The resurrection of a disease-linked gene
An unusual tale of a gene lost, then found, during human evolution.
A glimpse into the evolutionary history of a gene linked to Crohn's disease has revealed a bizarre example of just how dynamic genomes can be.
The gene, called Immunity-related GTPase M (IRGM), seems to have been destroyed in the ancestor of Old and New World monkeys millions of years ago, only to be brought back to life again in the common ancestor of humans and great apes when a retrovirus lurking in the genome inserted itself into the gene.
It is probably the first example of a resurrected gene. "It's like lightning striking twice in the same spot," says Evan Eichler, a human geneticist at the University of Washington in Seattle.
In most mammals, IRGM is a member of a large family of related genes thought to help eliminate pathogens, such as the bacterium responsible for tuberculosis, that invade host cells and then thrive within them. But in humans and some primates, the family has withered away to only two members, IRGM and IRGC. It is not known how humans survive the loss of so many IRGM genes; mice that lack family members are more vulnerable to infection1.
There is reason to suspect that IRGM may have an important function in humans, however. Researchers have found that some people carry a deletion in front of the IRGM gene that may alter expression of the gene and increase the risk of Crohn's disease, a painful autoimmune disease of the digestive system2.
When lightning strikes
In a study reported this week in PLoS Genetics, Eichler and his colleagues compared the sequence of human IRGM to the same gene in other primates3. They found that a short fragment of repeated DNA that is found scattered throughout the human genome had inserted into the gene in the common ancestor of Old and New World monkeys over 40 million years ago. The insertion inactivated IRGM, abolishing the gene's ability to form a functional protein.
Then, about 20 million years later, a retrovirus in the ancestors of humans and apes happened to insert into just the right location within IRGM to allow the gene to once again produce a protein.
It is still possible, Eichler notes, that the human IRGM protein is nothing more than an accident and serves no real function. But he adds that the association of IRGM variants with Crohn's disease suggests the gene could play a role in the immune system.
For now, IRGM is the only gene known to have been killed and then brought back to life during its evolutionary history. "Is this some kind of very strange example of something we will only see once or is this something of more general importance?" asks Mikkel Schierup, a population geneticist at the University of Aarhus in Denmark. "We will probably know that very soon because we are getting more comparative genomics data that can be mined for examples."
Schierup notes that the discovery blurs the lines between genes and what are called 'pseudogenes', the non-functional remnants of genes destroyed by mutations. "The study shows that pseudogenes actually matter a little bit — they have the potential to regain their function."
"You can't really count a dead gene out until it's really gone," agrees Eichler. "The only way to be sure it won't come back is to delete it."
- Collazo, C.M. et al. J. Exp. Med. 194, 181-188 (2001).
- McCarroll, S. et al. Nature Genetics 40, 1107-1112 (2008).
- Bekpen, C. et al. PLoS Genetics 5, e1000403 (2009).