Ancient retroviruses played a key role in the evolution of vertebrate brains

Researchers report February 15 in the journal Cell that ancient viruses may be to thank for myelin -- and, by extension, our large, complex brains. The team found that a retrovirus-derived genetic element or "retrotransposon" is essential for myelin production in mammals, amphibians, and fish. The gene sequence, which they dubbed "RetroMyelin," is likely a result of ancient viral infection, and comparisons of RetroMyelin in mammals, amphibians, and fish suggest that retroviral infection and genome-invasion events occurred separately in each of these groups.

"Retroviruses were required for vertebrate evolution to take off," says senior author and neuroscientist Robin Franklin of Altos Labs-Cambridge Institute of Science.

"If we didn't have retroviruses sticking their sequences into the vertebrate genome, then myelination wouldn't have happened, and without myelination, the whole diversity of vertebrates as we know it would never have happened."

Myelin is a complex, fatty tissue that ensheathes vertebrate nerve axons.

It enables rapid impulse conduction without needing to increase axonal diameter, which means nerves can be packed closer together.

It also provides metabolic support to nerves, which means nerves can be 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 unclear what molecular mechanisms triggered its appearance.

The researchers noticed RetroMyelin's role in myelin production when they were examining the gene networks utilized by oligodendrocytes, the cells that produce myelin in the central nervous system.

Specifically, the team was investigating the role of noncoding regions including retrotransposons in these gene networks -- something that hasn't previously been explored in the context of myelin biology.

"Retrotransposons compose about 40% of our genomes, but nothing is known about how they might have helped animals acquire specific characteristics 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 are helping evolutionary processes, specifically in the context of myelination."

In rodents, the researchers found that the RNA transcript of RetroMyelin 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 within 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's been an evolutionary drive to make impulse conduction of our axons quicker because having quicker impulse conduction means you can catch things or flee from things more rapidly," says Franklin.

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

To answer these questions, they constructed a phylogenetic tree from 22 jawed vertebrate species and compared their RetroMyelin sequences.

The analysis revealed that RetroMyelin sequences were more similar within than between species, which suggests that RetroMyelin was acquired multiple times through 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.

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Madagascar mouse lemur retroviruses are diverse and surprisingly similar to ones found in polar bears or domestic sheep

Madagascar is home to a unique biodiversity with a large number of endemic species, among those many lemur species, including the mouse lemurs. This diversity is also found in their retroviruses, a team led by scientists from the Leibniz Institute of Zoo and Wildlife Research (Leibniz-IZW) and the University of Stirling reports in the journal "Virus Evolution." They analysed the mouse lemur genome and identified viruses of two classes that represent ancient infections of the mouse lemur germline. The viruses now behave similarly to lemur genes and are thus called endogenous retroviruses (ERVs). It was surprising that some of the identified retroviruses are closely related to viruses found in other, very different mammals such as polar bears or domestic sheep. This suggests an intriguing and complex pattern of host switching of retroviruses, much more complex than previously thought.

For their analysis, the team collected blood samples from four species of Malagasy mouse lemurs and screened them using high throughput sequencing. The scientists identified two gamma and three beta retrovirus sequences in the lemurs' genomes, representing ancient infections of the mouse lemur germlines. Since then, the virus DNA has been incorporated in the host genomes and the viruses are no longer active or infectious. "We were surprised to find that one of the two identified gamma retroviruses was related to an ERV described in polar bears," states Dr Sharon Kessler, a German Academic Exchange Service (DAAD) supported scientist and Assistant Professor at the University of Stirling. The polar bear virus is young from an evolutionary point of view whereas the lemur virus is old. "How these related viruses infected such geographically separated species is unclear," Kessler says.

There were further surprises among the beta retroviruses. A virulent retrovirus that infects domestic sheep called Jaagsiekte sheep retrovirus (JSRV), which also forms ERVs in domestic sheep, is thought to be a virus confined to domestic sheep, goats and their relatives -- the first cloned sheep "Dolly" had to be euthanised after a JSRV infection and subsequent illness. The mouse lemurs have a closely related JSRV-like virus in their genome. "This suggests that JSRV-like viruses have been more widespread among mammals and are considerably older than previously thought. Why they only show up in such disparate species and in such a punctuated way is curious," says Prof Alex Greenwood, head of the Leibniz-IZW Department of Wildlife Diseases, where the sample screening was conducted. Similarly, the team also identified a virus in the mouse lemurs related to retroviruses found in squirrel monkeys, vampire bats and marsupials. "This group of viruses is becoming more interesting over time as more and more examples of similar viruses are being found in many places including very young ones that may still have currently infectious exogenous counterparts in nature," says Greenwood.

Much of the mouse lemur retroviral diversity observed is associated with non-primate viruses, suggesting a complex pattern of viral host switching around the time the ancestors of lemurs colonized Madagascar. Further studies of viral diversity will help to clarify the complex history of retroviral transmission among mammals.

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Ancient viral elements embedded in human genome not from fossil retrovirus

Using a next generation sequencing analysis to examine human endogenous retrovirus (HERV) integration sites, researchers from Kumamoto University, the National Institute of Genetics (Japan), and the University of Michigan (USA) have discovered that these ancient retroviruses can undergo retrotransposition (DNA sequence insertion with RNA mediation) into iPS cells. The team believes that their discovery places a spotlight on a possible risk that HERVs pose when using iPS cells in regenerative medicine.

The study of ancient retroviruses embedded in our genome requires knowledge about our coexistence with viral threats throughout history. We know that HERVs occupy approximately 8% of the human genome and obtain mutations and deletions over long periods. HERVs are also expressed in early embryos and play several physiological roles in human development. For example, HERV-W and HERV-FRD Env proteins are important for placental formation, and HERV-K is thought to protect host cells from exogenous retrovirus infection. However, uncontrollable HERV-K expression is also thought to be associated with various diseases, including various cancers and neurological diseases, but the details of this association is not well known in humans.

Since no one has yet discovered replication competent HERVs in our genome, it is thought that they are from an extinct (fossil) virus. In their current work, the research team from Japan and the US discovered that HERV-K is expressed in SOX2-expressing cells, such as those in early embryos, cancer stem cells and iPS cells. They also found that some HERV-K are newly integrated into the host genome in the absence of Env, the viral envelope glycoprotein. This integration was dependent on reverse transcriptase, integrase and protease, thus the researchers hypothesized that the HERV-K embedded in our genome is actually not from a fossil virus, but moves on the genome through the synthesis of proviral DNA reverse transcription. Interestingly, when the researchers compared the HERV-K integration sites between iPS and fibroblast cells from the same donor, they found new HERV-K integration sites in iPS cells. However, the new integration sites were rarely preserved and disappeared during long-term culturing. HERV-K is likely to be randomly integrated into genome, thus the possibility remains that HERV-K retrotransposed-cells predominantly survive depending on their integration site.

The movement of HERV-K on the genome might cause cancer and neurological diseases by altering the gene expression profile. The researchers believe that the risk of HERV-K transposition is low in iPS cells but suggest that monitoring HERV-K integration sites should be seriously considered to improve the safety of regenerative medicine using iPS cells.

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