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Junk No Mo: Scientists Turn Genetic Junk into Master Controller

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You’ll pardon two Aussies for their mixed metaphors. They represent the cutting edge of young scientists who have ditched the “junk DNA” label entirely. They now recognize the powerful regulatory role of micro-RNAs in the non-coding portions of the genome. Writing at The Conversation, Pamela Ajuyah (PhD student) and Nham Tran (lab head) at the University of Technology in Sydney begin their metaphors with a familiar irritation: junk mail.

Up until about two decades ago, one type of RNA, called microRNA, or just miRNA — by virtue of them being very short, only 18-25 letters long — were thought to be the junk mail of the genome, with no biological function. But today we know that these miRNA are actually not junk but play a very important role in regulating the activity of other parts of your DNA. [Emphasis added.]

After reviewing a little history about the Central Dogma and the Human Genome Project, they recount the surprise that only 2 percent of the human genome codes for proteins. “So the question is: what does the remaining 98 percent of our DNA actually do?” That’s the spirit; seek function, and ye shall find. Biologists had made a big mistake by filtering the 98 percent into the spam folder.

For biologists, those important emails that slipped into the junk mail folder and were disregarded were miRNAs. That was until the first functional miRNA, lin-4, was officially discovered in 1993. Scientists were looking at the development of the nematode worm, Caenorhabditis elegans, and found that lin-4 inhibited protein synthesis of the lin-14 gene.

They subsequently found that miRNA can physically bind to mRNA and stop it creating proteins. Thus it effectively suppresses the activity of a gene. This discovery was the first evidence of miRNA negatively regulating RNA coding for proteins.

So, it turns out that the 98% of our genome that was regarded as “junk” might have a function after all.

After a little more history, catching up to the current count of 1,800 known functional miRNAs, they switch metaphors:

We now understand that miRNA control numerous genes and processes vital for cellular life such as metabolism, development and the immune system.

While two decades ago genes and proteins were seen as the most important players in what happens in our body, miRNAs are now recognised as the puppet masters, pulling the strings of various genes on the molecular biology stage.

Ajuyah and Tran appear genuinely excited about the prospects for discovering more function in the junk email (or more strings for the puppet master to pull). They talk about how cancerous tumors sometimes switch off the miRNAs that would otherwise activate anti-tumor proteins. This provides avenues for designing miRNAs to target tumors. Since miRNAs latch onto messenger RNAs promiscuously, it might allow miRNA-based drugs to target multiple genes simultaneously.

Back to the email analogy, they conclude:

The interest in miRNA in the scientific community has increased exponentially in the last few years as researchers join in the race to develop a functional and effective miRNA-based therapeutic for cancer.

Far from being junk mail, miRNAs are the commands that redirect other messages, enabling some activities to go ahead and others to cease entirely. And now that biologists have updated their filters, they’re now coming to grips with how powerful miRNAs can be.

We don’t mind if the “puppet master” sets the “email filters” as long as everyone gets the message that the junk-DNA label belongs in the rear view mirror. (Mixing metaphors is addictive, isn’t it?) What’s going on here is one of the biggest paradigm reversals in decades: discovering that the junk is the master. Intelligent design theory expected that unknowns would prove functional. One only wonders how much further along genetics would be if the expectation of design had guided research two decades ago.

More Micro-RNA Function

A paper in Science, meanwhile, finds another function for miRNA: silencing the noisy genome. Hofman and Pilpel describe that discovery, then extend it into the search for additional functions of non-coding DNA:

And the story need not end with miRNAs. A most profound revolution in genomics is the realization that there are many additional types of RNA. For instance, “antisense” RNAs may also act in noise filtration, especially when coregulated with their corresponding sense transcript. Perhaps some long noncoding RNAs, too, contribute to fine tuning of gene expression programs.

The Discarded Imagery

More evidence for the paradigm shift is seen in a review by Nathaniel Comfort in Nature of three new genetics books (including one, by Nessa Carey, reviewed by Casey Luskin here last week). His title is, “We are the 98 percent”:

Today, junk DNA is at the heart of the most radical transformation of how we understand the genome since the information metaphor. Three books — The Deeper Genome by John Parrington, Junk DNA by Nessa Carey, and Biocode by Dawn Field and Neil Davies — present a vision of the twenty-first-century genome. Their relative success hinges on metaphor and imagery, both in how they conceive the genome and in the writing itself.

It’s time for new metaphors, Comfort says; the encyclopedia image of the Central Dogma proved too static, the junk-DNA metaphor too limiting. He’s not ready to believe all the non-coding regions are functional, but both metaphors (instruction book of life versus junk DNA) are outdated. “The old metaphor [instruction book] is not wrong; it is incomplete,” he explains. “In the new genome, lines of static code have become a three-dimensional tangle of vital string, constantly folding and rearranging itself, responsive to outside input.”

So what should be the new metaphor to describe a genome that is “more than a set of rules and parts descriptions”?

Finding apt imagery to replace the dead metaphor of the ‘instruction book of life’ could enable us to break free of the clich� of nature versus nurture. It could usher in a more democratic conception of life, in which all the world’s a cell, and all the genes and genomes merely players.

That’s a bit weird, but at least it’s not dismissive of the genome as mostly junk. These are dynamic times as scientists revise old notions of the genome and try to visualize its complex functions. It appears that the concept of “junk DNA” itself is the thing most likely to end up on the junk pile.

Image: Junk mail, by Dvortygirl (Own work) [CC BY-SA 3.0], via Wikimedia Commons.

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