I love population genetics for its ability to peer back into human history through the medium of DNA's ATCGs.

One of the stars of this discipline is Sarah Tishkoff, a standout in African genetics, someone who will readily haul a centrifuge into the bush in Cameroon.

Tishkoff of the University of Pennsylvania is lead author on a paper published online July 26 in Cell that details whole-genome sequencing of five individuals each from three extant hunter-gatherer groups—the Pygmies of Cameroon as well as the Hadza and the Sandawe of Tanzania. The results reveal millions of newly discovered genetic variants—differences in single genetic letters, the ATCGs—and indicate that early modern humans may have interbred long ago in Africa with another species of hominid (although the fossil record does not provide much support for the latter finding).

Tishkoff answered a few questions for us about this paper, co-authored with Joseph Lachance and 11 other researchers. An edited version of the interview appears below:

Please describe the research that led to the paper that was published today:

We're the first ones to look at these diverse groups of hunter-gathers in Africa who descend from some of the most ancestral lineages in the world. They're interesting because they have very unique and distinct lifestyles There are few populations that maintain this active hunter-gatherer lifestyle.

This is the most extensive study in Africa using high-coverage deeply detailed sequence data. We focused on three groups because they're anthropologically interesting. They're thought to be descended from groups that are ancestral to all modern humans. We wanted to understand the genetic basis of adaptation to their local environment including, for instance the short stature trait in Pygmies.

So what did you find?

We discovered 13 million variants and, of those variants, greater than 3 million are completely novel, meaning that they have not been reported in any database. The current public database has 40 million variants. So we found 3 million novel variants by simply sequencing 15 individuals. That increases by about 8 percent all known human genetic variation. It also demonstrates that we're missing a lot of really important variation that's out there, particularly in Africa, which is the homeland of modern humans and a place where there's been a lot of time for differentiation to have occurred in very diverse environments. What this means is that there's s probably a lot of regional or population-specific variation out there that has not been that well characterized, some of which is functionally very important.

What about natural selection?

Natural selection seems to be operating more on the non-coding genome [the regulatory portion that does not contain genes] than the coding region. A lot of people are doing exome sequencing [looking only at genes]. I think they're missing a lot of important variation.

In our study, we looked at what regions of these groups' genomes were uniquely differentiated to their local environments. There wasn't a huge amount of overlap between the groups—or between them and other non-hunter-gatherer groups from Africa. Due to natural selection, we found there were distinctive adaptations for immunity, taste and smell.

In the Pygmies, we discovered genes involved with thermal regulation, immunity and stature, all likely to be adaptive to a tropical environment. We pinpointed genes related to pituitary and thyroid function, the latter perhaps an adaptation to a low-iodine environment.

In the Sandawe, we found a variant for melanin, a gene involved in skin color. The Sandawe are among the most fair-skinned groups in Africa. When I went to work with them, they said, 'We're like brothers and sisters because you look like us.' This is not because of any European admixture; they look like the San [a hunter-gatherer group from southern Africa]. When I said: 'Where do you come from, they pointed to a mountain in the distance. When I said 'Can you take me there?" we went but there was no road. We went through the bush and they showed me cave paintings. Having lived in South Africa, I've seen the cave paintings of the San.

What about interbreeding with other human species?

A number of studies have shown a low amount of interbreeding between early modern humans outside of Africa and archaic species outside of Africa including Neandertals and, in Asia, with the species they call Denisova.They've never found any evidence of Neandertal DNA in Africa. The problem is that you just don't get good preservation of fossils in Africa. So what we did was collaborate with Josh Akey and Ben Vernot at the University of Washington and used a statistic they developed to recognize regions of genome that appear to be of archaic origin.

The first thing we did is to test this statistic by applying it to non-Africans and we found a very strong enrichment for Neandertal DNA in those genomes. But we didn't see that in the Africans. They had no Neandertal DNA. When we applied the statistic to Africans, though, we still saw a lot of evidence for interbreeding from a hominid who diverged from a common ancestor that we shared about 1.2 million years ago, about the time that Neandertals split off as well. This suggests that there could have been a sister species in Africa. What it was nobody knows. But it seems to show that modern humans have been interbreeding and it's not unique to non-African species.

Why are African genetics so exciting?

Africa was the site of origin of all modern humans and if you want to learn about when, where and how we evolved, you want to look at this continent. It has a long history of population subdivision and adaptation of those populations to very distinct environments and a broad range of phenotypes, ranging from the short stature of the Pygmies to the very tall stature of the pastoralists in the east. It also has very different disease exposure and very different disease prevalence throughout.

What's next?

We want to expand our genome-wide analysis to other populations, and we want to do so with larger sample sizes. We're going to continue to try to correlate genetic variants with different phenotypic traits. We'd love to do functional studies of these genes to see, for instance, how they are regulating pituitary development. Is there some totally novel mechanism involved. We're going to look at the Pygmies and other groups with a systems approach. You can't look at height, as an example, by itself. You have to look at it in relation to metabolism and immunity and see how everything interacts.

Image source: Sarah Tishkoff