Some genes just won't stay dead. Between 40 million and 50 million years ago, a slice of DNA called IRGM stopped functioning in the ancestors of modern-day monkeys. But 25 million years later, in the lineage that led to humans and great apes, three random events turned the gene back on.
In mammals such as rats and dogs, IRGM (immunity-related GTPase family, M) helps protect from bacterial pathogens such as salmonella. Humans and apes also appear to use the gene. Our bodies produce a functional version of the IRGM protein, and genetic studies have identified deletions near the gene as a risk factor in Crohn's disease, an autoimmune condition of the gastrointestinal tract. But the precise role of IRGM in humans and apes remains unclear.
Interested in the gene's evolution, Evan Eichler, a human geneticist at the University of Washington, Seattle, and his colleagues sequenced IRGM in various species of primates. In monkeys, the team discovered a piece of what could be "junk DNA" wedged in at the start of the gene. This insertion mucks up the gene's promoter, a critical region for protein production. To make matters worse, the monkey gene sports a number of "stop codons," a type of genetic red light that prevents the production of any functional protein. "We looked at about 15 species of New and Old world monkeys," says Eichler. "[A]ll of those species ... have multiple stop codons, telling us that the gene is dead."
But humans, apes, and monkeys share a common ancestor, so IRGM must have been resurrected somewhere along the line. As Eichler's group reports today in PLoS Genetics, the most plausible explanation--unlikely as it sounds--is that three random events brought the gene back to life.
Based on genetic differences between monkeys, apes, and humans, Eichler's group was able to create a picture of how the gene evolved over the past 50 million years. First, the DNA remains of an ancient virus, called an endogenous retrovirus, jumped from somewhere else in the genome into the region directly upstream of the dormant IRGM gene, creating a brand-new promoter. Then, two more mutations removed the remaining stop signs. Together, these three unrelated events restored the gene's function.
Eichler says that there's still much to learn about IRGM. "The million-dollar question is: Does the new gene act the same way as the old gene did? And we're not 100% sure." Perhaps the body is still getting used to it, says Steven McCarroll, a geneticist at the Massachusetts Institute of Technology in Cambridge. He notes that different human populations show different IRGM activity patterns. This may be because humans are still working out exactly how to use this relatively new gene, he says: "This locus is revealing itself to be 'under construction.'"