Ancient retroviruses played a key role in vertebrate brain evolution, researchers suggest

Researchers’ report in the journal Cell that ancient viruses could be the origin of myelin – and, by extension, our large and complex brains.

The team discovered that a retrovirus-derived genetic element or “retrotransposon” is essential for myelin production in mammals, amphibians and fish. The genetic sequence, which they dubbed “RetroMyelin,” is likely the result of an ancient viral infection, and comparisons of RetroMyelin in mammals, amphibians, and fish suggest that retroviral infection and invasion events of the genome occurred separately in each of these groups.

“Retroviruses were necessary for vertebrate evolution to take off,” says lead author and neuroscientist Robin Franklin of the Altos Labs-Cambridge Institute of Science. “If we didn’t have retroviruses inserting their sequences into the vertebrate genome, then myelination would not have occurred, and without myelination, all vertebrate diversity as we know it would never have occurred.”

Myelin is a complex fatty tissue that coats the nerve axons of vertebrates. It allows rapid conduction of impulses without the need to increase axonal diameter, meaning nerves can be brought closer together. It also provides metabolic support to the nerves, meaning the nerves can be made longer.

Myelin first appeared in the tree of life around the same time as jaws, and its importance in vertebrate evolution has long been recognized, but until now it was not known what mechanisms molecules had triggered its appearance.

Researchers noticed RetroMyelin’s role in myelin production when they looked at the gene networks used by oligodendrocytes, the cells that produce myelin in the central nervous system. Specifically, the team was investigating the role of non-coding regions, including retrotransposons, in these gene networks, which has never been explored before in the context of myelin biology.

“Retrotransposons make up about 40% of our genome, but little is known about how they might have helped animals acquire specific traits during evolution,” says first author Tanay Ghosh, a computational biologist at Altos. Labs-Cambridge Institute of Science. “Our motivation was to know how these molecules contribute to evolutionary processes, particularly in the context of myelination.”

In rodents, researchers found that the RetroMyelin RNA transcript regulates the expression of myelin basic protein, one of the key components of myelin. When they experimentally inhibited RetroMyelin in oligodendrocytes and oligodendrocyte progenitor cells (the stem cells from which oligodendrocytes are derived), the cells could no longer produce myelin basic protein.

To examine whether RetroMyelin is present in other vertebrate species, the team searched for similar sequences in the genomes of jawed vertebrates, jawless vertebrates, and several invertebrate species. They identified analogous sequences in all other classes of jawed vertebrates (birds, fish, reptiles and amphibians), but did not find a similar sequence in jawless vertebrates or invertebrates.

“There has been an evolutionary trend to make the impulse conduction of our axons faster, because faster impulse conduction means you can grab objects or run away from them faster,” says Franklin.

Next, the researchers wanted to know whether RetroMyelin was once incorporated into the ancestor of all jawed vertebrates or whether there were distinct retroviral invasions in the different branches.

To answer these questions, they constructed a phylogenetic tree from 22 species of jawed vertebrates and compared their RetroMyelin sequences. The analysis revealed that RetroMyelin sequences were more similar within species than between them, suggesting that RetroMyelin was acquired multiple times during the process of convergent evolution.

The team also showed that RetroMyelin plays a functional role in myelination in fish and amphibians. When they experimentally disrupted the RetroMyelin gene sequence in the fertilized eggs of zebrafish and frogs, they found that the developing fish and tadpoles produced significantly less myelin than usual.

The study highlights the importance of non-coding regions of the genome for physiology and evolution, the researchers say. “Our results open a new avenue of research to explore how retroviruses are more generally involved in driving evolution,” says Ghosh.