selection. We therefore infer that there is cryptic variation in the mutation rate. However, although this variation in the mutation rate is not associated with the adjacent nucleotides, we show that there are highly nonrandom patterns of nucleotides that extend approximately 80 base pairs on either side of sites with coincident SNPs, suggesting that there are extensive and complex context effects. Finally, we estimate the level of variation needed to produce the excess of coincident SNPs and show that there is a similar, or higher, level of variation in the mutation rate associated with this cryptic process than there is associated with adjacent nucleotides, including the CpG effect. We conclude that there is substantial variation in the mutation that has, until now, been hidden from view.

Figure 1. The Number of Human SNPs at Each Site of the Human–Chimpanzee Alignments Used in the Analysis

Figure 2. Heterogeneity in Triplet Frequencies

This figure gives the log value from a chi-square test of heterogeneity of triplet frequencies at each site of the human–chimpanzee alignment versus the average triplet frequencies across the whole alignment for (A) alignments containing a coincident SNP, and (B) alignments without a coincident SNP, but with a chimpanzee SNP at the central position. The line marks the point above which 5% of the chi-square values are expected to fall by chance alone. The chi-square values are not given for the central three sites because the presence of the chimpanzee SNP in the centre of the alignment means that triplets cannot be counted at positions 0, +1, and −1.