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Of Mice and Men

U of T team finds that few protein-coding genes remain to be discovered, but a single gene can spawn thousands of different proteins

Just two years after the completion of the Human Genome Project, U of T researchers appear to have answered the question on all life scientists’ lips: Do any genes remain to be discovered?

If you remember your high school biology class, you know that human DNA is made up of molecules called nucleotides – about 2.85 billion of them – arranged in a double helix configuration. Only some sections of the double helix contain genes, which serve as “instructions” for the creation of proteins. (These proteins form an essential part of all living organisms.)

Now imagine a cluster of miniature electronic probes, each containing about 60 nucleotides. Called micro-arrays, these clusters can track down the segments of DNA that hold our genetic instructions and distinguish them from the long stretches of filler DNA in between.

To the uninitiated, all this sounds very sci-fi. To U of T molecular biology professor Timothy Hughes, it’s life as usual in the lab. In collaboration with Brendan Frey, a professor in the department of electrical and computer engineering, Hughes’s research team has spent the past three years using micro-arrays in mouse DNA to hunt for its genes.

Hughes’s team fed the nucleotide sequences collected from the micro-arrays into a spreadsheet, seeking to detect meaningful patterns. That’s where Frey came in. “We developed a computer algorithm to distinguish patterns suggesting true genes from more random patterns,” explains Frey.

Crunch crunch crunch, went the numbers, yielding the startling result: “It turns out there are few, if any, protein-coding genes remaining to be discovered,” says Hughes. “This flies in the face of research that predicted several-fold more genes than the currently known ones.” Published in Nature Genetics, the results also confirmed that genes that have starring roles in some tissues may play second fiddle – or remain silent – in others. “There’s clearly a relationship between the function of a tissue and the genes that get expressed in that tissue,” says Hughes.

Frey says the work closes a chapter in genomic research, but leaves open the question: with only 20,000 to 25,000 genes in the human genome, where on Earth does all the human diversity come from? The upturned noses, grumpy dispositions or aptitude for chess?

Frey’s ongoing research might well solve this mystery. “My colleagues and I have now started an even more exhaustive project, with more probes,” he says. Funded by Genome Canada, the $22-million project compares gene expression in healthy and diseased tissue. “We’re targeting common and complex diseases, such as heart disease and cancer, in hopes of discovering many discrepancies.”

The project has already unearthed startling new evidence for gene variation. “We already knew that the same DNA sequence could be read in different ways, resulting in different proteins as end products,” Frey explains. “What we’ve done is to map these different ‘readings’ throughout the genome.” As it turns out, “a single gene can yield up to thousands of different proteins.” This phenomenon helps explain how so few genes can spawn so much biological diversity, including, possibly, those upturned noses.

The long-range impact? “If we can pinpoint the gene differences in diseased tissue, we can work toward correcting these differences,” says Frey. For example: “Once we identify the genes that get over-expressed in cancer, we could develop drugs to inactivate those genes.”

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