Researchers discover methylation can persist despite loss of DNA methyltransferase

Methylation is a heritable information pattern found in living organisms - distinct from the DNA sequence - that governs expression of genes. Methylation does not occur in all species, but it is not uncommon. Until this publication the methylation pattern has been understood by scientists to rely on enzymes to deposit and maintain it.

Researchers at the University of California San Francisco (UCSF) have found Cryptococcus neoformans - a pathogenic yeast - has a specific epigenetic pattern on its DNA sequence but lacks the gene which typically encodes DNA methyltransferase. 

Madhani and his team observed that the seeming common ancestor of C. neofrmans had two enzymes that controlled DNA methylation. One, commonly called the de novo methyltransferase, was responsible for adding methylation marks to the DNA that didn’t have any, and the other enzyme worked during DNA replication and copied methylation marks onto DNA that didn’t have a methyl group.

The study, published in Cell on Jan. 16, suggests that Cryptococcus neoformans lost the de novo DNA methyltransferase around the time when dinosaurs roamed the earth.  Despite this loss specific epigenetic marks have been retained on the DNA sequence when current models would have predicted the methylation pattern to have disappeared. 

This finding, by Hiten Madhani, M.D., Ph.D, and professor of biochemistry and biophysics at UCSF, and his research team could turn what we know of natural selection on its head. 

“What we’ve seen is that methylation can undergo natural variation and can be selected for over million-year time scales to drive evolution,” explained Hiten Madhani, MD, PhD, professor of biochemistry and biophysics at UCSF and senior author of the new study.

"Natural selection is maintaining methylation at much higher levels than would be expected from a neutral process of random gains and losses. This is the epigenetic equivalent of Darwinian evolution," said Madhani. "This is a previously unappreciated mode of evolution that's not based on changes in the organism's DNA sequence."