May 8, 2009

Out of Africa: study will guide disease-gene hunt

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Scott Williams, Ph.D., and colleagues have traced the genetic structure of Africans to ancestral populations. (photo by Susan Williams)

Out of Africa: study will guide disease-gene hunt

In the most comprehensive study of its kind, researchers have traced the genetic structure and history of Africans to 14 ancestral populations.

The findings, reported April 30 in Science Express, lay the foundation for teasing apart the complex evolutionary history of Africans and African-Americans and have implications for studies aimed at finding disease genes in these populations.

“Nothing of this scale has ever been done before,” said Scott Williams, Ph.D., an investigator in the Vanderbilt Center for Human Genetics Research and senior author of the landmark study.

Africa is the source of modern humans, but the pattern of genetic variation among African populations — and how that variation relates to language, culture and geography — is largely uncharacterized.

Sarah Tishkoff, Ph.D., a geneticist at the University of Pennsylvania, began to tackle this problem more than a decade ago by establishing a database of genetic diversity among African populations — with the aim of using the database to reconstruct modern human origins and aid genetic epidemiology research.

Tishkoff, Williams and collaborators collected blood samples and information from members of more than 100 African ethnic groups, many of which have never been sampled before.

The researchers genotyped 1,327 DNA markers in 2,432 Africans (from 113 geographically diverse populations), 98 African-Americans and 21 Yemenites. In their analysis of genetic variation and ancestral groups, the investigators included pre-existing genetic data from eight other African populations and from populations of European, Indian, Native Australian, Oceanian and Native American descent.

“We were able to reconstruct the genetic structure and some aspects of the history of migration, language, culture, and means of subsistence,” Williams said. The study “confirmed the obvious — Africa is more genetically diverse than anywhere else in the world. As one moves away from Africa, genetic diversity declines rather dramatically.”

Importantly, the study mapped how the variation is partitioned within Africa. The findings describe 14 ancestral populations in Africa and pinpoint the “presumed ancestral population of all humans” as being located in the area of the South Africa-Namibia border.

The researchers also found that the “waypoint” for migration out of Africa was near the middle of the Red Sea in East Africa, Williams said.

Like Africans, African-Americans are a genetically diverse group, he noted.

“If you look at an individual African-American, parts of that person's genome are derived from one group, parts from another group, and parts from even a third or fourth group,” Williams said.

This information is particularly critical to genetic association studies that search for disease genes.

The presumption in a standard genetic association study is that cases (individuals with the disease) and controls (individuals without the disease) are randomly selected from the same source population, Williams explained.

If the source populations for a study are mixed or stratified, then one ends up “finding spurious associations with any genes that differentiate the ancestral populations,” he said.

“We can't improve the design of genetic studies unless we've got the information showing that these populations are different. We now provide that information.”

For genetic studies involving black Americans in particular, Williams noted, “we can't consider people of African descent as a homogeneous group, because they're not.”

The research was supported by the National Institutes of Health, the National Science Foundation, the Leakey Foundation, and the Wenner-Gren Foundation.