Multifarious Evolutionary Pathways of a Nuclear RNA Editing Factor: Disjunctions in Coevolution of DOT4 and Its Chloroplast Target rpoC1eU488SL

Abstract

Despite the fundamental importance of single nucleotide polymorphisms (SNPs) to human evolution, there are still large gaps in our understanding of the forces that shape theirdistribution across the genome. SNPshavebeenshowntonotbe distributedevenly,with directly adjacent SNPs found unusually frequently.Why this is the case is unclear.We illustratehowneighboring SNPs that cannot be explained by a singlemutation event (thatwe termhere sequential dinucleotidemutations [SDMs]) are driven by distinct processes to SNPs and multinucleotide polymorphisms (MNPs). By studying variation across populations, including a novel cohort of 1,358 Scottish genomes,we show that, SDMs are over twice as common asMNPs and like SNPs display distinctmutational spectra across populations. These biases are not only different to those observed among SNPs and MNPs but are also more divergent between human population groups.We show that the changes that make up SDMs are not independent and identify a distinct mutational profile, CA! CG! TG, that is observed an order of magnitude more often than expected from background SNP rates and the numbers of other SDMs involving the gain and deamination of CpG sites. Intriguingly particular pathways through the amino acid code appear to have been favored relative to that expected fromintergenic SDMrates and the occurrences of coding SNPs, and in particular those that lead to the creation of single codon amino acids. We finally present evidence that epistatic selection has potentially disfavored sequential nonsynonymous changes in the human genome.