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Genes Don’t Just Make Proteins

How Non-Coding RNA is Revolutionizing Genomics

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Genes Don’t Just Make Proteins

Nucleotide Bases That Make RNA

Sponk via Wikimedia Commons
Updated February 20, 2013

In the last 10-15 years, genetic researchers discovered a completely unrecognized category of genes. First there was a 1993 article that described a small RNA molecule regulating the expression level of a worm gene, then a 1998 seminal publication by Andrew Fire and Craig Mello that showed a previously unknown system regulating genes with short double-stranded RNA molecules. At this point, the perception of RNA, a molecule similar to DNA that was thought to just act as temporary copies of short stretches of DNA, began to change.

RNA Is a Messenger

As every high school biology student learns, DNA, the code of life, actually encodes the chains of amino acid polymers that define the proteins that make up the organism. It is DNA that carries the code of which amino acids to put together to make every protein that creates the structure and run the chemical reactions in each cell. RNA, it was thought, just functions as a messenger to copy and carry the code from the DNA to the part of the cell where the protein is made.

Of course, it's been known for many years that small RNA molecules, known as transfer RNAs, help translate messenger RNA to protein. Also, ribosomal RNAs were an important part of this process too. Other than these, however, it was not known that RNA molecules might play an important function in a cell other than simply carrying a short stretch of DNA code to make a protein.

What's with All the Junk DNA?

Oddly, though, all the protein-coding DNA and the few RNA molecules involved in making proteins accounts for only ca. 5% of the total DNA in the genome. While there are short sequences in the DNA to regulate when genes are expressed, and some specialized DNA structures to hold the 3 feet of DNA contained in every cell together, over 90% of the DNA seemed extraneous. It was often denigrated as junk DNA.

RNAs Found to Regulate Genes

With the discovery of small RNA molecules that regulate the expression levels of genes, the idea that DNA which doesn't explicitly define some protein is extraneous came under more scrutiny. Not immediately, of course. At first, it was thought that microRNAs, as the small gene interfering RNAs that were suddenly being discovered in all sorts of animals and plants, were called, were just a specialized class of RNA, like the few already known to be involved in protein translation.

In 1996, however, Neil Brockdorff's lab at Oxford showed that a relatively large RNA molecule, as large as most messenger RNAs, was directly responsible for X-chromosome inactivation, the developmental process in mammals to shut down one of the two X-chromosomes. While, in hindsight, this suggested that the non-coding RNA species might be more diverse and more numerous than just a few specialized classes, long non-coding RNAs are not so consistent in structure or conserved between different organisms as microRNAs. As a result, it took more time to explore this class of non-coding RNAs.

A Whole New Set of Genes

In 2005, RIKEN Genome Science Laboratory, coordinating with a global network of laboratories, identified all the DNA in the mouse genome that had appeared to code for RNA, and found over 34,000 sections that appeared designed to make long non-coding RNA. The October 2012 release of the Encyclopedia of DNA Elements (Encode) for the human genome—a massive project funded by the National Human Genome Research Institute to map all the functional elements in the human genome—found 9,277 long non-coding RNA elements and anticipate the number could as much as double in the next several year as analysis continues.

Of course, some of these non-coding RNA regions in the genome are probably not functional. However, there are only approximately 20,000 protein coding genes in humans and mice so there appear to be almost as many, or more, non-protein-coding genes. This finding means that, until recently, investigators trying to understand the genes regulating some response were completely overlooking half the candidates!

There Is Still Plenty of Junk DNA

Of course, the discovery of previously unrecognized classes of genes hiding in what was thought to be non-function extraneous DNA doesn't mean there is no junk DNA. All the non-coding RNA genes still account for only a small percentage of the genome. As Michael White, a biologist at the Center for Genome Sciences and System Biology, notes, it is clear that there is still plenty of junk DNA and good biological reasons for it.

Evolution is a messy process. The challenge is to sort out the important functional parts of the DNA from all the junk, and that’s turning out to be trickier than anticipated. While millions of years of evolution may have produced a lot of extraneous junk, it has also produced some very complex genetics.

The Genomics Era Is Starting, Not Ending

As the last millennium ended, a major scientific milestone of sequencing the full human genome was realized with the completion of the Human Genome Project. It was an astounding achievement that gave us the full instructional program for the network of chemical reactions that make us human. Some hailed it as the advent of the post-genomic era where the focus of research would shift towards proteomics the study proteins, the products of genes.

However, as the final DNA bases of the human genome were being deciphered, the discovery of large classes of genes that did not make proteins made it clear that, in fact, we still didn’t even know how to find half or more of the instructions. With the new millennium, whole new areas of genomic investigation are opening up as scientists uncover the functions of these new type of genes.

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