Significant new breakthroughs in understanding how the genes in mammals are controlled

An international consortium of genome research institutes and investigators, including Jackson Laboratory Staff Scientists Carol J. Bult, Ph.D., and Martin Ringwald, Ph.D., has reported significant new breakthroughs in understanding how the genes in mammals are controlled.

According to Dr. Bult, "The studies provide unprecedented insights into both the dynamic nature of the genome and the importance of genome organization on its function. The data will serve as a basis for discovery for many years."

The past five years have seen the completion of several mammalian genome sequences, but these are of limited value unless we can decode the way that they are translated into functions required to create a mature animal. Only around 2% of the genome is translated into proteins (coding transcripts), the building blocks of the cells that make up our bodies. But which 2%, and how is it controlled?

The key intermediate is the transcriptome, which now has been subject to the most comprehensive characterization ever. The groundbreaking study has used new technology that accurately tags the beginning and end of each of over 20 million RNA messages (transcripts) created by genes, resulting in a powerful profile of the regulating control of genes. In addition, it has also shown that overlapping sense/antisense transcript pairs (both strands) are almost universal in the genome, and that sense/antisense pairs are especially abundant in imprinted loci, keeping with the putative role of non-coding RNA in the mechanism of gene silencing.

Since mammals only have slightly more conventional genes (around 22,000) than a comparatively simple nematode, the results of the FANTOM Consortium study clearly indicate that while proteins comprise the essential components of our cells, the development of multicellular organisms like mammals is controlled by vast amounts of regulatory non-coding RNAs that until recently was not suspected to exist or be relevant to our biology. The findings suggest that the difference between mouse and man may well lay in the control systems of these genes, and not in the structures of the proteins some of them code for.

"We have provided the biomedical research community with the tools to understand the controls that are needed to make a mammal. We have deciphered the genome sequence not only for the code for making the parts (proteins) of a mammal, but also the code for making the right forms, in the right amounts, in the right place, at the right time." states project leader Yoshihide Hyashizaki.

The findings were published in two papers in the Sept. 2 issue of the journal Science by the FANTOM Consortium for Genome Exploration Research Group, RIKEN Genomic Sciences Center (GSC), RIKEN Yokohama Institute and Genome Science Laboratory, Discovery and Research Institute, and RIKEN Wako Institute (Genome Network Core Group). Dr. Bult is a long-time member of the FANTOM Consortium. She and her team at Jackson contributed to the analysis of the RIKEN data and to its integration with existing biological knowledge about the laboratory mouse in the publicly available Mouse Genome Informatics database (http://www.informatics.jax.org).

These studies have been carried out mainly on mice, the most widely used experimental mammalian species. Equivalent human data is not far behind, and RIKEN and many FANTOM members are actively involved in the next phase, the Genome Network consortium (http://www.mext-life.jp/genome/english/index.html), which aims to use these new tools to understand human development and disease. Associated with the publication of the Science papers, all of the information will be publicly released on the Internet: http://www.ddbj.nig.ac.jp/, http://fantom3.gsc.riken.jp/db/.

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