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Large-Scale Genome Sequencing Study Unravels History, Traits of Understudied African Populations

NEW YORK – A new genomic study of diverse African ethnic groups has provided clues about the continent’s complex demographic history, shared ancestry between populations, and the genetic basis of local adaptation of traits such as skin color, immune response, height, and metabolic processes.

"Despite the essential role that Africa has played in the origin and evolution of anatomically modern humans, Africans are still underrepresented in human genomics studies," a team led by researchers at the University of Pennsylvania wrote in a paper appearing in Cell on Thursday, noting that individuals of African ancestry in the US also carry a high burden of common diseases, in part likely due to unknown genetic factors. For their study, the researchers performed whole-genome sequencing on samples of 180 Africans from 12 indigenous populations from Ethiopia, Tanzania, Cameroon, and Botswana — 15 individuals from each group.

They identified more than 32 million SNPs, including 5.3 million that were new, most of them population-specific. Among those, 154 SNPs had previously been reported as pathogenic or likely pathogenic in the ClinVar database. However, the researchers said that a number of these have likely been misclassified and are probably benign, as they are common in at least one African population but uncommon in other populations, such as Europeans, that currently dominate clinical genomic databases.

"The results are telling us how critically important it is to include ethnically diverse populations, and particularly those from Africa, where we see the most genetic variation in the world," said corresponding author Sarah Tishkoff, a professor of genetics and biology at the University of Pennsylvania. "This could have major implication for precision medicine."

The researchers also discovered genetic variants within different groups that appear to play a crucial role in local adaptation to environments, diets, or pathogens.

For instance, the San population, who have lighter skin than other African ethnic groups, had several unique SNPs near genes that have been implicated in skin pigmentation, including one SNP that appears to influence the expression of PDPK1, a gene that regulates melanocyte proliferation.

Meanwhile, the investigators also found variants near genes associated with bone growth in Central African rainforest hunter-gatherers who are known for their short stature.

In the Hadza hunter-gatherers in East Africa, who tend to walk long distances each day, they found a unique enrichment of variants near genes that play a role in heart development and function. "My lab is now following up with some of these genes to see whether we can learn about the genetics of heart muscle development," Tishkoff said in a statement.

Another important finding was that the San and the Central African rainforest hunter-gatherers appear to share the same ancestry, forming a sister clade. Previous studies had suggested that only the San were the descendants of the most ancient African population.

The researchers also found that Khoesan-speaking groups who are currently geographically isolated, and whose languages share click consonants but are highly distinct in their other features, are in fact closely related. "There could have been continuous gene flow between the Khoesan-speaking populations in eastern and southern Africa over long periods of time," the author noted.

One of the limitations of the study was the small sample size, both within each population and in terms of groups not covered, the authors cautioned. "We may be missing some rare but functionally important SNPs as well as SNPs that may be specific to populations from regions not well represented in the current study such as western and northern Africa," they wrote.