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Pseudogene Likely Regained Function in Human-Great Ape Lineage

NEW YORK (GenomeWeb News) – An immune system gene that was converted to a pseudogene during primate evolution about 40 million years ago appears to have been revived millions of years later in the lineage that led to humans and African great apes, according to a new study appearing online last night in PLoS Genetics.

A team of researchers from the US, Spain, Italy, and Germany used comparative sequencing and structural analyses to evaluate an immunity-related GTPase, or IRG cluster, called IRGM in prosimians, such as the gray mouse lemur, and in several so-called anthropoids, which include New and Old World monkeys as well as great apes. Their results suggest that a retrotransposition event in the anthropoid common ancestor disrupted the IRGM open reading frame, rendering it a pseudogene.

Millions of years later, though, in the human-great ape ancestor, the open reading frame appears to have become active once again, concurrent with an endogenous retroviral insertion in the genome. That suggests that dead genes hanging around in the genome can be revived under the right circumstances — a first-of-its-kind finding in the primate lineage and perhaps beyond.

"'I don't know of any other examples in primates,"' senior author Evan Eichler, a Howard Hughes Medical Institute investigator and professor in the University of Washington's Department of Genome Sciences, told GenomeWeb Daily News, calling the results "'pretty remarkable."'

In general, IRGs are thought to have a role in intracellular pathogen resistance. For instance, in mice, which have 21 versions of IRGM, the gene cluster appears to play a key role in warding off invasion by bacteria such as Mycobacterium and Salmonella via autophagy-targeted destruction.

Humans, on the other hand, carry a single copy of IRGM that's generally believed to be functional — particularly since IRGM haplotypes were recently implicated as risk factors for Crohn's disease. Before this study, Eichler said, they assumed IRGM was functional in other primates too. But when they assessed IRG gene family copy number and sequence organization in several non-human primates, the researchers found a very different story.

The team fished around in the NCBI Trace Archive and came up with whole genome shotgun IRGM sequences for the gray mouse lemur, a New World monkey species (the marmoset), two Old World Monkeys (the baboon and rhesus macaque), and three great ape species (chimpanzees, gorillas, and orangutans). They also used fluorescence in situ hybridization to look at the organization of genes.

But it wasn't until they'd re-sequenced the gene in every species — and often in several individuals from each species — that the researchers were confident in the results, Eichler said.

Similar to the pattern in humans, the IRGM region was contracted in monkeys and great apes. Whereas prosimian species such as the gray mouse lemur carried three versions of the gene, New World monkeys, Old World monkeys, and great apes had only one.

Unexpectedly, though, all of the monkeys evaluated — four New World monkey species and 11 Old World monkey species — carried a version of IRGM with premature stop codons. The researchers found that the pattern of these mutations was consistent with an Alu retrotransposition insertion into the gene, leading them to conclude that the monkey version of IRGM is actually a pseudogene.

Humans and African great apes, on the other hand, carry a truncated version of IRGM without the premature stop codons observed in the monkey gene and do appear to be functional. Interestingly, though, orangutans, shared a premature stop codon-inducing substitution with Old World monkeys, suggesting ape ancestors once carried a pseudogene similar to that in monkeys. When they re-sequenced the region in a dozen orangutans, half of them had the substitution while half didn't.

The team found that the human-great ape version of the gene appears to have an ERV9 retroviral element at its 5' end — an addition that may have contributed to IRGM's revival in this lineage. Overall, the researchers propose that IRGM likely became a pseudogene in the anthropoid lineage roughly 40 million years ago but may have been resurrected in the human-great ape common ancestor roughly 20 million years ago. If so, Eichler said, ERV9 appears to have acted as a "'defibrillator"' for the gene.

"'We suggest that the rebirth or restoration of the gene coincided with the insertion of an endogenous retrovirus, which now serves as the functional promoter driving human gene expression,"' the authors explained.

Still, Eichler and his colleagues cautioned, there is at least one alternative explanation for their data: it's possible that IRGM is actually non-functional in humans and great apes, just as it is monkeys. They argued that this explanation is unlikely, though, since a deletion upstream of IRGM has been linked to Crohn's disease.

In addition, Eichler said, some orangutans carry a copy of the dead gene while others carry a copy of the functional gene suggesting IRGM has "'one foot in the grave and one out"' in that species, which sits at the first branching point in the great ape lineage. Even so, while Eichler said he is about 90 percent convinced that their resurrected gene theory is correct, he'd like to see more experiments done to assess IRGM's function in humans.

If the resurrected gene notion is right, Eichler said, it raises a host of questions about IRGM. For instance, since IRGM appears to play a critical role in bacterial immunity in mice, it's unclear what led to this gene's obsolescence in the monkey-ape ancestor. And more research is needed to address whether the revitalized form of the gene has the same function as its predecessor or whether it now has additional roles.

For his part, Eichler believes the locus is probably still involved in immunity and possibly auto-immunity. He speculated that another immune mechanism may have evolved around the same time that IRGM became a pseudogene, making it redundant and less crucial.

Either way, Eichler said, it's clear that the genome is a dynamic and plastic place. His advice: don't count a gene out until it's completely gone.

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