Directionality of point mutation and 5-methylcytosine deamination rates in the chimpanzee genome

Cizhong Jiang,Zhongming Zhao

doi:10.1186/1471-2164-7-316

Abstract

BackgroundThe pattern of point mutation is important for studying mutational mechanisms, genome evolution, and diseases. Previous studies of mutation direction were largely based on substitution data from a limited number of loci. To date, there is no genome-wide analysis of mutation direction or methylation-dependent transition rates in the chimpanzee or its categorized genomic regions.ResultsIn this study, we performed a detailed examination of mutation direction in the chimpanzee genome and its categorized genomic regions using 588,918 SNPs whose ancestral alleles could be inferred by mapping them to human genome sequences. The C→T (G→A) changes occurred most frequently in the chimpanzee genome. Each type of transition occurred approximately four times more frequently than each type of transversion. Notably, the frequency of C→T (G→A) was the highest in exons among the genomic categories regardless of whether we calculated directly, normalized with the nucleotide content, or removed the SNPs involved in the CpG effect. Moreover, the directionality of the point mutation in exons and CpG islands were opposite relative to their corresponding intergenic regions, indicating that different forces govern the nucleotide changes. Our analysis suggests that the GC content is not in equilibrium in the chimpanzee genome. Further quantitative analysis revealed that the 5-methylcytosine deamination rates at CpG sites were highly dependent on the local GC content and the lengths of SNP flanking sequences and varied among categorized genomic regions.ConclusionWe present the first mutational spectrum, estimated by three different approaches, in the chimpanzee genome. Our results provide detailed information on recent nucleotide changes and methylation-dependent transition rates in the chimpanzee genome after its split from the human. These results have important implications for understanding genome composition evolution, mechanisms of point mutation, and other genetic factors such as selection, biased codon usage, biased gene conversion, and recombination.

Highlights

The pattern of point mutation is important for studying mutational mechanisms, genome evolution, and diseases
Mutation direction in the chimpanzee genome We identified 702,590 biallelic single nucleotide polymorphisms (SNPs) that were uniquely mapped in the non-repetitive sequences in the chimpanzee genome and had at least 100 nucleotides at each flanking side of the SNPs
5mC deamination rates The results presented above consistently indicate the influence of the hypermutability of methylated CpGs on the mutational spectrum in the chimpanzee genome, especially in the exonic regions

Summary

Introduction

The pattern of point mutation is important for studying mutational mechanisms, genome evolution, and diseases. One recent analysis revealed a bias toward fixation of A/T→G/C mutations with no significant difference between the G/C→A/T and A/T→G/C changes at the polymorphic sites, suggesting that these two changes differed significantly between fixed and polymorphic sites in the 1.8-Mb noncoding regions examined [13] Another prominent feature in the genome composition evolution is the hypermutability of methylated CpG dinucleotides. One way to approach this is to measure the 5mC deamination rate, which is calculated by the difference between CpG transition rate and GpC transition rate [20], because the GpC dinucleotides are not methylated in mammalian genomes [21] This analysis found that the 5mC deamination rates were highly dependent on local GC content in the human genome [20]

Methods

Results

Discussion

Conclusion