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Genome Sequencing Study Offers Clues to History, Adaptations of Hunter-Gatherer Populations in Africa

NEW YORK (GenomeWeb News) – In a study appearing online today in Cell, an international team led by University of Pennsylvania investigators delves into the population history of three African hunter-gatherer groups, uncovering clues about genetic adaptations within each group.

The researchers sequenced and analyzed the whole genomes of 15 African men: five individuals from Western Pygmy populations living in the forests of the Republic of Cameroon and five individuals each from the Hadza and Sandawe populations from Tanzania, which speak distinct forms of "click," or Khoesan languages.

"I'm quite interested in how these groups have adapted to their local environments, both in terms of diet, in terms of infectious disease resistance, and, in the case of the Pygmies, the short stature trait," senior author Sarah Tishkoff, a genetics researcher at the University of Pennsylvania, told GenomeWeb Daily News.

Analyses of these high coverage genomes revealed millions of previously undetected variants, along with genetic signals that seem to stem from interbreeding between the modern human ancestors of all three hunter-gather groups and an unidentified archaic hominin species — an event estimated to have taken place around the same time that humans outside of Africa were mixing with Neandertals.

"We don't know what this [archaic] population could have been, but we see evidence that definitely seems to support that," the study's first author Joseph Lachance, a post-doctoral researcher in Tishkoff's UPenn lab, told GWDN.

The study also pointed to population-specific adaptations involving genes participating in everything from immunity and healing to sensory perception and metabolism. It also helped to uncover a block of Pygmy-specific variants near pituitary gland-related genes that are now suspected of contributing to short stature in both Western and Eastern Pygmy populations in Africa.

Previous studies done using Y chromosome and mitochondrial sequence data suggest that the ancestors of African hunter-gather groups have some of the earliest divergence times in the modern human lineage, Tishkoff explained, suggesting that present-day hunter-gatherer populations on that continent could be direct descendants of an ancestral group that's shared by diverse populations around the world.

For the current study, researchers focused on three of these hunter-gatherer populations, which have varied physical features, cultural strategies, and environments. In Cameroon, for instance, expansions of agricultural Bantu-speaking populations into once-forested Pygmy regions have led to some mixing between the populations.

Likewise, in Tanzania, admixture between the Sandawe population and Bantu populations that have stretched into the region has been accompanied by a shift from a purely hunter-gather lifestyle to one with a more agricultural bent in some members of the Sandawe population, which has an estimated size of 30,000 individuals or more.

On the other hand, Tishkoff noted, the much smaller Hadza population — comprised of around 1,000 individuals — has largely resisted such assimilation and seems to have little in the way admixture with neighboring populations.

For the current study, Tishkoff and her colleagues relied on genome sequence data for five Hadza, five Sandawe, and five Western Pygmy men. The latter includes representatives from three Western Pygmy populations: the Baka, Bakola, and Bedzan.

When they compared the genomes — each sequenced to a mean depth of more than 60-fold by Complete Genomics — to the current human reference genome, researchers found 13.5 million SNPs or small insertions and deletions current. Among them are almost 3.1 million variants not described in dbSNP or in 1000 Genomes Project data.

At the population level, meanwhile, the team did not see signs of a closer than usual relationship between Tanzania's Hadza and Sandawe populations, despite their close geographical proximity and the fact that both belong to the Khoesan language group.

Instead, sequences for individuals from all three hunter-gather groups clustered similar distances away from those of a San individual, whose genome was sequenced by another research group in 2010.

Even so, the Western Pygmy individuals appeared to share a few more derived variants with the San. And the researchers' phylogenetic analysis pointed to a slightly earlier divergence time for the ancestors of present-day Pygmy populations than ancestors of the Hadza and Sandawe, though Tishkoff noted that more research is needed to rule out historical admixing between populations that might have muddied this analysis.

Researchers' simulations also suggest that individuals from all three hunter-gather populations share some archaic hominin ancestry: signals in the newly sequenced genomes showing patterns consistent with archaic admixture around the same time that modern humans outside of African were canoodling with Neandertals.

But because conditions in Africa are far less forgiving than the often-chilly climes where Neandertal and Denisovan remains have been discovered, the identity of the archaic species involved in this apparent interbreeding in Africa is difficult to discern.

"What it was, we have no idea," Tishkoff said. "Africa's a really problematic region to get ancient DNA because of the conditions."

When they compared the hunter-gatherer populations to three agricultural or pastoral populations from Africa — using publicly available data from Complete Genomics that includes genome sequences for 10 Yoruban individuals from Nigeria, four Maasai from Kenya, and four Luhya, also from Kenya — researchers did not find large-scale genomic patterns that were shared across the hunter-gatherer groups, Lachance noted.

But the team's search for signals of selection and variants found at especially high frequencies within one or more of the hunter-gatherer groups did offer insights into population-specific adaptations, he explained. "When you start to zoom in on individual loci or individual regions of the genome, you start to see very different patterns for different populations: on that fine-scale, you start to see local adaptation."

In both the Hadza and Sandawe populations, for instance, researchers found fast-evolving regions of the genome containing genes involved in immune function. Pygmy and Sandawe populations showed signs of adaptation involving a gene called BTN1A1 that contributes to lipid content in breast milk, while Pygmy and Hadza populations had adaptations involving smell receptor genes.

Within the Pygmy individuals tested, population-specific analyses pointed to some of the same regions uncovered in a recent study from Tishkoff's lab that focused on finding potential contributors to stature and related traits in Africa's Western Pygmy populations. But there were some differences, too.

For instance, authors of the new study tracked down a cluster of 44 Pygmy-specific alleles in complete linkage disequilibrium on chromosome 3. This group of so-called ancestry informative markers fell not far from a 15 million base pair region that researchers flagged in the previous Pygmy study. Among the closest candidate genes here, though, was HESX1, a pituitary gland development related gene that has been linked to short stature in past studies.

Other apparent pituitary gland players came out of the Western Pygmy population analysis as well, suggesting variants affecting pituitary function might be behind not only African Pygmy height, but also other some of the metabolic, sexual, and immunity-related traits described in the populations.

In follow-up studies, researchers saw that at least some of the ancestry informative marker on chromosome 3 are also found at fairly high frequencies in the Mbuti population, an Eastern Pygmy population from the Democratic Republic of Congo, Tishkoff explained, suggesting that they arose prior to the split between Western and Eastern Pygmy populations in Africa some 150,000 years ago.

As such, Tishkoff said, the whole-genome sequence data "complements and expands on" results from her team's earlier array-based search for genetic contributors to height in African Pygmies.

More generally, she said the latest results highlight the additional information that can be gained using data for complete genomes rather SNP chips, which were developed using data on just a few human populations.

Going forward, researchers hope to continue sequencing individuals from various African populations. They are also planning to do studies in mouse models aimed at determining whether variants belonging to Pygmy-specific haplotypes influence pituitary gland function, perhaps through regulatory mechanisms.

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