Retroviruses aided brain evolution

Myelin

The myelin sheath (green) around nerve fibers is produced by special cells called oligodendrocytes. © Peggy Assinck/Altos Labs-Cambridge Institute of Science

Our nerve fibers are surrounded by an insulating layer of myelin. This enables stimuli to be transmitted quickly and effectively and was a prerequisite for the complex brains of vertebrates to develop. A study now shows that an area in our genome that is essential for the production of myelin was probably introduced into our genome by retroviruses hundreds of millions of years ago.

Our nervous system transmits signals via long nerve fibers called axons. In order for this transmission to work as quickly as possible, the axons of the first animals initially became increasingly thicker. But around 420 million years ago, the ancestors of today's vertebrates, including us humans, developed a more effective solution: the so-called myelin sheath. It surrounds the axons as an insulating layer and enables rapid transmission of stimuli in much thinner nerve fibers. In addition, thanks to the myelin layer, the nerve fibers can lie closer together without the signals interfering with each other.

On the trail of an evolutionary trick

“This evolutionary innovation, which first appeared in jawed vertebrates, enabled rapid transmission of nerve impulses and was the prerequisite for more complex brains,” explains a team led by Tanay Ghosh from the University of Cambridge in Great Britain. But how did it happen? To answer this question, Ghosh and his team analyzed gene activity in so-called oligodendrocytes, the cells that produce myelin in the central nervous system.

They placed a particular focus on non-coding regions, i.e. sections of our genome that are not themselves converted into proteins but can have important regulatory tasks. In rats, they discovered such a non-coding section that apparently regulates the production of the so-called basic myelin protein - an indispensable component of the myelin sheath. If they inhibited the corresponding regulatory region, the affected cells could no longer produce myelin basic protein.

Viral DNA in the genome

Sequence comparisons showed that this regulatory unit, which they named RetroMyelin, originally came from ancient retroviruses that integrated their own genetic material into the DNA of early animals. Numerous places in our genome have already been proven to originate from viruses. While many of these so-called endogenous retroviruses have lost their function over time, others are still active today - with some positive and some negative effects. They are involved in making male muscles grow and supporting the formation of the placenta during reproduction. On the other hand, some of these viral fragments are associated with an increased risk of cancer, dementia and multiple sclerosis.

The current study now suggests that endogenous retroviruses played a crucial role in the development of our brain. “Retroviruses were the prerequisite for the evolution of vertebrates to take off,” says Ghosh’s colleague Robin Franklin. “If there had been no retroviruses inserting their sequences into the vertebrate genome, there would have been no myelination, and without myelination the full diversity of vertebrates as we know them would never have existed.”

Vertebrates became infected several times independently of each other

In further studies, the team demonstrated that corresponding RetroMyelin sections occur not only in mammals, but also in all other classes of vertebrates with jaws, i.e. birds, fish, reptiles and amphibians. However, such a sequence was missing in jawless vertebrates such as lampreys and in invertebrates such as fruit flies and nematodes, which do not have myelin sheaths. The researchers also demonstrated that the RetroMyelin sequence also plays a functional role in zebrafish and frogs. If they blocked the sequence in the fertilized eggs of these animals, the myelin production of the offspring was disrupted.

To find out whether RetroMyelin was uniquely incorporated into the DNA of the common ancestor of all jawed vertebrates or whether there were multiple independent infections, Ghosh and his team compared the RetroMyelin sequences from 22 different vertebrates from all clades. It turned out that the sequences in the different vertebrate classes are genetically so far apart that the infections with the responsible retrovirus probably only occurred after the different classes had already separated from each other. “Our results open a new research avenue to investigate how retroviruses generally control evolution,” says Ghosh.

Source: Tanay Ghosh (University of Cambridge, UK) et al., Cell, doi: 10.1016/j.cell.2024.01.011

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