Abstract
BackgroundA major goal in the study of molecular evolution is to unravel the mechanisms that induce variation in the germ line mutation rate and in the genome-wide mutation profile. The rate of germ line mutation is considerably higher for cytosines at CpG sites than for any other nucleotide in the human genome, an increase commonly attributed to cytosine methylation at CpG sites. The CpG mutation rate, however, is not uniform across the genome and, as methylation levels have recently been shown to vary throughout the genome, it has been hypothesized that methylation status may govern variation in the rate of CpG mutation.ResultsHere, we use genome-wide methylation data from human sperm cells to investigate the impact of DNA methylation on the CpG substitution rate in introns of human genes. We find that there is a significant correlation between the extent of methylation and the substitution rate at CpG sites. Further, we show that the CpG substitution rate is positively correlated with non-CpG divergence, suggesting susceptibility to factors responsible for the general mutation rate in the genome, and negatively correlated with GC content. We only observe a minor contribution of gene expression level, while recombination rate appears to have no significant effect.ConclusionsOur study provides the first direct empirical support for the hypothesis that variation in the level of germ line methylation contributes to substitution rate variation at CpG sites. Moreover, we show that other genomic features also impact on CpG substitution rate variation.
Highlights
A major goal in the study of molecular evolution is to unravel the mechanisms that induce variation in the germ line mutation rate and in the genome-wide mutation profile
To investigate differences of the five explanatory variables among the three datasets defined by the presence or absence of CpG islands (CGIs) and DNase I hypersensitive sites (DHSs), we computed their mean values and variances for each dataset (Table 1)
In light of the expected impact of selection on regions containing CGIs and DHSs, non-CpG divergence is unexpectedly similar for the three datasets
Summary
A major goal in the study of molecular evolution is to unravel the mechanisms that induce variation in the germ line mutation rate and in the genome-wide mutation profile. Examples of factors suggested to be related to mutation rate variation are genetic recombination [6,7], transcription [8,9], replication [10,11], chromatin structure [12,13], distance to telomeres [5], exon density [14] and sequence variables, such as the local GC content [14,15] Several of these factors are strongly interrelated with each other, which complicates unraveling the driving forces of mutation rate variation. This process is initiated via a spontaneous deamination reaction of 5-methylcytosine directly leading to thymine, which is less efficiently repaired by the DNA repair machinery than the cytosine to uracil deamination reaction [20]
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