The human genome is littered with remnants of over a billion years of evolution: genes that are the same as ones found in other species, genes that are slightly different, and genes that have been silenced with no function. Many scientists are studying this phenomenon in a type of genetic archaeology to understand our evolutionary past better and to ultimately advance human health in the present.

Because these so called "pseudo-genes" are all around the genome (they total one for every two functional genes) and don't result in the production of a protein, scientists believed that they were just random duplications made inert by time and non-use. But a research paper out of Stanford University and published in the online journal eLife now sheds light on how these seemingly dead genes and the RNA they produce may hold the key to new treatments for neurological disorders, autoimmune diseases, and cardiovascular disorders.

Inflammation And Zombie Genes

"Inflammation tells your body something is wrong," said the study's senior author, Howard Chang, M.D., Ph.D., professor of dermatology at Stanford, in a press statement. "But after it does its job of alerting immune cells to a viral or bacterial infection or spurring them to remove debris from a wound site, it has to get turned off before it causes harm to healthy tissue." One such "undead" zombie gene does just this, and the Stanford researchers have named it "Lethe" after the stream from Greek mythology that makes the dead forget who they had once been.

The Lethe gene produces a long non-coding RNA (lncRNA) sequence, meaning that this RNA does not become translated into becoming a protein, as happens with regular genes. The researchers found that when they treated cells with an infection response protein called TNF-alpha — which activated NF-Kappa-B, a complex of proteins within a cell that acts in a pro-inflammatory manner — Lethe's lncRNA was produced. LncRNA is known to help control the regulation of other genes and is increasingly understood to play a key role in inflammation.

"Pseudogenes have been considered to be completely silent, ignored by cells' DNA-reading machinery," Chang said. "But we got a real surprise. When a cell is subjected to an inflammatory stress signal, it's like Night of the Living Dead." Additionally, when cells were directly exposed to bacterial or viral components, different groupings of these lncRNAs were activated and produced. "They're not really dead, after all. They just need very specific signals to set them in motion."

Long noncoding RNA can block inflammation

The lncRNA Lethe was found to act as a negative feedback for NF-Kappa-B by blocking the ability of the pro-inflammatory protein complex from binding to DNA and activating more pro-inflammatory genes. This process would enable a higher level of regulation so that inflammation does not spiral out of control, and while fighting an infection, the immune system stops short of destroying healthy tissues.

Many had theorized that pseudo-genes are just genetic noise, mistakes made during the DNA copying process millions of years ago, because they are situated on the genome next to their corresponding functional gene most of the time. "There's a tendency to assume it's some protein-coding gene that NF-kappa-B is really targeting, and to downplay the activation of a lncRNA as noise, a 'ripple effect' like the one you see when a boat goes by," Chang said.

But the researchers also found that the pro-inflammatory factor TNF-alpha did not activate protein-coding regions on either side of Lethe, showing that the occurrence was tightly regulated and not just an artifact of simple copying of close DNA regions. Additionally, two other pseudo-genes similar to Lethe were not activated by TNF-alpha either, lending further credence to the specificity of this process. TNF-alpha is a target of current therapy for autoimmune diseases, such as rheumatoid arthritis and colitis, and antibodies blocking it are commonly perscribed drugs like Remicade and Humera.

Possible Drug Treatments

The scientists, then, wanted to determine the role that steroids would play in the regulation of Lethe. Steroids are known to be anti-inflammatory and are given to patients with autoimmune diseases to quell the immune system. Dexamethasone, a commonly prescribed anti-inflammatory steroid drug, was found to activate Lethe. But other steroid hormones that do not have anti-inflammatory properties, such as vitamin D or estrogen, did not induce the production of Lethe lncRNA. Because steroids have other serious side effects, the researchers are looking into methods of using other drugs to activate Lethe. "We're wondering whether there might be ways to artificially raise Lethe levels without steroids. These drugs have potentially deleterious side effects such as elevated blood pressure and blood sugar, thinning of bones and general suppression of the immune system," Chang said.

This research goes a long way to understand the so-called "junk DNA" that makes up the majority of the genome. When the human genome was sequenced, it was estimated that people only have around 20,000 genes, far fewer than the over 30,000 genes in a tomato and less than the over 31,000 genes found in the water flea, a microscopic freshwater crustacean. Most of the space between genes was thought to just be filler, performing no functional role in a species' development and function. But the more research is done, the more we discover that the intervening spaces between genes play a vital role, leading to future treatments for human inflammatory diseases.

Source: Rapicavoli N, Qu K, Zhang J, Mikhail M, Laberge R, Chang H. A mammalian pseudogene lncRNA at the interface of inflammation and antiinflammatory therapeutics. eLife. 2013.