Linked mutations at adjacent nucleotides have shaped human population differentiation and protein evolution

Abstract Despite the fundamental importance of single nucleotide polymorphisms (SNPs) to human phenotypes there are still large gaps in our understanding of the forces that shape their distribution across the genome. SNPs have been shown to not be distributed randomly, with directly adjacent SNPs found more often than expected by chance. Why this is the case is unclear. In this study we illustrate how neighbouring SNPs are driven by distinct mutational processes and selective pressures. By characterising multi-nucleotide polymorphisms (MNPs) across multiple populations, including a novel cohort of 1,358 Scottish genomes, we show that, like SNPs, MNPs display distinct mutational spectra across populations. These biases are though not only different to those observed among SNPs, but more clearly define population groups. The changes that make up MNPs are not independent, with CA→CG→TG changes observed an order of magnitude more often than other changes involving the gain and subsequent deamination of CpG sites, suggesting these changes are driven by a distinct mutational process. In coding regions these particular biases have favoured the creation of single codon amino acids, offsetting the low frequency with which they are created by SNPs. Intriguingly selection has favoured particular pathways through the amino acid code, with epistatic selection appearing to have disfavoured sequential non-synonymous changes.