Let me remind you of two recent postings. First, the RNA world has played a crucial role in the evolution of the human brain. Second, as I have hinted, evolution by gene duplication echoes a teleological essence to evolution. Let me now unite these two themes with another phenomenon – functional pseudogenes.

Pseudogenes are sequences of DNA that are similar to functional genes, but have acquired defects that prevent the expression of functional products. Such sequences are generated by gene duplication, where one duplicate undergoes some lesion that is not selected against. As a result, the defective gene (now a pseudogene) may continue to undergo further mutational insult, effectively causing it to decay into oblivion over time.

Yet because the cellular architecture entails that an RNA world exists in parallel with a protein world, might many of these pseudogenes simply be genes escaping the constraints of the protein world in order for the opportunity to more fully participate in the RNA world?

Recently, a study of human chromosome 22 identified 525 pseudogenes. [1] Remarkably, the study found about 20% of these pseudogenes to be transcribed, such that the RNA products were continuously synthesized. Might some of these RNA be fishing for a function?

At this point, let’s turn to the snail Lymnaea stagnalis. It expresses a nitric oxide synthase (NOS) pseudogene in its central nervous system. [2] Better yet is that the pseudogene is co-expressed with the normal NOS gene in a particular set of neurons. The researchers who made this discovery were able to show that the NOS pseudogene RNA and the NOS gene RNA were able to form an RNA-RNA duplex that inhibits translation. In other words, the pseudogene is acting as natural anti-sense RNA to regulate expression of the NOS gene downstream of transcription. Since nitric oxide, the product of NOS, is a neurotransmitter, this raises the possibility that this pseudogene can play an important role in the central nervous system. And indeed, a more recent study has shown that this pseudogene is involved in nothing less than learning and memory [3].

In my opinion, pseudogenes exist on a continuum of function, where at one end many have become completely functionless and are in a true process of decay, while at the other end others may function similarly to the NOS pseudogene and play significant roles in physiology or development. In between, we have the pseudogenes that may simply be tweaking regulation or enhancing evolvability.

Yet we come full circle with the two previous postings I mentioned. Here again we see the reach of gene duplication, a biological process that not only sends out “feelers” for evolution, but amplifies the regulatory possibilities for an evolving system. As for brains, maybe one day we will find that a human pseudogene makes it possible for you to read and understanding what I am writing.

1. Zheng D, Zhang Z, Harrison PM, Karro J, Carriero N, Gerstein M. 2005. Integrated pseudogene annotation for human chromosome 22: evidence for transcription. J Mol Biol. 349:27-45.

2. Korneev SA, Park JH, O’Shea M. 1999. Neuronal expression of neural nitric oxide synthase (nNOS) protein is suppressed by an antisense RNA transcribed from an NOS pseudogene. J Neurosci. 19:7711-20.

3. Korneev SA, Straub V, Kemenes I, Korneeva EI, Ott SR, Benjamin PR, O’Shea M. 2005. Timed and targeted differential regulation of nitric oxide synthase (NOS) and anti-NOS genes by reward conditioning leading to long-term memory formation. J Neurosci. 25:1188-92.