The RNA Code: Pseudogenes Functional, Help Prevent Cancer
A surprising function has been discovered for a “pseudogene” – an apparently mutated copy of a regular gene that till recently was thought to be genetic junk. This pseudogene, reported in Nature today,1 not only has a function unrelated to the production of proteins, but a function that could save your life. It is part of the tumor-suppression system. Without this piece of “junk DNA” your chances of getting cancer go up dramatically.
The old paradigm about pseudogenes appears poised for demolition. The old story was that these were relic copies of good genes that, over time, started mutating away because natural selection no longer acted on them. The new story is that they are essential players in a complex interplay with coding genes and other genetic regulators that control when, where, and how much genes get expressed into proteins. Science Daily recounted the old Central Dogma of genetics (DNA is the master controller of proteins), but said the new study “suggests there is much more to RNA than meets the eye.”
The particular pseudogene studied by Poliseno et al (primarily from Harvard Medical School) is named PTENP1. It has a clever way of working to regulate the coding gene, PTEN, which is known to be a tumor suppressor. It acts as a kind of “decoy.” Since it differs from PTEN by a “mutation” at the start of what would be its coding region, it does not get translated into protein. It does, however, get transcribed into messenger RNA (mRNA). As such, it closely resembles the regular PTEN transcript, like a decoy duck resembles a real duck. The decoy lures the same micro-RNAs (miRNA) to latch onto it that latch onto PTEN. Whereas the miRNAs suppress the action of PTEN, the decoys “un-suppress” the suppressors by stealing them away from the protein-producing gene. In short, said the Harvard scientists, “These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.”
Isidore Rigoutsos (Thomas Jefferson U) commented on this discovery in the same issue of Nature, under News and Views.2 He expanded this one case to a whole new fruitful area of research:
Poliseno and co-workers’ findings could have broader implications beyond PTEN regulation. They suggest that any two co-expressed genes – let’s call them g and G – that are regulated by the same non-coding RNA (R) can, in principle, act as decoys for one another. Moreover, for such a pair, any other molecule (R’) that directly affects the abundance of g will also indirectly affect the abundance of G by modulating the number of decoys g presents to G, and vice versa. Knowledge of shared targets as well as of the relative amounts of g and G would now become relevant experimental considerations.
The commentary began by calling it “surprising news” that “pseudogenes are functional and could have a role in the control of cancer.” While Rigoutsos noted that “pseudogenes have been presumed to be largely vestigial,” he pointed to other recent findings that they are functionally connected to other RNA regulatory elements. In the same News and Views article, and Frank Furnari (UC San Diego) said this:
Defining ‘junk DNA’ is getting trickier. Pseudogenes, for instance, have been viewed as non-essential genomic elements and have mostly been ignored. Well, they shouldn’t be anymore, according to Poliseno and colleagues, who show a clear functional relationship between the tumour-suppressor gene PTEN and its pseudogene PTENP1 (Fig. 1). This study could have major implications for understanding mechanisms of disease, and of cancer in particular.
Furnari also pointed to other possible diseases where breakdown of the tight regulation of the PTEN could be responsible. Two of those are human breast and colon cancers. He said it may be time for a “redefinition of this seemingly vestigial pseudogene as a tumour-suppressor gene.” In closing, Furnari expanded the particular case to the general principle: “The authors find similar associations between other well-known cancer-associated genes and their corresponding pseudogenes. They thus demonstrate that this unexpected mechanism of gene regulation could have broader implications in tumorigenesis and could potentially offer new targets for anticancer drugs.”
Poliseno et al made no mention of evolution in their research paper. Rigoutsos captioned his figure “Evolutionary relatives cooperate,” but nowhere explained why PTEN and PTENP1 were related by evolution, how the pseudogene evolved a function, or how evolutionary theory enlightened the discussion or led to the discovery. Science Daily’s article (a press release from Beth Israel Deaconess Medical Center [BIDMC], part of Harvard Medical School) did not mention evolution, either, but instead depicted nature as a crafty designer: “The new findings suggest that nature has crafted a clever tale of espionage such that thousands upon thousands of mRNAs and noncoding RNAs, together with a mysterious group of genetic relics known as pseudogenes, take part in undercover reconnaissance of cellular microRNAs, resulting in a new category of genetic elements which, when mutated, can have consequences for cancer and human disease at large.”
