An endogenous retrovirus that supports placenta formation in females also helps male mice build muscle, according to a study.
A protein called syncytin, which is of viral origin but several times over evolutionary history has integrated into the genomes of mammals, supports the increase of muscle mass in male mice, according to a study published this week (September 13) in PLOS Genetics. Syncytin was already known to enable placenta formation, and its role in males may help explain why male mammals tend to be bigger and stronger than females.
“This is the first strong line of evidence that retroviral envelope proteins play an important role beyond the placenta,” Cedric Feschotte, an evolutionary biologist at the University of Utah who was not involved in the research, told Nature.
In viruses, syncytin enables membrane fusion with host cells to empty a virus’s genomic content into the cytoplasm. In mammals, the protein plays a similar role in directing cell fusion during the formation of the outer layer of the placenta. “It’s a little mind-boggling to think that cellular fusion is directed by a virus we acquired 30 million years ago,” Lars-Inge Larsson, a pathologist at the University of Copenhagen who did not participate in the study, toldNature.
When virologist Thierry Heidmann of France’s National Centre for Scientific Research (CNRS) and the Université Paris-Sud and his colleagues deleted one version of syncytin (syncytin B) from the mouse genome, however, male knockout mice weighed 18 percent less than animals with both syncytin A and syncytin B. And given that only males were affected, malformation of the placenta clearly wasn’t to blame. “We were very, very surprised to see that the differences were in males but not females,” Heidmann told Nature.
Syncytin was already known to be active in immature muscle cells called myoblasts, and mature muscle cells formed via the fusion of immature myoblasts. Sure enough, the small size of the male syncytin Bknockout mice could be explained by reduced muscle mass, with these animals displaying 20 percent fewer muscle fibers and fewer nuclei per fiber. Further experiments demonstrated that both forms of syncytin were active during muscle formation and that blocking them reduced cellular fusion by more than 40 percent, Nature reported.
Syncytins have also been found to be active in immune cells, and of course, many other retrovirus remnants still linger in the genome. In terms of biological functions for these ancient viral proteins, “what we’re seeing is probably just the tip of the iceberg,” Fechotte told Nature.
The Loom
Mammals Made By Viruses
If not for a virus, none of us would ever be born.
In 2000, a team of Boston scientists discovered a peculiar gene in the human genome. It encoded a protein made only by cells in the placenta. They called it syncytin.
The cells that made syncytin were located only where the placenta made contact with the uterus. They fuse together to create a single cellular layer, called the syncytiotrophoblast, which is essential to a fetus for drawing nutrients from its mother. The scientists discovered that in order to fuse together, the cells must first make syncytin.
What made syncytin peculiar was that it was not a human gene. It bore all the hallmarks of a gene from a virus.
Viruses have insinuated themselves into the genome of our ancestors for hundreds of millions of years. They typically have gotten there by infecting eggs or sperm, inserting their own DNA into ours. There are 100,000 known fragments of viruses in the human genome, making up over 8% of our DNA. Most of this virus DNA has been hit by so many mutations that it’s nothing but baggage our species carries along from one generation to the next. Yet there are some viral genes that still make proteins in our bodies. Syncytin appeared to be a hugely important one to our own biology. Originally, syncytin allowed viruses to fuse host cells together so they could spread from one cell to another. Now the protein allowed babies to fuse to their mothers.
It turned out that syncytin was not unique to humans. Chimpanzees had the same virus gene at the same spot in their genome. So did gorillas. So did monkeys. What’s more, the gene was strikingly similar from one species to the next. The best way to explain this pattern was that the virus that gave us syncytin infected a common ancestor of primates, and it carried out an important function that has been favored ever since by natural selection. Later, the French virologist Thierry Heidmann and his colleagues discovereda second version of syncytin in humans and other primates, and dubbed them syncytin 1 and syncytin 2. Both virus proteins seemed to be important to our well-being. In pre-eclampsia, which gives pregnant women dangerously high blood pressure, levels of both syncytin 1 and syncytin 2drop dramatically. Syncytin 2 also performs another viral trick to help its human master: it helps tamp down the mother’s immune system so she doesn’t attack her baby as a hunk of foreign tissue.
In 2005, Heidmann and his colleagues realized that syncytins were not just for primates. While surveying the mouse genome, they discovered two syncytin genes (these known as A and B), which were also produced in the same part of the placenta. This discovery allowed the scientists to test once and for all how important syncytin was to mammals. They shut down the syncytin A gene in mouse embryos and discovered they died after about 11 days because they couldn’t form their syncytiotrophoblast. So clearly this virus mattered enormously to its permanent host.