A new type of evolutionary process has been highlighted

Evolution and natural selection takes place at the DNA level, because genes mutate and genetic traits persist or get lost over time. But now biologists believe that evolution can take place on a whole new scale - transmitted not by genes, but by molecules linked to their surface and responsible for their methylation. This mechanism would allow the conservation of an epigenome by enzymatic processes through several tens of millions of years, according to a process analogous to that of the Darwinian evolution of the genome.

These molecules, known as "methyl groups", modify the structure of DNA and can turn genes on and off. The alterations are known as "epigenetic changes". Many organisms, including humans, have DNA dotted with methyl groups, but creatures like Drosophila and roundworms have lost the genes necessary to do so during the evolutionary period.

Another organism, the yeast Cryptococcus neoformans , also lost key genes for methylation during the Cretaceous, about 50 to 150 million years ago. But remarkably, in its current form, the fungus still has methyl groups in its genome. Now, scientists theorize that C. neoformans was able to conserve epigenetic changes for tens of millions of years, thanks to a new mode of evolution. The study was published in the journal Cell.

Methyl groups present in C. neoformans

The authors generally study C. neoformans to better understand how yeast causes fungal meningitis in humans. The fungus tends to infect people with weak immune systems and causes about 20% of all AIDS-related deaths.

Hiten Madhani, professor of biochemistry and biophysics at the University of California, and his colleagues, spend part of their days researching the genetic code of C. neoformans , looking for critical genes that help yeast invade human cells.

But the team was surprised when reports emerged, suggesting that the genetic material was adorned with methyl groups. In vertebrates and plants, cells add methyl groups to DNA using two enzymes. The first, de novo methyltransferase, links methyl groups to unadorned genes.

Diagram explaining the functioning of methylation via the intervention of de novo methyltransferase and maintenance methyltransferase. Credits: Nature

The enzyme adds to each half of the helical DNA strand the same methyl group pattern, creating a symmetrical design. During cell division, the double helix unwinds and builds two new strands of DNA from the corresponding halves. At this stage, an enzyme called "maintenance methyltransferase" intervenes to copy all the methyl groups from the original strand to the newly constructed half.

De novo methyltransferase loss and maintenance of methyltransferase compensation

Madhani and his colleagues examined existing evolutionary trees to trace the history of C. neoformans over time and found that, during the Cretaceous period, the ancestor of the yeast had the two enzymes necessary for the methylation of l DNA. But somewhere along the line, C. neoformans lost the gene needed to make de novo methyltransferases

During its evolutionary process, C. neoformans lost de novo methyltransferase and retained the maintenance methyltransferase. Credits: Sandra Catania et al. 2020

Without the enzyme, the body could no longer add new methyl groups to its DNA - it could only copy existing methyl groups by using its maintenance enzyme. In theory, even when working alone, the maintenance enzyme could keep DNA covered with methyl groups indefinitely - if it could make a perfect copy every time.

Natural selection at the origin of the conservation of a methylation mechanism

In reality, the team discovered that the enzyme makes mistakes and loses track of methyl groups every time the cell divides. When grown in a petri dish, C. neoformans cells occasionally gain new methyl groups in the same way that random mutations occur in DNA. However, cells lost methyl groups about 20 times faster than they could gain new ones.

In about 7,500 generations, each last methyl group would disappear, leaving nothing to be copied by the maintenance enzyme, the team estimated. Given the speed at which C. neoformans multiplies, the yeast should have lost all of its methyl groups in about 130 years. Instead, it retained the epigenetic changes for tens of millions of years.

Despite the loss of DNMT, C. neoformans can still use methylation thanks to compensation by its maintenance methyltransferase. A process preserved by natural selection. Credits: Sandra Catania et al. 2020

“ Because the rate of loss is higher than the rate of gain, the system would slowly lose methylation over time if there were no mechanism to maintain it. This mechanism is natural selection, ”explains Madhani. In other words, even if C. neoformans gained new methyl groups much more slowly than it lost them, methylation considerably increased the endurance of the organism, which meant that it could surpass individuals with less methylation.

Use methylation to control transposons

Enduring individuals have prevailed over those with fewer methyl groups, and thus, methylation levels have remained higher over millions of years. But what evolutionary advantage could these methyl groups offer to C. neoformans ? Well, they could protect the yeast genome from life-threatening damage.

Transposons, also known as "jumping genes", jump into the genome at will and often fit into very impractical places. For example, a transposon could jump to the center of a gene necessary for cell survival; this cell could malfunction or die. Fortunately, the methyl groups can cling to the transposons and lock them in place. It may be that C. neoformans maintain a certain level of DNA methylation to control transposons.

Understanding methylation in C. neoformans

Many mysteries still surround DNA methylation in C. neoformans . Besides copying methyl groups between strands of DNA, maintenance methyltransferase appears to be important in terms of how yeast causes infection in humans, according to a 2008 study by Madhani. Without the intact enzyme, the body cannot attack cells as effectively.

The enzyme also requires large amounts of chemical energy to function and copies only the methyl groups on the pristine half of the replicated DNA strands. In comparison, the equivalent enzyme in other organisms does not require additional energy to function and sometimes interacts with naked DNA, devoid of any methyl group. Further research will reveal exactly how methylation works in C. neoformans and whether this new form of evolution occurs in other organisms.


Evolutionary Persistence of DNA Methylation for Millions of Years after Ancient Loss of a De Novo Methyltransferase

Sandra Catania, Phillip A. Dumesic, Harold Pimentel,  Ammar Nasif
Caitlin I. Stoddard
Jordan E. Burke
Jolene K. Diedrich
Sophie Cook
Terrance Shea
Elizabeth Geinger
Robert Lintner
John R. Yates III
Petra Hajkova
Geeta J. Narlikar
Christina A. Cuomo
Jonathan K. Pritchard
Hiten D. Madhani

Published:January 16, 2020


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