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Web Date: June 13, 2007

Finding Function In The Genome

Consortium uncovers surprising features in the human genetic blueprint
Department: Science & Technology
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ENCODE
consortium members Tullius (from right) and graduate students Stephen Parker and Eric Bishop use a capillary DNA sequencer to determine DNA cleavage patterns that provide information about the shape of the DNA backbone
Credit: Vernon Doucette/Boston University
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ENCODE
consortium members Tullius (from right) and graduate students Stephen Parker and Eric Bishop use a capillary DNA sequencer to determine DNA cleavage patterns that provide information about the shape of the DNA backbone
Credit: Vernon Doucette/Boston University

Following on the heels of the massive Human Genome Project, which revealed the sequence of the human genome, a huge consortium of scientists has unveiled its preliminary progress in analyzing the functions of various stretches of that genetic blueprint (Nature 2007, 447, 799 and entire issue of Genome Res. 2007, 17).

Participants in the ENCODE (Encyclopedia of DNA Elements) project devised and tested a wide variety of high-throughput experimental and computational methods for identifying functional elements in a representative fraction of the genome. Such functional elements include sequences that code for proteins, sequences that don???t code for proteins, regulatory sequences that control the transcription of DNA, and sequences that control the packaging of the genome.

The consortium???s effort has revealed quite a few surprises about the genomic landscape. For instance, the team reports that the majority of DNA???whether it encodes proteins or not???is transcribed into RNA. This pervasive pattern of transcription challenges the longstanding notion that the human genome consists of a relatively small number of discrete genes surrounded by a plethora of seemingly irrelevant "junk" DNA, they say.

"We are increasingly being forced to pay attention to our nongene DNA sequences," notes John M. Greally of Albert Einstein College of Medicine in a commentary in Nature accompanying the consortium???s report. He adds that the consortium???s observations follow recent reports that many single-nucleotide genomic variations associated with disease are found outside of genes.

Also, contrary to conventional wisdom, about half of the functional elements identified by consortium scientists appear to have been under little or no evolutionary constraint. That is, their sequences don???t seem to be conserved across different species. One possible explanation for this observation comes from Boston University chemistry professor and consortium member Thomas Tullius, whose lab is surveying the local DNA-backbone structure of functional elements in the genome (Genome Res. 2007, 17, 940 and 947). "Maybe sequence isn???t the final answer," he says. "I suspect we might find that the structure, not the sequence, of these functional elements is, in fact, what???s been conserved during evolution."

The consortium???s first-stage report covers 1% of the human genome, or roughly 30 million base pairs, selected to give a representative cross-section of the genetic blueprint. In the future, its members hope to produce a comprehensive catalog of all functional elements in the human genome.

"The glimpse we are provided by the ENCODE consortium into the ordered complexity of 1% of the human genome is tantalizing," Greally notes. But, he adds, it remains to be seen whether the researchers??? findings during the pilot phase will extend to the other 99% of the human genome. Consortium scientists face not only the work of scaling up the project???s methods but also the challenge of proving that their insights, obtained from easy-to-culture human cell lines, are representative of the many different types of primary cells found in the human body.

In the meantime, "because of the hard work and keen insights of the ENCODE consortium, the scientific community will need to rethink some long-held views about what genes are and what they do, as well as how the genome???s functional elements have evolved," comments Francis S. Collins, director of the National Human Genome Research Institute at the National Institutes of Health in Bethesda, Md. "This could have significant implications for efforts to identify the DNA sequences involved in many human diseases."

 
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