Sex chromosomes appear to be outliers in terms of genomic divergence, primarily because they spend different relative amounts of time in the male and female germlines compared to autosomes. However, a recent study indicated that regional variation in divergence, at least in rodents, is better captured by segments approximately 1 Mb in size, and that variation within autosomes is more significant than that among autosomes. Many studies have indicated that either whole autosomes or regions of conserved synteny are 'units' within which substitution rates are relatively homogeneous. Īnother area of interest is the scale and evolutionary conservation of variation in substitution rates. Recombination rate is another important predictor of mammalian divergence, and mechanistically can lead to increased mutation rates through incorrect repair of double-strand breaks, although for humans this has not been demonstrated unequivocally and is still debated. The relationship between divergence and GC content was found to be biphasic, that is, to show a curved trend, perhaps reflecting the presence of mutational hotspots at CpG sites. Interestingly, neutral substitution rates have also been shown to correlate with GC content, local recombination rates, and distance to telomeres. Moreover, such rates have been shown to co-vary with other measures of change in chromosomal DNA, including rates of small insertions and deletions, insertions of transposable elements, and single nucleotide polymorphisms (SNPs), leading to the hypothesis that some regions in the genome are more prone to evolutionary change of any kind compared with other regions. Rates of nucleotide substitution (divergence) at neutral sites are known to vary within mammalian and other genomes. Improvements in these models may play a role in the development of more accurate computational methods for the identification of functional elements. Additionally, identifying and quantifying the effects of genomic parameters that predict neutral substitution rates is crucial for pursuing a more realistic modeling of neutral versus selective processes acting on the human genome. Finally, our results suggest that the performance of conservation-based prediction methods can be improved by accounting for neutral rates.Ī better understanding of mutation processes is important for investigating the causes of human genetic diseases and studying the dynamics of molecular evolution. We also have evidence that the nonlinear increase in rates at high GC levels may be largely due to hyper-mutability of CpG dinucleotides. Our results suggest that while female recombination may be mainly responsible for driving evolution in GC content, male recombination may be mutagenic, and that other mutagenic mechanisms acting near telomeres, and mechanisms whose effects are shared across mammalian genomes, play significant roles. Finally, we find the neutral rate to be negatively correlated with the densities of several classes of computationally predicted functional elements, and less so with the densities of certain classes of experimentally verified functional elements. Additionally, we demonstrate that the previously observed biphasic relationship between neutral rate and GC content can be accounted for by properly combining rates at CpG and non-CpG sites. Using regression analyses we find that male mutation bias, male (but not female) recombination rate, distance to telomeres and substitution rates computed from orthologous regions in mouse-rat and dog-cow comparisons are prominent predictors of the neutral rate. Here we investigate the human-macaque neutral substitution rate as a function of a number of genomic parameters. The evolutionary distance between human and macaque is particularly attractive for investigating local variation in neutral substitution rates, because substitutions can be inferred more reliably than in comparisons with rodents and are less influenced by the effects of current and ancient diversity than in comparisons with closer primates.
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