Sci. Aging Knowl. Environ., 10 October 2001
Mining for Genes: Comparative sequence analysis unearths hidden gem
Key Words: apolipoprotein APOAV comparative sequence analysis triglyceride coronary artery disease
Abstract: With the Human Genome Project nearing completion, finding the genes involved in aging-related disorders and other unwelcome afflictions is closer than ever. But obtaining the sequence is only the first step; locating genes among the sea of 3 billion nucleotides still poses a formidable challenge.
Pennacchio and colleagues now illustrate the power of comparative sequence analysis to pinpoint genes, even in well-studied chromosomal regions. Their find: a gene that influences risk for a common malady of old age, namely coronary artery disease. The method hinges on the fact that natural selection maintains sequences that perform important functions. As a result, genes--as opposed to the stretches of DNA that lie between them--tend to be conserved among species. With this principle in mind, the researchers staked out a region of chromosome 11 that carries an apolipoprotein gene cluster; they sought sequences shared by humans and mice, hoping to find spans of DNA that regulate the expression of these previously identified genes. Instead, their comparison turned up an entirely new member of the group, a gene they call APOAV. Like other apolipoproteins, APOAV affects the concentrations of lipids in the bloodstream. Blood plasma triglyceride concentrations in mice engineered to overproduce Apoav are a third as great as those in wild-type animals; conversely, triglyceride concentrations in mice that lack the gene are four times as high. Results from additional experiments suggest that certain versions of APOAV correlate strongly with elevated triglyceride levels in humans.
The discovery could reach beyond fighting heart disease: Elevated triglyceride levels are also a risk factor for strokes, so therapies that target APOAV or the protein it encodes could potentially reduce both strokes and the vascular dementia that commonly accompanies them.
L. A. Pennacchio, M. Olivier, J. A. Hubacek, J. C. Cohen, D. R. Cox, J.-C. Fruchart, R. M. Krauss, E. M. Rubin, An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science 294, 169-173 (2001). [Abstract] [Full Text]
Citation: C. Aschwanden, Mining for Genes: Comparative sequence analysis unearths hidden gem. Science's SAGE KE (10 October 2001), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/2/nw6
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