Genome-wide survey for biologically functional pseudogenes by Orjan Svensson, Lars Arvestad, and Jens Lagergren, PLoS computational biology, early online release



A pseudogene is a piece of noncoding DNA very similar in sequence to a normal "true" gene but containing disablements that prevent its expression into a functional protein. Pseudogenes were long thought to be relatives of functional genes that were formerly active in the ancient genome but now constitute part of the "junk" DNA. Recently, there has been speculation that some pseudogenes may actually be functional at the RNA level. The RNA of one mouse pseudogene was found to be critical for the translation of its homologous coding gene, and mice in which the pseudogene was knocked out died or had nasty deformities (see figure above).

This paper uses a comparative genomics approach to identify the pseudogenes most likely to be functional. The authors say it can be applied to any pair of genomes, but they use human-mouse and human-chimp (though the results here were too noisy as we are too closely related). The filters they used are plausible evolutionary history (ancient origin of pseudogene + high conservation), synteny (true gene and corresponding pseudogene are in conserved order in human and mouse), transcriptional evidence, and sequence conservation.

Criticisms: 1) no wet lab experimental confirmation of any predictions!, 2) I don't think synteny should be a required filter for functionality, and 3) they looked for transcriptional evidence by BLASTing against the EST database, which may not be a comprehensive catalog of all transcripts.

Another possible filter could be conservation in the promoter regions because if any portion of the pseudogene gets transcribed, it needs a functional promoter (i.e. disablements here could be more significant than disablements in the coding sequence). Maybe they could have added a complementary section with a detailed look at one predicted functional pseudogene. But overall, it was a solid approach with well designed filters. It also prompts a call for the sequencing of more primate genomes to get a sense of varying evolutionary distance. Chimp was great, but it would help to have gorilla and orangutan in addition to rhesus macaque.