New small gene class found by Dartmouth geneticists may exert far reaching influence on cell behavior

October 25, 2001

Geneticists at Dartmouth Medical School have discovered a new family of unusually small genes that act in the finely tuned yet remarkably versatile orchestration of development and behavior, adding still another dimension to the diversity and complexity of the cell.

Unlike most genes, these new-found ones do not encode for proteins, but rather produce tiny regulatory RNAs, dubbed "microRNAs" because they are far smaller than other RNA molecules. If as abundant and varied in all species as they seem, this novel class of regulators offers promising and potentially far-reaching opportunities to understand critical steps in development.

The new molecules are reported in the Oct. 26 issue of Science by Victor Ambros, professor of genetics and Rosalind C. Lee, a research associate, the same team who identified the first of these little RNAs in a microscopic roundworm a decade ago.

Until recently, that original small RNA, the product of the worm lin-4 gene, was the only example. Now Lee and Ambros report that "there are dozens, probably hundreds of little genes like lin-4." Two other research groups who independently had similar results have published their work in the same issue.

RNA, short for ribonucleic acid, comes in numerous forms. Each RNA is a copy of a gene, part of the cell's DNA (deoxyribonucleic acid). Organisms have thousands of genes that collectively hold information for all the components of an organism. The Dartmouth researchers found 15 new genes in the worm, C. elegans, which all fit this microRNA family and document evidence for many more. Moreover, analysis showed that two of these particular small RNAs are also found in humans, including one that could play a role in the development of heart tissue.

The work demonstrates that these microRNAs, also called miRNAs, are an extensive and diverse class of regulators. "Each miRNA is probably matched to one or more other genes whose expression it controls. Their potential importance to control development or physiology is really enormous. If there are hundreds of these in humans and each has two or three targets that it regulates, then there could be many hundreds of genes whose activity is being regulated this way." said Ambros. "It's important to find all the human miRNA genes and understand what they do."

Ambros, a geneticist, adapted traditional gene discovery approaches to identifying these little genes. Such studies only became possible since the genomes --the total package of hereditary information-- of humans and other species have been sequenced, and since bioinformatics advances have facilitated computer analysis of vast genetic data stores.

In the commonality of life, C. elegans, with its relatively simple genetic apparatus, is a stepping stone to discovering important gene products that are probably performing similar functions in humans. Sequencing tiny RNAs found in C. elegans and comparing their sequences with genome databases of other worms, as well as with insects, mice and humans, the researchers identified the new genes.

"These little RNAs are unusual; they don't make protein. What they actually do is interfere with the messenger RNAs that do make protein. The key is that here is a match between the little RNA and its target, and the microRNA binds to the target and makes it incompetent to translate its message into protein," Ambros said.

Genomes contain sequences that are important for what a gene does, as well as other, less important regions; the important sequences are often similar or identical across species. By looking for identical sequences in different genomes, scientists can zero in on those that are functionally important.

Ambros first compared the genomes of C. elegans, sequenced in 1999 and a related worm, C. briggsae, completed in June. The work illustrates how quickly genetics is moving. "Suddenly we could compare these two genomes, and that broke a logjam in gene discovery." The two worms, 10 million years apart, are close enough in evolutionary time to develop the same way, he continued, "so when we see identical DNA sequences, we infer that this signifies genetic machinery doing the same thing."

The findings built on work over the past decade in roundworm mutants with striking developmental defects. In 1991, Lee and Ambros found lin-4, a surprisingly small gene that produced a particular hook-shaped RNA. This little gene seemed to be a temporal switch in development, but unlike most timing controls, instead of synthesizing protein, it repressed protein production from certain other genes.

Lin-4 was the first gene of its kind identified, but was an only example in just one organism. "So initially, we worked on something novel, a gene important for C. elegans development, but whether or not it was important for other animals, let alone medical science, was in doubt," Ambros recalled. Things moved forward after a second, different small RNA also identified in the roundworm was found throughout the evolutionary tree--from sea urchins to insects and mice, to humans.

Several of the small RNAs identified in the current work are also evolutionarily ancient. Among these is mir-1, found in worms, flies and humans, which appears relatively specific to heart tissue. Ambros speculates that mir-1 may play a role in heart development and holds importance in some diseases of the heart.

The next step is to identify all the new RNAs and determine how they function. Roundworms alone contain at least 100, Ambros estimates conservatively. "The nice thing about uncovering this many microRNAs is that it places before us a buffet of questions and research projects larger than any one group could possibly pursue."

The excitement lies in these unanswered questions and new opportunities. The convergence of researchers in different disciplines sparks unanticipated collaborations to explore intriguing possibilities and the outcomes can be useful and far ranging. An area rich for collaborative investigation is in the field of genomics, which encompasses volumes of information and poses computational challenges.

"We've developed and applied a way of finding many of a new class of genes and think that in a year we may have found all of the C. elegans miRNAs. If we do, we're not focussing on one gene like we used to, but a whole class of genes," Ambros said. "We'd like to answer broad questions about how they work as well as specific questions about individual genes. The challenges escalate as the number of genes increase and the analyses become more complex. With lots of data we have to be able to weed out what's garbage and what's real so computer tools and bioinformatics expertise are essential."

The Geisel School of Medicine at Dartmouth

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