Linked Mutations at Adjacent Nucleotides Have Shaped Human Population Differentiation and Protein Evolution

Area of Science:

• Genetics
• Human Evolution
• Genomics

Background:

• Single nucleotide polymorphisms (SNPs) are crucial for human evolution, but their genomic distribution and the forces shaping them remain incompletely understood.
• Adjacent SNPs occur more frequently than expected, a phenomenon not fully explained by current models.

Purpose of the Study:

• To investigate the distinct evolutionary processes driving sequential dinucleotide mutations (SDMs), which are adjacent SNPs not explained by a single mutation event.
• To compare the frequency, mutational spectra, and population divergence of SDMs with SNPs and multinucleotide polymorphisms (MNPs).

Main Methods:

• Analysis of variation across diverse human populations, including a new cohort of 1,358 Scottish genomes.
• Characterization of mutational spectra and biases associated with SDMs, SNPs, and MNPs.
• Investigation of specific mutational profiles and their prevalence, such as the CA → CG → TG pathway.

Main Results:

• SDMs are over twice as common as MNPs and exhibit distinct mutational spectra compared to SNPs and MNPs.
• SDM biases show greater divergence between human population groups than those of SNPs and MNPs.
• A specific mutational profile (CA → CG → TG) is observed at a much higher frequency than expected, and certain amino acid pathways appear favored.

Conclusions:

• SDMs are driven by processes distinct from SNPs and MNPs, with significant population-specific mutational biases.
• The non-independent nature of SDM changes and favored amino acid pathways suggest unique evolutionary pressures.
• Evidence suggests epistatic selection may disfavor sequential nonsynonymous changes in the human genome.