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Methods for incorporating the hypermutability of CpG dinucleotides in detecting natural selection operating at the amino acid sequence level.

ABSTRACT: In detecting natural selection operating at the amino acid sequence level by comparing the rates of synonymous (r(S)) and nonsynonymous (r(N)) substitutions, the rates of synonymous and nonsynonymous mutations are assumed to be approximately the same. In reality, however, these rates may not be the same if different proportions of synonymous and nonsynonymous sites overlap with CpG dinucleotides, which are known to be hypermutable in some organisms. Here, we develop the evolutionary pathway methods for comparing r(S) and r(N) at multiple codon sites (all-sites analysis) and at single codon sites (single-site analysis) that take into account the hypermutability at CpG dinucleotides in estimating the number of synonymous substitutions per synonymous site (d(S)) and nonsynonymous substitutions per nonsynonymous site (d(N)). Computer simulations show that the direction and magnitude of the bias in the estimation of d(N)/d(S) caused by the hypermutability of CpGs are determined by both the number of CpGs and the relative proportions of synonymous and nonsynonymous sites overlapping with CpGs. This bias is greatly reduced when using the methods we propose to account for the hypermutability of CpG dinucleotides. In an all-sites analysis of protamine 1 genes from primates, d(N)/d(S) > 1 was observed for many pairs if the hypermutability was ignored. However, d(N)/d(S) becomes

SUBMITTER: Suzuki Y

PROVIDER: S-EPMC2766935 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Methods for incorporating the hypermutability of CpG dinucleotides in detecting natural selection operating at the amino acid sequence level.

Suzuki Yoshiyuki Y Gojobori Takashi T Kumar Sudhir S

Molecular biology and evolution 20090706 10

In detecting natural selection operating at the amino acid sequence level by comparing the rates of synonymous (r(S)) and nonsynonymous (r(N)) substitutions, the rates of synonymous and nonsynonymous mutations are assumed to be approximately the same. In reality, however, these rates may not be the same if different proportions of synonymous and nonsynonymous sites overlap with CpG dinucleotides, which are known to be hypermutable in some organisms. Here, we develop the evolutionary pathway meth ...[more]

PMID: 19581348

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Project description:BackgroundLoss of CpG dinucleotides in genomic DNA through methylation-induced mutation is characteristic of vertebrates and plants. However, these and other eukaryotic phyla show a range of other dinucleotide frequency biases with currently uncharacterized underlying mutational or selection mechanisms. We developed a parameterized Markov process to identify what neighbour context-dependent mutations best accounted for patterns of dinucleotide frequency biases in genomic and cytoplasmically expressed mRNA sequences of different vertebrates, other eukaryotic groups and RNA viruses that infect them.ResultsConsistently, 11- to 14-fold greater frequencies of the methylation-associated mutation of C to T upstream of G (depicted as C?T,G) than other transitions best modelled dinucleotide frequencies in mammalian genomic DNA. However, further mutations such as G?T,T (5-fold greater than the default transversion rate) were required to account for the full spectrum of dinucleotide frequencies in mammalian sequence datasets. Consistent with modeling predictions for these two mutations, instability of both CpG and CpT dinucleotides was identified through SNP frequency analysis of human DNA sequences. Different sets of context-dependent mutations were modelled in other eukaryotes with non-methylated genomic DNA. In contrast to genomic DNA, best-fit models of dinucleotide frequencies in transcribed RNA sequences expressed in the cytoplasm from all organisms were dominated by mutations that eliminated UpA dinucleotides, observations consistent with cytoplasmically driven selection for mRNA stability. Surprisingly, mRNA sequences from organisms with methylated genomes showed evidence for additional selection against CpG through further context-dependent mutations (eg. C?A,G). Similar mutation or selection processes were identified among single-stranded mammalian RNA viruses; these potentially account for their previously described but unexplained under-representations of CpG and UpA dinucleotides.ConclusionsMethods we have developed identify mutational processes and selection pressures in organisms that provide new insights into nucleotide compositional constraints and a wealth of biochemical and evolutionarily testable predictions for the future.

Project description:BackgroundPapillomaviruses and polyomaviruses are small ds-DNA viruses infecting a wide-range of vertebrate hosts. Evidence supporting co-evolution of the virus with the host does not fully explain the evolutionary path of papillomaviruses and polyomaviruses. Studies analyzing CpG dinucleotide frequencies in virus genomes have provided interesting insights on virus evolution. CpG dinucleotide depletion has not been extensively studied among papillomaviruses and polyomaviruses. We sought to analyze the relative abundance of dinucleotides and the relative roles of evolutionary pressures in papillomaviruses and polyomaviruses.MethodsWe studied 127 full-length sequences from papillomaviruses and 56 full-length sequences from polyomaviruses. We analyzed the relative abundance of dinucleotides, effective codon number (ENC), differences in synonymous codon usage. We examined the association, if any, between the extent of CpG dinucleotide depletion and the evolutionary lineage of the infected host. We also investigated the contribution of mutational pressure and translational selection to the evolution of papillomaviruses and polyomaviruses.ResultsAll papillomaviruses and polyomaviruses are CpG depleted. Interestingly, the evolutionary lineage of the infected host determines the extent of CpG depletion among papillomaviruses and polyomaviruses. CpG dinucleotide depletion was more pronounced among papillomaviruses and polyomaviruses infecting human and other mammals as compared to those infecting birds. Our findings demonstrate that CpG depletion among papillomaviruses is linked to mutational pressure; while CpG depletion among polyomaviruses is linked to translational selection. We also present evidence that suggests methylation of CpG dinucleotides may explain, at least in part, the depletion of CpG dinucleotides among papillomaviruses but not polyomaviruses.ConclusionsThe extent of CpG depletion among papillomaviruses and polyomaviruses is linked to the evolutionary lineage of the infected host. Our results highlight the existence of divergent evolutionary pressures leading to CpG dinucleotide depletion among small ds-DNA viruses infecting vertebrate hosts.

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Methods for incorporating the hypermutability of CpG dinucleotides in detecting natural selection operating at the amino acid sequence level.

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Methods for incorporating the hypermutability of CpG dinucleotides in detecting natural selection operating at the amino acid sequence level.

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