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Staying ahead in the evolutionary arms race with viruses

This week's paper uses molecular methods to reveal new details of the evolutionary arms race between primates, including humans, and viruses. "Protein kinase R reveals an evolutionary model for defeating viral mimicry" was published in Nature by Nels Elde and colleagues in Seattle.

Protein kinase R (PKR) is an important defense against viruses in many species, from humans to yeast. When it detects a virus inside a cell, it activates eIF2-alpha, which shuts down protein production in that cell. With protein production blocked, the virus can't replicate and spread to other cells. Viruses, however, have evolved counter-measures. These include molecules that resemble eIF2-alpha. These molecular mimics interact with PKR and prevent its normal defensive activity.

Viral epidemics can be a major cause of death, so we expect populations to evolve PKR resistant to the eIF2-alpha-mimics produced by viruses. Can we find evidence of such evolution in primates?

The authors compared the DNA sequences of PKR genes in humans, other apes, and monkeys. Using a family tree for these species, they could infer the DNA sequence in the common ancestor of chimps and bonobos, their common ancestor with humans, our common ancestor with gorillas, and our common ancestor with orangutans. They did the same thing with the monkey family trees and then a combined primate family tree. See the Tree of Life web page for details on the primate family tree.

Once they had DNA sequences for each species and various ancestors they could infer changes in the PKR gene along each branch of the tree. A few changes might occur at random, but they were interested in nonrandom changes: those due to natural selection, presumably imposed mainly by viruses. They detected selection using the ratio of nonsynonymous changes (those where a change in DNA actually changed the PKR protein) to synonymous changes (those where DNA changed without changing the protein). This widely used method is based on the fact that some amino acids, the building blocks of proteins, are coded for by two or more different triplets of three DNA bases. Random mutation is equally likely to change any of these bases. But natural selection tends to eliminate mutants with the "wrong" amino acids in their protein. If the current protein is working well (resisting the virus), then the "wrong" amino acid is anything different than the current one. But if the current PKR protein isn't working, perhaps because the virus evolved, then natural selection will eliminate those with the current version and replace them with mutants whose PKR works better.

Nonsynonymous (protein-changing) changes in PKR outnumbered synonymous ones along most branches of the primate family tree. The most extreme discrepancy (22:0 !), indicating strongest selection by viruses, was along one of the branches shared by monkeys but not humans. For the branch leading to our common ancestor with gorillas and chimps, the ratio was only 1.1, indicating only weak selection by those viruses that interact with PKR. Maybe those monkeys should start covering their mouths when they cough.

How did viruses respond to evolution of resistance in their hosts? The researchers did a similar analysis of evolutionary changes in viruses. Again, nonsynonymous changes were more common, showing that primates impose selection on virus populations to evolve new counter-measures against PKR.

Earlier, I mentioned that yeast cells also make PKR. This made it possible for the researchers to test different PKR versions against different viruses. (Apparently, nobody at the Yeast Liberation Front volunteered as test subjects.) When a yeast cell is infected by a virus, yeast PKR shuts down protein production, just as in primate cells, resulting in easily detectable slowing growth. In yeast, our PKR (and that of other apes) works much better against some viruses than monkey PKR does. The researchers went on to identify key amino acids responsible for resistance and susceptibility.

Interestingly, eIF2-alpha itself doesn't seem to have evolved much. This evolutionary arms race has mainly involved viruses evolving new mimics of eIF2-alpha and primates evolving new versions of PKR, resistant to the viral mimics, but still able to activate real eIF2-alpha.

How soon (and in what countries) will we see attempts to increase virus resistance in humans, using germ-line modification of PKR?

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