Seeking a continent’s history in its DNA

Sarah Tishkoff, Ph.D. ’96, has lost count of the trips she’s made to Africa since 2001 to study the continent’s genetic history. “By looking at your blood,” she explains to sub-Saharan villagers, “we can learn something about your mother, your father, your grandparents.”

Through the villagers’ DNA, Tishkoff has traced the history of malaria and dairy farming. She’s suggested a link between pygmies’ stature and a genetic mutation that strengthens their immune systems. She’s found the common ancestors of East Africa’s only two click-speaking populations. And her studies reveal greater genetic diversity among Africans than in any other ethnic group and suggest that all humans came from Africa more recently than previously believed.

Her most recent research, featured on the cover of the August 3 issue of the journal Cell, analyzed the fully sequenced genomes of 15 Africans from three hunter-gatherer groups. The study—which she described as the first high-coverage whole-genome population genomics study in humans and the most extensive in Africa—identifies several million previously unknown genetic mutations in humans, finds evidence that the direct ancestors of modern humans may have interbred with members of an unknown ancestral group of hominins, and suggests that different groups evolved distinctly in order to reap nutrition from local foods and defend against infectious disease. “Our analysis sheds light on human evolution, because the individuals we sampled are descended from groups that may have been ancestral to all other modern humans,” Tishkoff said. “A message we’re seeing is that even though all the individuals we sampled are hunter-gatherers, natural selection has acted differently in these different groups.”

Her work has attracted attention from Scientific American, National Geographic, and PBS’s Nova. But none have been more interested than the villagers themselves. “In one village, a man had a copy of the Jehovah’s Witnesses’ magazine Watchtower with a picture of a double helix in it. He asked me, ‘That’s what you’re studying, right?’ I said, ‘That’s right.’ And he said, ‘So could you trace where the blacks in the U.S. are from?’ ”

Studies of Africans were scarce when Tishkoff came to Yale in 1989. Her advisor, Kenneth K. Kidd, Ph.D., professor of genetics, of ecology and evolutionary biology and of psychiatry, had DNA samples from just two African populations in his lab. “The Mbuti and Biaka Pygmies from Central Africa are probably the least representative of African populations, but nobody knew that at the time,” said Tishkoff, the David and Lyn Silfen University Professor in the departments of genetics and biology at the University of Pennsylvania Perelman School of Medicine.

Tishkoff found more than she expected in those samples, specifically in a stretch of DNA on chromosome 12. “All Europeans looked similar to each other. All Asians looked similar to each other. But I wasn’t seeing anything similar in these African groups,” she said. “So I looked through the literature, contacted the people who were studying Africans, asked if they’d like to collaborate; they sent some DNA, and we ended up publishing in Science in 1996.”

In the study, Tishkoff, Kidd, and their collaborators revealed more genetic diversity among sub-Saharan Africans than among Northern Africans or non-Africans and suggested that humans came from Africa about 100,000 years ago. While researchers already favored the Out-of-Africa theory over a multi regional theory, Tishkoff’s study was the first to support it by using the same type of DNA used in forensics—nuclear DNA, which reveals more about an individual’s evolutionary history than does mitochondrial DNA.

When scrutiny of other genes continued to suggest that Africans differed more widely from one another than from anyone else, Tishkoff wanted to know the continent’s entire genetic history. She started in South Africa in 1997, where, as a postdoc at the University of Witwatersrand, she first heard about the Hadza and Sandawe of Tanzania. Though the two groups are the only click-speakers in East Africa, no one knew whether they are related. Tishkoff had to find out.

While waiting for local permissions for studies in Tanzania and Ethiopia (it took years), she continued her postdoctoral work at Pennsylvania State University, studying a gene related to malaria resistance. By determining when the gene first appeared in African populations, Tishkoff and her colleagues provided support for a long-held theory that malaria became endemic only after agriculture had been introduced.

Tishkoff was a professor at the University of Maryland when she and her team finally got permission to conduct her studies in Tanzania in 2001. She traveled the country in a Land Rover whose floor had almost completely rusted out. The vehicle, however, proved its worth—the team connected their centrifuge to that rusty Land Rover to process blood samples. The Bush Lab, as they dubbed the vehicle, helped Tishkoff, students, and collaborators learn that the click-speakers’ last common ancestors had lived 15,000 years ago. The languages and the people were barely related. The team also linked the gene responsible for lactose tolerance in Africans to the beginning of African dairy farming 7,000 years ago.

African collaborators, including researchers, nurses, and schoolteachers, are a major key to Tishkoff’s success. Through a study of 121 African populations, four African American, and 60 non-African populations, Tishkoff and her collaborators have shown that Africans have the highest level of intrapopulation genetic diversity. The knowledge that Africans are more diverse than other populations will affect future study designs and biomedical research and—Tishkoff hopes—encourage further study.

Throughout her work, Tishkoff has trained numerous African scientists from high school to the postdoctoral level to carry on research in Africa themselves. “That’s one of the things I am most proud of.”