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Are self-identified labels of race useful in large-scale population genetic studies? Kevin Davies looks at a provocative commentary from a leading Stanford University geneticist that has fuelled controversy.

By Kevin Davies

Sept. 9, 2002 | In 1991, a group of geneticists led by the distinguished Stanford University professor Luca Cavalli-Sforza made a bold appeal in the journal Genomics that it was time to launch a human genome diversity project (HGDP). They stated, "It would be tragically ironic if, during the same decade that biological tools for understanding our species were created, major opportunities for applying them were squandered." Although well intentioned, the proposal floundered in a storm of outrage from ethnic organizations, which alleged that scientists were at best seeking to exploit endangered populations, at worst compiling the tools for genocide.

While prospects for an international genome diversity project remain bleak a decade later,

Featured Report 
N. Risch, E. Burchard, E. Ziv, and H. Tang, "Categorization of humans in biomedical research: genes, race and disease." Genome Biology 3(7):comment2007.1-2007.12: 1 July 2002. 
there has been no shortage of fascinating studies of late tracking genetic variations through the female line (in mitochondrial DNA) or the male line (the Y chromosome) to shed light on the origins and migration of human populations. As populations have become more amenable to DNA genotyping studies, scientists have stressed repeatedly that there is no significant correlation between race and genetic differences. "Prejudice does not require a rational basis, let alone an evolutionary one," Mary-Claire King, a geneticist at the University of Washington, opined in Science a few years back, "but the myth of major genetic differences across 'races' is nonetheless worth dismissing with genetic evidence." During the White House human genome ceremony in June 2000, J. Craig Venter stated, "The concept of race has no genetic or scientific basis." A recent editorial in the New England Journal of Medicine argued that, "race is biologically meaningless." And in his book Mapping Human History, science writer Steve Olson states: "The word 'race' has become so burdened with misconceptions, so weighed down by social baggage, that it serves no useful purpose. The sooner its use can be eliminated, the better."

Numerous surveys of genetic variation among populations around the world indeed show that about 85 percent of the total genetic variation occurs between individuals within a given population, far more than the 15 percent or so in members of different populations. However, this does not mean, as is sometimes inferred, that individuals of the same race exhibit greater variation than people of different races.

Understanding the pattern of genetic variation within and between populations is critically important for clinical reasons. The presence of SNPs (single nucleotide polymorphisms) can exert a profound effect on the activity of drug-metabolizing enzymes (DMEs), sometimes producing toxic side effects, other times rendering medications ineffective. These differences exist, of course, between individuals of the same racial group, but there may also be significant average differences between different populations — differences that must be appreciated during clinical trials.


Desegregation Debate 
In a paper last year in Nature Genetics, David Goldstein and colleagues suggested that the classification of DME genetic variants could be undertaken more efficiently using a program (called STRUCTURE) to cluster groups genetically, rather than relying on common ethnic labels (such as African-American, Asian, Caucasian). Goldstein concluded that, "commonly used ethnic labels ... are insufficient and inaccurate descriptions of human genetic structure," and favors a "race-neutral" approach to genetic studies.

But in a new commentary published in the July 1 issue of Genome Biology, Stanford University geneticist Neil Risch and colleagues charge that the apparent rush to decouple genetic variation with race "does not derive from an objective scientific perspective." The greatest genetic variation in humans is seen in the oldest population — Africans — with Caucasians, Asians, East Asians, and Pacific Islanders forming the four other classically recognized races. This classification scheme is fully upheld by genetic studies, which underscores that race must have at least some biological basis. Races are commonly (albeit imperfectly) distinguished on the basis of skin pigmentation, which is governed by variations in genes influencing melanin production. While there is no logic in correlating skin color and drug metabolism, there is equally no reason to assume that more relevant genetic variants, in DMEs for example, could not have a racial distribution.

Risch's team suggests that Goldstein's data actually show a greater variance in DME distribution when classified by racial grouping, rather than genetic clustering. Favoring genetic classification schemes exclusively over self-reported ethnicity would likely mask non-genetic factors influencing disease risk, including socioeconomic, cultural, and epidemiological factors. Differences in diet or access to health care may be important contributory factors that might only emerge with information on ethnic background.

"Identifying genetic differences between races and ethnic groups, be they for random genetic markers, genes that lead to disease susceptibility, or variation in drug response, is scientifically appropriate," Risch and colleagues conclude, with a stern caveat: "What is not scientific is a [political] value system attached to any such findings."

While disagreeing with some of Risch's stark statements, Goldstein is strongly supportive of Risch's basic tenet, namely that geographic ancestry can be of medical significance. "We should not be afraid to admit that there are some genetic differences, on average, among people with ancestry in different parts of the world," Goldstein says.

Until individual genotyping becomes technically and economically viable, population differences should be taken into account, while the rights of all populations are carefully safeguarded. "We need to value our diversity rather than fear it," says Risch. "Ignoring our differences, even if with the best of intentions, will ultimately lead to the disservice of those who are in the minority."* 



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