Analyzing HGSI's Gene Collection - Brief Article

Applied Genetics News, March, 2000

Human Genome Sciences, Inc. (HGSI, 9410 Key West Ave., Rockville, MD 20850; Tel: 301/309-8504, Fax: 301/309-8512) and Compugen Ltd. (72 Pinchas Rosen St., Tel Aviv, Israel; Tel: 3-765-8585, Fax: 3-765-8555; Email: info@cgen.com, Website: www.cgen.com) scientists will collaborate to analyze HGSI's collection of human genes using the Compugen LEADS computational analysis platform. The work is expected to result in the creation of a chromosomal map of most expressed genes, the creation of a large collection of single nucleotide polymorphisms in expressed genes (called cSNPs), and the creation of a comprehensive description of human gene organization and splicing variants.

HGSI will pay Compugen a fixed multi-million-dollar fee for work to be completed within the next 12 months and will hold the exclusive rights to commercialize the results of the study.

HGSI has isolated and characterized what it believes to be more than 95% of all human genes. This HGSI gene collection is derived almost entirely from human messenger RNAs. To date, HGSI scientists have isolated more than 2.5 million messenger RNAs from a representative sample of all human organs and tissues, from more than 800 unrelated individuals.

The analysis of the gene data will also include information from public databases - including more than 1 billion nucleotides of human genome sequence, and sequences of more than 1 million messenger RNAs. Additional human genome sequences will be included in the analysis as these are released to the public over the next year, including what is expected to be a rough draft of the entire human genome sequence by the end of this year. The HGSI/Compugen collaboration should result in the first virtually complete chromosomal map of expressed human genes.

"HGSI and Compugen are in what may be a unique position to develop a comprehensive map of human genes," said Michael R. Fannon, vice president and chief information officer of HGSI. Compugen's LEADS technology should allow HGSI to map the expressed genes to precise chromosomal locations by matching the gene sequence of an individual messenger RNA with the corresponding sequence of chromosomal RNA. It is difficult to identify a gene from a genomic sequence unless a messenger RNA from of the gene has been previously isolated, according to Fannon.

"Associations between individual genes and inherited diseases can be quickly made because the precise location of a human gene will be known, says Craig Rosen, senior vice president of HGSI. "We know that the messenger-RNA approach to disease gene identification works because this approach has been used to identify genes responsible for inherited disease." HGSI scientists have used this method to identify three different genes responsible for inherited forms of human colon cancer.

The HGSI/Compugen collaboration is also expected to create what HGSI believes will be a significant collection of single nucleotide polymorphisms in expressed genes (cSNPs).

On average, there are about four single nucleotide polymorphisms per individual messenger RNA of any two unrelated people. HGSI estimates that there are more than 500,000 cSNPs in its gene collection of 2.5 million messenger RNAs. Comparison of these nucleotide differences in the messenger RNAs, obtained from 800 individuals by new computation methods, will identify such variants.

HGSI and Compugen scientists will analyze the organization of expressed human messenger RNAs and their variants. The LEADS technology allows direct comparison of the sequence of a messenger RNA to the corresponding chromosomal sequence. A comparison of messenger RNA sequence to that of the corresponding genomic sequence will reveal the exon-intron organization of a gene. HGSI and Compugen scientists will analyze the results of such comparisons on a gene-by-gene basis. The eventual result will be a comprehensive analysis of human gene organization.

The LEADS technology will also detect a second significant feature of human gene organization - variation in splicing of individual genes. The final structure of a messenger RNA may vary between organs and tissues, depending upon how the exons were spliced together to create a messenger RNA. Exons found the messenger RNA of a gene made in one tissue - the brain, for example - may not be included in the messenger RNA made for the same gene found in muscle. Spliced variants may produce proteins with substantially different functions.

"In the most extreme use, the two spliced variants may have opposing biological functions," notes Steve Ruben, vice president of research of HGSI. "For example, we have discovered several spliced forms of the gene messenger RNA that produces human growth hormone. Most of these spliced variants produce proteins that promote growth. However, at least two of the spliced variants we discovered have the opposite effect - i.e., produce proteins that inhibit growth."