05/06/2010).
The past decade has witnessed an explosion in observations of small RNAs in the nucleus. What are they there for? Since the function of pseudogenes, small RNAs and regulating mRNAs does not depend on the parts that code for proteins, they cannot have gotten their genetic information from DNA via the Central Dogma. Pier Paolo Pandolfi of BIDMC explained, “This means that not only have we discovered a new language for mRNA, but we have also translated the previously unknown language of up to 17,000 pseudogenes and at least 10,000 long non-coding (lnc) RNAs. Consequently, we now know the function of an estimated 30,000 new entities, offering a novel dimension by which cellular and tumor biology can be regulated, and effectively doubling the size of the functional genome.”
1. Poliseno et al, “A coding-independent function of gene and pseudogene mRNAs regulates tumour biology,” Nature 465, pp 1033?1038, 24 June 2010, doi:10.1038/nature09144.
2. Isidore Rigoutsos and Frank Furnari, “Gene-expression forum: Decoy for microRNAs,” Nature 465, pp. 1016?1017, 24 June 2010, doi:10.1038/4651016a.
An exciting, paradigm-shifting discovery has been made. We give it both the “Darwin and Evolution” and “Intelligent Design” tags in hopes of starting vigorous discussion about how this came to be. Darwinists may insist that it looks too clumsy to be designed, and could have evolved; creationists or ID people may respond that it is ingenious, too tightly regulated to arrive at by gradual changes, and contrary to Darwinian expectations. Biblical creationists might envision an original perfect system in partial working order. Many interesting questions are sure to follow, but one thing everyone is agreeing on: what was once considered junk is now known to be active and functional.
The important point for now is that the secular, Darwinist-leaning establishment was surprised by this discovery (see Young’s Law, right sidebar). Why were they surprised? It was because the picture of genetic junk, vestigial parts in a tinkerer’s toolbox and useless leftovers mutating away under relaxed selection pressure fit their world view. In the neo-Darwinian genetic picture, gene duplication is a source of both innovation and debris production. Two copies of a gene, made by copy mistakes, might produce two different functional genes, or leave one functioning and the other withering away under mutational load. That’s what “pseudogenes,” which didn’t make proteins or appear to do anything after getting transcribed, represented. They were just sad leftovers of copying errors, left to die on the vine. That’s why pseudogenes were ignored by the Darwinists for so long. They were vestigial; they were boring. Even the name they were given – pseudo genes – (not really genes, but pretenders) was demeaning.
The ID scientist looks at a complex system like genetic transcription, translation and regulation, sees all the complex activity and components, only some of which are understood, and thinks, If it’s there, there might be a reason for it. Rather than dismiss something out of hand as junk because it doesn’t fit the current Central Dogma, the ID scientist looks for evidence of function. He or she assumes an overarching purpose and design in the system, at least in its salient features. Maybe no function will be found for a particular phenomenon, but at least the ID scientist asks different questions: not “what is this junk doing in the way?” but “where does this puzzle piece fit in the picture?” In this particular case, an ID scientist would have been rewarded not with surprise so much as satisfaction: expectations fulfilled. The only surprise would be not that the unknown piece has a function, but that the function is more vast, marvelous and intricate than expected. Has the genome really just doubled? Picture the Darwinist and the IDer saying “Good heavens!” with completely different facial expressions and tones of voice at that revelation.
If all the geneticists had approached the black box of pseudogenes with the ID mentality, it is quite possible that our understanding of gene regulation would have been propelled forward by years or decades – and maybe even our progress toward curing cancer. Ideas make a difference.
Recommended resource: Signature in the Cell is one year old; have you read it yet? It just came out in paperback. Click here for more information.