University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

‘Living Fossil’ May Upend Basic Tenet of Evolutionary Theory

Natural Selection’s Reach Extends Beyond Genome into Epigenome, Study Suggests

By Jason Alvarez | | January 16, 2020

‘Living Fossil’ May Upend Basic Tenet of Evolutionary Theory

Hiten Madhani, MD, PhD, professor of biochemistry and biophysics at UCSF and senior author of the new study.

The field of evolutionary biology has seen its share of spirited debates. But if there's one principle that virtually every expert in the field agrees on, it’s that natural selection occurs at the level of the genome. 

But now, a UC San Francisco–led research team has discovered the first conclusive evidence that selection may also occur at the level of the epigenome — a term that refers to an assortment of chemical “annotations” to the genome that determine whether, when and to what extent genes are activated — and has done so for tens of millions of years. This unprecedented finding subverts the widely accepted notion that over geologic timescales, natural selection acts exclusively on variation in the genome sequence itself.

In a study published Jan. 16, 2020 in the journal Cell, the researchers show that Cryptococcus neoformans — a pathogenic yeast that infects people with weakened immune systems and is responsible for about 20 percent of all HIV/AIDS-related deaths — contains a particular epigenetic “mark” on its DNA sequence, which, based on their lab experiments and statistical models, should have disappeared from the species sometime during the age of the dinosaurs. 

But the study shows that this methylation mark — so named because it’s created through a process that attaches a molecular tag called a methyl group to the genome — has managed to stick around for at least 50 million years — maybe as long as 150 million years — past its predicted expiration date. This amazing feat of evolutionary tenacity is made possible by an unusual enzyme and a hefty dose of natural selection.

“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. “This is a previously unappreciated mode of evolution that’s not based on changes in the organism’s DNA sequence.”

Though not seen in all life forms, DNA methylation isn’t uncommon either. It’s found in all vertebrates and plants, as well as many fungi and insects. In some species, however, methylation is nowhere to be found.

“Methylation has a patchy evolutionary presence,” said Madhani, who is also a member of the UCSF Helen Diller Family Comprehensive Cancer Center and a Chan-Zuckerberg Biohub investigator. “Depending on what branch of the evolutionary tree you look at, different epigenetic mechanisms have been maintained or not maintained.”