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Prince or Pauper? Researchers Find Functional Pseudogene in Fruit Fly

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Suppose we introduced you to a friend and said he works as a pseudoscientist. You would be immediately suspicious of his white lab coat and apparent command of scientific language in subsequent conversation. After all, he just pretends to be a scientist. He's fake. He's false. He is bogus, sham, phony, mock, ersatz, quasi-, spurious, deceptive, misleading, assumed, contrived, affected, insincere, and all the other negative synonyms we associate with the prefix pseudo.

But then suppose we corrected the description and said that, actually, he is a "pseudo-pseudoscientist." The double negative suddenly opens the possibility that he really is a scientist. He's faking his fakery, contriving his contrivance, mocking insincerity for some reason. Maybe he's a psychologist studying the effects of perceived pretentiousness, using you as his lab rat. Maybe he's a real MD playing a doctor on a fictional TV show, leading us to believe he is "just an actor." Think of the guards in Mark Twain's The Prince and the Pauper who quickly escort the shabbily dressed prince off the palace grounds without noticing the royal seal in his pocket. Have scientists too quickly dismissed pseudogenes as broken genes, worthless transcripts of DNA without function? Could at least some of them be "pseudo-pseudogenes"?

A surprising paper in Nature actually uses that term: "Olfactory receptor pseudo-pseudogenes." Researchers in Switzerland found a case in a species of fruit fly that defies the pseudogene paradigm. Pseudogenes are often suspected of being broken genes when a premature termination codon (PTC) is found in the DNA sequence. Obviously, such a gene could not be translated into a functional protein, right? Translation would stop before the messenger RNA is complete. Often, that is the case. What good is that?

These scientists found something interesting about an olfactory receptor gene in Drosophila sechellia, "an insect endemic to the Seychelles that feeds almost exclusively on the ripe fruit of Morinda citrifolia." They looked at its Ir75a locus, a gene that encodes an olfactory receptor for acetic acid in its more famous cousin D. melanogaster, Finding a PTC in this species' Ir75a gene, they initially thought it was a broken gene -- a pseudogene. The abstract begins with the usual evolutionary rhetoric about pseudogenes:

Pseudogenes are generally considered to be non-functional DNA sequences that arise through nonsense or frame-shift mutations of protein-coding genes. Although certain pseudogene-derived RNAs have regulatory roles, and some pseudogene fragments are translated, no clear functions for pseudogene-derived proteins are known. Olfactory receptor families contain many pseudogenes, which reflect low selection pressures on loci no longer relevant to the fitness of a species. [Emphasis added.]

That's their setup for the surprise announcement. This pseudogene might just be a "pseudo-pseudogene"! It might be a prince masquerading as a pauper.

What started them on their paradigm-breaking find was noticing that this apparent pseudogene is fixed in the population, suggesting it has a function. Taking a closer look, they found that the translation machinery is able to "read through" the premature stop codon, the PTC. How? They're not sure, but they found something else interesting: the read-though operation works efficiently only in neurons, not other types of cells. That opens up a whole new way of looking at pseudogenes: some of them might be tissue-specific regulators.

It is not yet clear how the D. sechellia Ir75a PTC is read through. It cannot be because of insertion of the alternative amino acid selenocysteine (which is incorporated at UGA18). Moreover, no suppressor tRNAs are known in D. melanogaster and ribosomal frame-shifting is also unlikely because there is no change in the reading frame after the PTC. We suggest that read-through is due to PTC recognition by a near-cognate tRNA that allows insertion of an amino acid instead of translation termination. Although the trans-acting factors regulating read-through are unclear, the neuronal specificity of this process is reminiscent of RNA editing and micro-exon splicing, in which key responsible regulatory proteins are neuronally enriched. We therefore speculate that tissue-specific expression differences in tRNA populations underlie neuron-specific read-through.

We might be tempted to dismiss this as a rare case of evolutionary tinkering. The gene broke, but natural selection found a way to tinker with it and get it to work. Perhaps. But further experimentation with D. melanogaster suggests that "pseudogenization" has a logical function: it works to tune odor sensitivity. The part of the gene downstream from the PTC apparently affects the type of receptor produced. What's more, this kind of regulation might not be rare.

Read-through is detected only in neurons and is independent of the type of termination codon, but depends on the sequence downstream of the PTC. Furthermore, although the intact Drosophila melanogaster Ir75a orthologue detects acetic acid -- a chemical cue important for locating fermenting food found only at trace levels in Morinda fruit -- D. sechellia Ir75a has evolved distinct odour-tuning properties through amino-acid changes in its ligand-binding domain. We identify functional PTC-containing loci within different olfactory receptor repertoires and species, suggesting that such 'pseudo-pseudogenes' could represent a widespread phenomenon.

Experiments showed that the Ir75a 'pseudo-pseudogene' actually yields a functional odor receptor, but not for acetic acid as in D. melanogaster. Instead, it makes a receptor tuned for similar acidic odorants unique to food sources available on the Seychelles. The tissue-specific read-through capabilities of this gene provide the fly with a way to detect food sources it needs in its environment.

Perhaps nothing beyond chance mutation or neutral drift is needed to explain this. On the other hand, the research team may have stumbled onto an important function for pseudogenes.

Our efforts to understand the molecular basis of the loss of olfactory sensitivity to acetic acid in D. sechellia led us to discover a notable and, to our knowledge, unprecedented evolutionary trajectory of a presumed pseudogene. Efficient read-through of a PTC in D. sechellia Ir75a permits production of a full-length receptor protein, in which reduction in acetic acid sensitivity and gain of responses to other acids is due to lineage-specific amino acid substitutions in the LBD pocket. The PTC does not noticeably influence the activity of D. sechellia Ir75a, suggesting that it is selectively neutral from an evolutionary standpoint. We propose that it became fixed through genetic drift, given D. sechellia's persistent low effective population size.

They can call it an "evolutionary trajectory" if they wish. Another way of looking at this is a design feature. The premature stop codon, or PTC, may be more elegant than a stop sign. It may be a switch, telling the translation machinery to pay attention to the downstream code if -- and only if -- translation is taking place inside neuronal cell. In non-neuronal cells, the PTC might indeed say "stop," delivering the transcript to the trash. In neurons, though, environmental cues may trigger pre-existing routines to fine-tune the sensitivity to odorants available in food sources.

A design perspective could accelerate discoveries along this line. We've seen the tendency to dismiss things as evolutionary castoffs when their functions were not understood, only to find higher levels of organization at work. Introns are spliced out of messenger RNAs; they must be junk. Methyl groups interfere with translation; they must be mistakes. Retrotransposons must be parasites. Pseudogenes must be broken genes. Maybe not. If scientists had expected design, maybe they would have hit upon today's paradigms about epigenetics, alternative splicing and gene regulation sooner.

Intelligent design theory doesn't require everything to be designed. It does, however, prevent a "premature stop" to dismissing things as not designed.

Image: The Prince and the Pauper, 1881, via Wikipedia.