Estimation of DNA Sequence Context-dependent Mutation Rates Using Primate Genomic Sequences

Abstract

It is understood that DNA and amino acid substitution rates are highly sequence context-dependent, e.g., C --> T substitutions in vertebrates may occur much more frequently at CpG sites and that cysteine substitution rates may depend on support of the context for participation in a disulfide bond. Furthermore, many applications rely on quantitative models of nucleotide or amino acid substitution, including phylogenetic inference and identification of amino acid sequence positions involved in functional specificity. We describe quantification of the context dependence of nucleotide substitution rates using baboon, chimpanzee, and human genomic sequence data generated by the NISC Comparative Sequencing Program. Relative mutation rates are reported for the 96 classes of mutations of the form 5' alphabetagamma 3' --> 5' alphadeltagamma 3', where alpha, beta, gamma, and delta are nucleotides and beta not equal delta, based on maximum likelihood calculations. Our results confirm that C --> T substitutions are enhanced at CpG sites compared with other transitions, relatively independent of the identity of the preceding nucleotide. While, as expected, transitions generally occur more frequently than transversions, we find that the most frequent transversions involve the C at CpG sites (CpG transversions) and that their rate is comparable to the rate of transitions at non-CpG sites. A four-class model of the rates of context-dependent evolution of primate DNA sequences, CpG transitions > non-CpG transitions approximately CpG transversions > non-CpG transversions, captures qualitative features of the mutation spectrum. We find that despite qualitative similarity of mutation rates among different genomic regions, there are statistically significant differences.

Inference of Mutation Parameters and Selective Constraint in Mammalian Coding Sequences by Approximate Bayesian Computation

“…In agreement with previous work (Siepel and Haussler 2004;Zhang et al 2007), the transition:transversion mutation rate ratio is substantially higher at CpG than non-CpG sites. The transition:transversion ratio parameters are fairly consistent across the three taxa, but this contrasts with the substantial differences among taxa in the CpG:nonCpG mutation rate (a), most notably in primates.…”

“…Notably, the a estimate in primates is nearly twice that of murids and carnivores. Estimates of transition:transversion mutational parameters (b CG and b nCG ) are fairly similar between the two taxa and broadly agree with previous estimates from a different approach (i.e., b CG ¼ $10 and b nCG ¼ $4, respectively; Zhang et al 2007).…”

“…In analyzing real data, by definition we do not know the true parameter values, so assigning limits for priors can therefore be problematic. We therefore assigned limits for the mutation rate parameter priors that are wide ranges about empirically estimated values for mammals (Siepel and Haussler 2004;Zhang et al 2007). The prior limits for C S and C N include the maximum possible value (1) and a rate of synonymous or nonsynonymous evolution twice the neutral rate (i.e., C S and C N ¼ À1).…”

Epigenetic Inheritance: A Contributor to Species Differentiation?

“…CG decay rates were higher in CG islands that are methylated in neutrophils of human, chimp, and orang, relative to CG islands that are not methylated in these species. The rate of CG decay that we infer for the germline methylated CG islands is consistent with estimates obtained in other studies (Nachman and Crowell, 2000;Arndt et al, 2003;Kondrashov, 2003;Hwang and Green, 2004;Zhang et al, 2007); however, in this case the availability of somatic methylation data allowed us to distinguish CG islands that are methylated in the germline from those that are not . We also found evidence that CG islands whose somatic methylation differs in human and chimp are differentially methylated in the germline, supporting the idea that epigenetic events have contributed to the divergence of the two species, as discussed in this review.…”

Point Mutations, Their Transition Rates and Involvements in Human and Animal Disorders

“…In attempting to quantify the context dependence of nucleotide substitution rates, Zhang et al (2007) generated sequence data in baboon, chimpanzee and human by the NISC Comparative Sequencing Program. The study confirmed that C→T substitutions are enhanced at CpG sites compared with other transitions, and are relatively independent of the identity of the preceding nucleotide.…”