Abstract
DNA methylation is mediated by a conserved family of DNA methyltransferases (Dnmts). The human genome encodes three active Dnmts (Dnmt1, Dnmt3a and Dnmt3b), the tRNA methyltransferase Dnmt2, and the regulatory protein Dnmt3L. Despite their high degree of conservation among different species, genes encoding Dnmts have been duplicated and/or lost in multiple lineages throughout evolution, indicating that the DNA methylation machinery has some potential to undergo evolutionary change. However, little is known about the extent to which this machinery, or the methylome, varies among vertebrates. Here, we study the molecular evolution of Dnmt1, the enzyme responsible for maintenance of DNA methylation patterns after replication, in 79 vertebrate species. Our analyses show that all studied species exhibit a single copy of the DNMT1 gene, with the exception of tilapia and marsupials (tammar wallaby, koala, Tasmanian devil and opossum), each of which displays two apparently functional DNMT1 copies. Our phylogenetic analyses indicate that DNMT1 duplicated before the radiation of major marsupial groups (i.e., at least ~75 million years ago), thus giving rise to two DNMT1 copies in marsupials (copy 1 and copy 2). In the opossum lineage, copy 2 was lost, and copy 1 recently duplicated again, generating three DNMT1 copies: two putatively functional genes (copy 1a and 1b) and one pseudogene (copy 1ψ). Both marsupial copies (DNMT1 copies 1 and 2) are under purifying selection, and copy 2 exhibits elevated rates of evolution and signatures of positive selection, suggesting a scenario of neofunctionalization. This gene duplication might have resulted in modifications in marsupial methylomes and their dynamics.
Highlights
In vertebrate genomes, cytosine methylation is widespread (e.g., 60–90% of CpGs are methylated in mammals [1,2]) and plays pivotal roles in the silencing of gene expression and transposable elements, gene imprinting, and X-chromosome inactivation [3]
Our analyses reveal that all studied species have a single DNMT1 copy, with the only exception of tilapia and marsupials, each of which exhibit two putatively functional DNMT1 copies
The second copy is located in a very small scaffold (AERX01074151.1, 3084 nucleotides), which only covers exons 36–40 (184 amino acids; throughout this manuscript, exons for non-human DNMT1 genes are numbered based on the homologous exons in the human DNMT1, using the transcript encoding the Dnmt1s isoform)
Summary
Cytosine methylation is widespread (e.g., 60–90% of CpGs are methylated in mammals [1,2]) and plays pivotal roles in the silencing of gene expression and transposable elements, gene imprinting, and X-chromosome inactivation [3]. DNA methylation is mediated by a conserved family of DNA methyltransferases (Dnmts). Molecular evolution of DNMT1 in vertebrates role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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