Five hundred million years of methylation: tracing the mutational origins of vertebrate genome composition

A study examined the methylation-induced deamination of CpG sites in vertebrate and invertebrate genomes, aiming to determine how this affects the dinucleotide profile. The research found that CpG depletion was the most significant axis of variation among vertebrates' dinucleotides. Surprisingly, the strongest correlation with this depletion was not the expected TpG/CpA, but AG/CT, which showed consistent patterns across genomes.

Models based on human germline substitution rates did not predict either CpG loss or AG/CT enrichment when methylated-CpG mutability was excluded. However, adding a single CpG-specific mutability term, based on mammalian CpG ratios, explained both the depletion and enrichment of AG/CT. This suggests that AG/CT is a secondary consequence of context-dependent mutations.

In individual genomes, CpG depletion was most pronounced in transposable elements, diminishing as they moved away from these regions. The axis appeared more closely tied to Amniota, a group of vertebrates, than to endothermy, the ability to generate internal body heat. The presence of CpG depletion and AG/CT was the main distinction between vertebrates and invertebrates, with the latter showing significantly less of both phenomena.

The research concludes that methylation-associated changes create a defined axis in vertebrate dinucleotide composition, with AG/CT being its most prominent marker.