Survival of the Viral

Darwin 200 / by Abbie Smith /

Studying genetic "mistakes," like endogenous retroviruses, would have led us to a theory of evolution, even if Charles Darwin had not.

Endogenous retrovirus. Illustration by Emilie Clark

Science can be a strange kind of voodoo. Sometimes that’s true in a figurative sense — experiments don’t seem to work properly unless you click your heels three times, throw a pinch of salt over your left shoulder, and the Moon is in the right phase. Other times its literally voodoo, like when I bring the dead back to life on my lab bench, conjuring up viruses that were buried alive millions of years ago.

I work with endogenous retroviruses (ERV), remnants of viruses that went extinct long ago but that still inhabit the genome of every vertebrate on the planet.
This year, as we celebrate Charles Darwin and his theory of natural selection, I make this assertion: If Darwin had never been born, and if he and others hadn’t presented the idea of natural selection so persuasively, the study of endogenous retroviruses would have led us to the ideas of evolution and common descent.

You might think that evolutionary principles would have smacked the scientific community over the head like a sack of doorknobs once the technology to sequence entire genomes was available. And that’s partly true: Once we began comparing one genome with another, we would have noticed that humans had genes in common with chimpanzees and turtles; from there, we would have likely surmised that humans and chimpanzees and turtles all descended from a common ancestor.

But similarities among necessary genes could just as easily indicate that a Designer used similar building blocks to create its creatures, like a toddler building giraffes and castles and spaceships from the same bucket of Legos.

But it is the shared “mistakes,” like endogenous retroviruses, that would have guided us to evolution.

Normally, organisms carry their genetic information as DNA, which then transcribes to RNA, the temporary messages that cells use to make proteins. Retroviruses, on the other hand, go backward: Their genetic information begins as RNA but must turn into DNA in order for them to sneak into their host cell’s genome. Once the retrovirus sets up shop, the host cell thinks the virus is a “normal” gene and dutifully follows the virus’s DNA instructions — oblivious to the fact that it has become a replicating machine for deadly viruses.

Endogenous retroviruses are simply retroviruses that stumbled into a germ-line cell (like an egg or sperm) instead of their intended target, and became trapped. If the infected germ-line cell successfully participates in fertilization, then the resulting offspring will have the retrovirus’s code stamped into the DNA of its body’s every cell, including its germ-line cells. This creates a cycle in which the retrovirus is passed on vertically, from parent to offspring, as long as the lineage survives.

Though endogenization of a retrovirus is a relatively rare event, over geologic time scales of tens of millions of years, “rare” events happen with a certain frequency; consequently, 8 percent of the human genome is clearly retroviral.

So how would ERVs have led us to evolution? Let’s say we find an ERV in both humans and chimpanzees. This could have happened by common descent — that is, the common ancestor of humans and chimpanzees had the ERV and passed it on to both species. Or it could have resulted from two independent endogenization events — in which the same retrovirus endogenized in both humans and chimpanzees independently.

To find out which, we first need to figure out if the human and chimpanzee ERV used to be the same kind of retrovirus. We can do that by comparing their genes. Retroviruses are a diverse family of viruses with seven distinct genera, each with a cadre of species, and each with their own defining characteristics. Even within the same species, retroviruses have a lot of diversity, due to mistakes made in turning RNA into DNA.

Because of that diversity, if the genes in the human and chimpanzee ERV look a lot alike, then the ERV probably came from one endogenization event, not two.

But remember that once a retrovirus sneaks into the host cell’s genome, it is treated just like a normal cellular gene. This means that it can collect mutations and thus lose the ability to accurately code for viral proteins. (This is precisely what has happened with most of the ERVs in humans: only 46 of more than 34,000 retroviral genes in your genome still have the ability to code for a retroviral protein.) So if the genes in the human and chimpanzee ERV look alike, and they both have accumulated the same random, deleterious mutations over time, we can be even more convinced of common descent.

Finally, we would need to compare the precise location of the ERV in the human and chimpanzee genomes. Depending on their life cycle, some retroviruses tend to insert themselves near active genes, and some tend toward quiet genes for neighbors. But the precise location of insertion within their preferred region is completely random. So if the genes in the human and chimpanzee ERV look alike, and they both have accumulated the same random, deleterious mutations over time, and they have inserted themselves in precisely the same location in humans and chimpanzees, we can be quite confident in saying that this ERV is evidence that humans and chimpanzees have a common ancestor.

Of course, ERVs are not just static landmarks of past genomes, proof of Darwin’s big idea. They also actively spur further genomic evolution.

Every gene in your genome is controlled by a promoter — a short sequence that says “Hey! The gene starts here! Start making the messenger RNA here!” Retroviruses need promoters too, but theirs contain repetitive elements that can misalign during cellular duplication, duplicating genes and rearranging chromosomes. Host cells can also turn the tables on their viral guests, stealing the robust promoter of a nearby ERV to make messenger RNA for a cellular gene. Or sometimes cells domesticate endogenized viral genes and turn them into ‘normal’ cellular genes for a ‘normal’ function. For instance, mammals wouldn’t exist if one of the ERV genes hadn’t been tamed for use in placental formation many millions of years ago.

Understanding the evolution of ERVs is necessary for modern medical research. The vast majority of ERV genes are nonfunctional, and few still have the capability to assemble and release viral particles. Yet some still can. Today’s scientists monitor wayward ERV activity as a potential cause of numerous diseases like cancer and multiple sclerosis. We now have the ability to reanimate long-dead families of ERVs so we can understand the evolution of our immune system. Bringing conquered, extinct viruses back to life in the laboratory allows us to analyze how previous plagues were vanquished, in the hopes of gleaning clues for curing current retroviral epidemics, like HIV-1 in humans, or KoRV in koalas.

So as we celebrate Darwin, I’ll be in the lab performing my scientific séances to keep ERVs from rising from their genomic graves to cause cancer. Darwin and Wallace had no idea what a virus was, much less a retrovirus, much, much less an endogenous retrovirus. But ERVs were locked up tight in their genomes, supporting their theory of evolution.— Abbie Smith is a graduate student studying retroviral evolution at the University of Oklahoma. She blogs at ERV on ScienceBlogs.

    Darwin 200More From Our Darwin 200 Celebration.

Originally published February 12, 2009

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