Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation

Abstract

Transitions at CpG dinucleotides, referred to as ''CpG substitutions'', are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides) mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates. We show that CpG substitutions occur approximately 15 times more frequently than other single nucleotide substitutions in primate genomes, and that they exhibit substantial regional variation. Patterns of CpG rate variation are consistent with differences in methylation level and susceptibility to subsequent deamination. In particular, we propose a ''distance-decaying'' hypothesis, positing that due to the molecular mechanism of a CpG substitution, rates are correlated with the stability of double-stranded DNA surrounding each CpG dinucleotide, and the effect of local DNA stability may decrease with distance from the CpG dinucleotide. Consistent with our ''distance-decaying'' hypothesis, rates of CpG substitution are strongly (negatively) correlated with regional G+C content. The influence of G+C content decays as the distance from the target CpG site increases. We estimate that the influence of local G+C content extends up to 1,500,2,000 bps centered on each CpG site. We also show that the distance-decaying relationship persisted when we controlled for the effect of long-range homogeneity of nucleotide composition. GpC sites, in contrast, do not exhibit such ''distance-decaying'' relationship. Our results highlight an example of the distinctive properties of methylation-dependent substitutions versus substitutions mostly arising from errors during DNA replication. Furthermore, the negative relationship between G+C content and CpG rates may provide an explanation for the observation that GC-rich SINEs show lower CpG rates than other repetitive elements.

What Signatures Dominantly Associate with Gene Age?

“…It is well documented that GC content, as one of the most fundamental gene features, is highly correlated with multiple factors [including mutation (Fryxell and Moon 2005), selection for specific synonymous codons for translation efficiency and accuracy (Plotkin and Kudla 2011), horizontal gene transfer (Philippe and Douady 2003), methylation modification (Bird 1986; Elango et al 2008), and gene density (Duret et al 1995), etc.]. It is notable that even though we separately examined factors known to associate with GC content, including gene length, expression, codon usage, selection strength and methylation, we still observe the dominant significance of GC content in the evolution.…”

Estimates of the Effect of Natural Selection on Protein-Coding Content

“…We sought to assess the robustness of the models to these biases. We chose primate introns as they experience the same mutagenic environment as their flanking exons (Green et al 2003; Duret et al 2006, Elango et al 2008), they are not affected by selection for protein-coding content, and they are mostly nonfunctional (Siepel et al 2005). Using these sequences, we were able to demonstrate that ω = 1 (i.e., no effect of protein-coding selection) from our new model but that previous models led to inaccurate estimates of ω ≠ 1. ω was estimated from intronic sequences using the trinucleotide rather than codon model variants as introns can include trinucleotides that are invalid for codon models (see Theory and Methods).…”

Doubts about complex speciation between humans and chimpanzees

“…For the same reason, estimating α from human–macaque divergence might not accurately reflect α for recent human or chimpanzee molecular evolutionary history. Indeed, genome-scale data show that male-biased mutation is considerably lower in Old World monkeys than in hominoids [39–41]. …”