After eons of genetic gaffes, the genomes of nearly all organisms have accumulated heaps of broken genes that seem to just take up space. Now it appears these so-called pseudogenes actually churn out tiny RNA molecules that serve a function: to safeguard related RNAs from premature destruction. The findings, published in the 1 May issue of Nature, suggest that cells manipulate genetic mishaps to their advantage.
Pseudogenes are dysfunctional bits of DNA that resemble working genes. Researchers think they arise from occasional mistakes during cell division, when DNA is jumbled up and copied. In the human genome, there are at least 20,000 pseudogenes; some gene families, like the one that controls our sense of smell, have more of these genetic train wrecks than working members. Their existence baffles molecular biologists, who know that a vast number can make unfinished RNA bits, but not proteins. After all, if the genome worked efficiently, you'd think pseudogenes would be removed over time.
But when Shinji Hirotsune and colleagues at the University of California, San Diego, School of Medicine accidentally disabled a pseudogene while making genetically modified mice, they found severe birth defects and a drastically limited life-span in offspring from the mutant animals. This suggested that the fragmentary gene bit was somehow required for healthy life.
As with many pseudogenes, this one turned out to be an abridged version of a sister gene, called Makorin1, which resides on another chromosome. The pseudogene is less than half the size of its relative and yields only a tiny snippet of RNA that can't produce a protein. As small as it is, however, this "pseudo-RNA" has the very large task of protecting the full-length Makorin1 RNA from destruction. The researchers still don't know exactly how this happens, but if the pseudogene is missing in mouse or human cells, its counterpart's RNA also ceases to exist, they found. One possibility is that because the pseudogene's RNA looks so much like the first half of the Makorin1 RNA, it is able to lure destructive enzymes away from their intended victim. "This could be a new way that genes are regulated," says Anthony Wynshaw-Boris, a co-author.
"I'm very enthusiastic," says Mark Gerstein, a biochemist and biophysicist at Yale University. "There have been hints that pseudogenes have some functional utility in organisms like yeasts; now we see that they indeed have a function in humans and higher eukaryotes."