Zombie Genes Arise!

When Zombie Genes Walk the Earth

Biological evolution has been in operation for a long time, billions of years. Our genomes are chock full of hitch-hiking sequences of nucleic acids that we had always thought were just “junk DNA” or “dead DNA,” without a purpose. But we are learning that junk DNA can have a useful purpose, and dead DNA can be brought to life.

…only one-fiftieth of the vast stretches of DNA that constitute our chromosomes consists of protein-coding genes. The rest of it was long looked at as little more than a junkyard composed of vast expanses of genetic gibberish.

There’s been a sea-change in scientific perceptions of “junk DNA.” In recent years the applicable metaphor has been less a junkyard than a graveyard, littered with broken skeletons of, for example, viruses and other creepy-crawlies that had curled up in the genome and gone to sleep forever.

Scattered among that detritus are a large number of pseudogenes. These are DNA sequences that closely resemble genes but don’t code for proteins. There are more than 11,000 in the human genome – that’s about one for every two bona fide protein-coding genes. Scientists figure pseudogenes are extra copies of working genes that were accidentally inserted into the genome during divisions of our ancient ancestors’ germ cells. Redundant but harmless, these DNA doppelgangers were permitted by evolution to come along for the ride. Over the intervening eons, pseudogenes have gradually piled up, mutated and decayed to the point where, it’s thought, they no longer do anything at all.

It turns out that although they don’t generate proteins, pseudogenes can generate RNA, which intrigues Stanford molecular biologist Howard Chang, MD, PhD. RNA is best known as the intermediate material in classic protein production. Gene-reading machines in cells produce RNA copies, or “transcripts,” of protein-coding genes. These RNA transcripts leave the cell nucleus and head for the cytoplasm, where they transmit genes’ instructions to protein-making machines situated there. _Stanford

Stanford scientists have been scrutinising one particular “zombie gene,” Lethe, to determine what it might accomplish once it is brought back to life.

Lethe, which the investigators found is activated by NF-kappa-B, subdues the master regulator’s massive influence on the genome, curtailing the inflammatory response. MedXPress

Scientists hope to use this discovery to unlock more of the mysteries of NF kappa B, including its effect on cancer, ageing, and other maladies.

The function of Lethe is to stop inflammation before cellular damage occurs from inflammation.

Chronic inflammation plays a role in cancer and in autoimmune, cardiovascular and neurodegenerative diseases. The continued experience of inflammation produces cellular function breakdown and has been associated with aging.

The researchers hope to use the structure of the newly discovered gene to develop new drugs that mimic the action of Lethe in stopping inflammation without producing the side effects of anti-inflammatory steroid drugs. The discovery also explains how and why anti-inflammatory steroid drugs work. Examiner

More on zombie genes:

To see which lncRNAs were induced during inflammation, Chang and his colleagues exposed cultured fibroblasts from embryonic mice to TNF-alpha, an immune-signaling protein known to trigger NF-kappa-B. They found that levels of hundreds of lncRNAs inside the cells were driven either up or down by TNF-alpha stimulation.

Of those lncRNAs, a total of 54 were copied from so-called pseudogenes: DNA sequences that, while they closely resemble genes, don’t code for proteins. More than 11,000 pseudogenes—one for every two protein-coding genes—have been identified in the human genome. Scientists believe pseudogenes are copies of actual genes that, during the replication of some ancestral organism’s germ cell, were accidentally inserted into the genome and, redundant but harmless, came along for the evolutionary ride. Over the intervening eons, these genetic doppelgangers have roamed along the genome, mutated and decayed to the point where, it is believed, they no longer do anything at all.

“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.”

Equally surprising, Chang said, is that different signaling chemicals or microbial components (such as bits of bacterial cell walls or of viral DNA) wake up different groups of lncRNA-encoding DNA sequences, including pseudogenes. “They’re not really dead, after all. They just need very specific signals to set them in motion.”

Lethe was one such pseudogene tripped off by stimulation of NF-kappa-B. Lethe directly interfered with the complex’s ability to seat itself on appropriate DNA sequences, shutting down the pro-inflammatory genes the transcription factor ordinarily activates.

Several pseudogenes were activated in a selective manner. For example, TNF-alpha and another circulating signaling protein—but not microbial parts—activated Lethe. MXP

The detectable levels of these zombie-generated non-coding RNAs rise and fall in response to the triggers which activate the zombie genes. This suggests another level of sophistication in gene expression which had been unanticipated until recently.

Some scientists believe that they can trace the history of cellular and nuclear activity by the pattern of lncRNAs over time.

Even more interesting, it may be possible to “play” these pseudogenes like a symphony, using the proper sequence of trigger stimuli.

Can you imagine the potential that may possibly be tied up in your graveyard of zombie genes? Perhaps a means to limb regeneration, a cure for ageing or degenerative diseases, or a way to build a more powerful, productive, and happy brain — from the inside out.

We have just begun to sort the workings of only one of these genes, Lethe. But the door to the tomb has been breached, and there is no telling what may be uncovered.

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