Evolutionary preservation of CpG dinucleotides in RAG1 may elucidate the relatively high rate of methylation-mediated mutagenesis of RAG1 transposase

TL;DR

This study explores why RAG1, a gene involved in immune system development, has a higher rate of mutations caused by CpG methylation compared to other genes.

Contribution

The study reveals that RAG1 retains a higher proportion of ancestral CpG dinucleotides, making it more susceptible to methylation-mediated mutagenesis.

Findings

57.57% of RAG1 pathogenic mutations and 51.6% of disease-causing mutations are linked to CpG methylation.

RAG1 has a higher percentage of ancestral CpG (6%) compared to RAG2 (4.2%).

CpG loci in RAG1 are more methylated in sperm compared to RAG2.

Abstract

Recombination-activating gene 1 (RAG1) is a vital player in V(D)J recombination, a fundamental process in primary B cell and T cell receptor diversification of the adaptive immune system. Current vertebrate RAG evolved from RAG transposon; however, it has been modified to play a crucial role in the adaptive system instead of being irreversibly silenced by CpG methylation. By interrogating a range of publicly available datasets, the current study investigated whether RAG1 has retained a disproportionate level of its original CpG dinucleotides compared to other genes, thereby rendering it more exposed to methylation-mediated mutation. Here, we show that 57.57% of RAG1 pathogenic mutations and 51.6% of RAG1 disease-causing mutations were associated with CpG methylation, a percentage that was significantly higher than that of its RAG2 cofactor alongside the whole genome. The CpG scores and densities for all RAG ancestors suggested that RAG transposon was CpG denser. The percentage of the ancestral CpG of RAG1 and RAG2 were 6% and 4.2%, respectively, with no preference towards CG containing codons. Furthermore, CpG loci of RAG1 in sperms were significantly higher methylated than that of RAG2. In conclusion, RAG1 has been exposed to CpG mediated methylation mutagenesis more than RAG2 and the whole genome, presumably due to its late entry to the genome later with an initially higher CpG content.

The online version contains supplementary material available at 10.1007/s12026-023-09451-8.

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