Text B. Ethnic Differences Traced to Variable Gene Expression

Finding could explain why ethnic groups suffer from particular common diseases

By Nikhil Swaminathan

Tay-Sachs disease seems to favor Jews of Eastern European descent. Cystic fibrosis has an affinity for Caucasians. Type 2 diabetes strikes Latin Americans and people of African descent more often than it does those of other ethnic groups, appearing at rates of incidence that are 90 and 60 percent higher, respectively, than in Caucasians. Researchers have been conducting studies such as the International HapMap Project--a global effort to catalogue common single-nucleotide variations, such as the addition, deletion or substitution of a base in the code of a gene--to get to the bottom of long-observed correlations between ethnicity and common complex diseases.

But those efforts have borne little fruit, according to Vivian Cheung, a human geneticist at the University of Pennsylvania School of Medicine. So, rather than characterize these individual nucleotide changes in genes, Cheung and geneticist Richard Spielman employed microarray technology--essentially a genome chip that allows a researcher to analyze the expression of many genes at once--to study across Chinese, Japanese and European populations many different traits that are coded for in a type of white blood cell.

Their results, reported in this week's Nature Genetics, were that different ethnic groups not only carried different genes, but there were greater disparities than previously believed in the degrees to which genes that were the same among ethnic groups were expressed. Further, the genes themselves did not control the levels of their own expression, rather noncoding regions adjacent to them determined whether to ratchet up or down the proteins or other functional end products the genes encoded.

The authors of the new study note that large-scale changes to DNA--such as specific substitutions or deletions of genetic material--almost certainly also contribute to differences between ethnic groups. But Cheung says that expression levels likely can explain some of the ethnic underpinnings of Tay-Sachs and cystic fibrosis as well as hypertension, which plagues those of Afro-Caribbean descent at a higher rate than other populations.

From its microarray, the team measured 4,197 genes expressed by cells. (After measuring expression levels of those genes, Cheung, Spielman and their colleagues decided to lump the Japanese and Chinese groups together due to similar results.) When the researchers then compared the Asian populations with the Caucasian sampling, they noted that 1,097, more than 25 percent, of the genes had differing expression levels.

After analyzing some of the nearly 1,100 genes in detail, Cheung and Spielman believe that the expression level discrepancies were due to nucleotide differences in noncoding regions around the genes, and not the genes themselves. "We were able to pinpoint 11 genes where people have different forms of the regulator," Cheung reveals, providing an example: "Let's say that among the Caucasian population, maybe the regulator that turns on the gene more happens to be more frequent--overall the expression level of that gene will be higher. Whereas in the Asian population, more people have the regulator that causes the expression level to be lower."

Steve McCarroll, a population and medical geneticist at the Massachusetts Institute of Technology's Broad Institute says that with so many genetic variants out there, researchers need all the help they can get determining which ones actually will affect cell function. "One of the things that's exciting about this work is that identifying the genetic variants that account for gene expression differences could help the field to find those genetic variants that affect disease risk," he says. (From Scientific American Online, January 9, 2007)

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