Evaluating the contributions of methylation and transcription to male-biased evolution

Abstract

Male biased mutation is thought to be a consequence of mutations introduced during DNA replication. Studies of male bias have generally been restricted to an examination of bias in the total substitution rate rather than the substitution process. In this analysis, the potential contributions of germline sex differences in methylation and transcription to male biased mutation are examined via their effects on the substitution process. It is first shown that one of the post popular methods for modeling the effects of sequence context on nucleotide substitution rates detects an effect of context when none exists, which has important consequences particularly for models that aim to detect natural selection. Transitions involving CpG dinucleotides, which characteristically arise from methylation, are found to make a large contribution to male bias because of CpG frequency differences between the X chromosome and the autosomes. Germline transcription is also found to contribute to male bias, and may completely account for the bias observed in the chimpanzee lineage. These observations indicate that male bias is caused by multiple processes, and the contribution of replication errors is smaller than previously believed.