Event

Cryptococcus neoformans is opportunistic yeast pathogen responsible for ~200,000 deaths annually. We recently investigated cytosine DNA methylation, an epigenetic mechanism involved in genome defense, in this organism. In humans, cytosine methylation is initiated by so called de novo DNA methyltransferases (DNMTs) which can be subsequently ‘remembered’ by a maintenance enzyme that methylates hemimethylated DNA produced by DNA replication. CpG methylation in C. neoformans is mediated by Dnmt5, the only DNMT in C. neoformans. Biochemical analysis revealed it to be an exquisitely-specific maintenance type enzyme that only recognizes hemimethylated DNA. In vivo, methylation is not globally restored once the gene for Dnmt5 is removed from cells and then re-introduced. This indicates that Dnmt5 acts as a maintenance enzyme in cells. As Dnmt5 is the only DNMT in C. neoformans, how then was methylation ever established in the first place? Our evolutionary studies revealed that the ancestor of C. neoformans harbored both a gene for Dnmt5 but also a gene for a second Dnmt, DnmtX, which we show is a de novo enzyme. The gene for DnmtX was lost between 50 and 150 million years ago, thus DNA methylation has been maintained for millions of years without a de novo enzyme. We next performed experimental evolution experiments and phylogenetic analysis of DNA methylation itself. These studies revealed that methylation has been maintained by a Darwinian process in which random rare losses and rarer gains of methylation occur and are then maintained by natural selection for methylation on transposable elements. This Darwinian mode of methylation evolution indicates that DNA sequence is not the only substrate for evolution.

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References:

Catania et al. (2020) Cell 180, 263-277

Dumesic et al. (2020) Molecular Cell epub ahead of print May 20, 2020