A dead gene comes back to life in humans

Why is there "junk DNA"? What is Junk DNA? What is a Pseudogene? What is Gene Duplication?

Goodness, you certainly do have a lot of questions. And some of them can be answered, or at least addressed, on examination of a very interesting new paper recently published about a gene that became a useless "pseudogene" a very long time ago and has recently been revived by evolution to serve once again as an active member of the community we know of as the genome. In humans.

"Junk DNA" is mainly DNA that is not used in the day to day course of coding for various products such as proteins. There is probably some hidden functionality among the Junk, and further research may discover utility among the often vast quantities of DNA "code" that seems to code for nothing. However, most researchers feel that the junk is mainly junk and not much will come of it. (Of course, it is also true that if you say anything that suggests that you might have more than a certain, very limited level of hope for some of this junk having a purpose, a number of scientists will band together, lite their torches, and drive you into a swamp. So to avoid such a thing, let me be clear that I am not taking a position on Junk DNA in this blog post. Even though it is about research that might suggest latent function. I know that latent function is not function, OK?)

Anyway, some of this junk consists of pseudogenes. "Pseudogene" is probably a poor choice of terminology, because to me a "pseudo-thing" is something that resembles the thing but is not the thing. Pseudogenes were genes at one time, but have been "turned off" probably following some mutation that made the gene go rogue in some way (although that is not necessarily how all peudogenes get turned off ... the fact remains that pseudogenes are ex-genes, not fake genes). Calling a gene a pseudogene is like calling a dead person a pseudo-person.

Lots of the functioning genome in various organisms consists of gene duplicates or sister genes. These are genes that occur in more than one place in the genome because of something that happened historically, and these, essentially, come from a common ancestral gene. For example, there are many "globin" genes, which code for globins such as hemoglobin. It is thought that they all descend from a common ancestor that existed in an ancestral bacteria-like organism, and subsequently have diversified into many genes with a broader range of function than the original ancestral gene had.

If there are two similar genes that seem to have had a common ancestor, but were duplicated at some point in the past, and both are functioning, these are called sister genes. If there are two or more DNA sequences that look like genes and, say, only one functions, we can assume that the other copies were sister genes that got turned off. Those are pseudogenes.

It has long been speculated that pseudogenes could be the raw material for future evolutionary change. Certainly duplicate sister genes are, as demonstrated with the globin family of genes. But if a gene gets turned off, is there any way for it to get turned back on again?

Apparently, yes. From the recently published PLoS Genetics paper:

Immunity-related GTPases (IRG) play an important role in defense against intracellular pathogens. One member of this gene family in humans, IRGM, has been recently implicated as a risk factor for Crohn's disease. We analyzed the detailed structure of this gene family among primates and showed that most of the IRG gene cluster was deleted early in primate evolution, after the divergence of the anthropoids from prosimians (about 50 million years ago). Comparative sequence analysis of New World and Old World monkey species shows that the single-copy IRGM gene became pseudogenized as a result of an Alu retrotransposition event in the anthropoid common ancestor that disrupted the open reading frame (ORF). We find that the ORF was reestablished as a part of a polymorphic stop codon in the common ancestor of humans and great apes. Expression analysis suggests that this change occurred in conjunction with the insertion of an endogenous retrovirus, which altered the transcription initiation, splicing, and expression profile of IRGM. These data argue that the gene became pseudogenized and was then resurrected through a series of complex structural events and suggest remarkable functional plasticity where alleles experience diverse evolutionary pressures over time. Such dynamism in structure and evolution may be critical for a gene family locked in an arms race with an ever-changing repertoire of intracellular parasites.

How rare is this in real life? Well, the claim in this paper is that it is very rare, but it also may be the sort of thing that we'll find more of now that a case has been well documented. Nonetheless, if de-pseudo-ization of a gene (if I may call it that) were really common, we would certainly know this by now, because it would be an obvious overarching pattern in genetic variation. So there likely will be more cases, and they will be interesting, but the fundamental nature of evolutionary change over long time scales is probably not going to be rethought because of this finding.

Cemalettin Bekpen, Tomas Marques-Bonet, Can Alkan, Francesca Antonacci, Maria Bruna Leogrande, Mario Ventura, Jeffrey M. Kidd, Priscillia Siswara, Jonathan C. Howard, Evan E. Eichler (2009). Death and Resurrection of the Human IRGM Gene PLoS Genetics, 5 (3) DOI: 10.1371/journal.pgen.1000403