Methylation-driven model for analysis of dinucleotide evolution in genomes

Abstract

Background: CpGs, the major methylation sites in vertebrate genomes, exhibit a high mutation rate from the methylated form of CpG to TpG/CpA and, therefore, influence the evolution of genome composition. However, the quantitative effects of CpG to TpG/CpA mutations on the evolution of genome composition in terms of the dinucleotide frequencies/proportions remain poorly understood. Results: Based on the neutral theory of molecular evolution, we propose a methylation-driven model (MDM) that allows predicting the changes in frequencies/proportions of the 16 dinucleotides and in the GC content of a genome given the known number of CpG to TpG/CpA mutations. The application of MDM to the 10 published vertebrate genomes shows that, for most of the 16 dinucleotides and the GC content, a good consistency is achieved between the predicted and observed trends of changes in the frequencies and content relative to the assumed initial values, and that the model performs better on the mammalian genomes than it does on the lowervertebrate genomes. The model's performance depends on the genome composition characteristics, the assumed initial state of the genome, and the estimated parameters, one or more of which are responsible for the different application effects on the mammalian and lower-vertebrate genomes and for the large deviations of the predicted frequencies of a few dinucleotides from their observed frequencies. Conclusions: Despite certain limitations of the current model, the successful application to the higher-vertebrate (mammalian) genomes witnesses its potential for facilitating studies aimed at understanding the role of methylation in driving the evolution of genome dinucleotide composition.

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“…Interestingly, the data of Cagan et al, 2022 reveal that C>T transitions in mtDNA with age occur commonly within a CpT context (particularly at GCT motifs), in keeping with our data showing extensive CpT representation within regions of differential methylation. mtDNA methylation may therefore not be only of interest in a mechanistic context but also in an evolutionary context, in which C>T transitions within certain regions may have shaped the mitochondrial genome through time ( 44 ). It would therefore be of interest to determine whether C>T transitions within the mtDNA are located within distinct regions across genera.…”