Feature: Exploring the bounds of human genetic diversity

Did you know that there is more genetic diversity between two individuals living only 800 kilometres apart in the Kalahari desert in southern Africa than there is between a European and an Asian living half a world apart?

If it wasn’t for the southern African genome project, co-led by Vanessa Hayes, no-one would have known this remarkable fact about humanity.

Actually, if it weren’t for Hayes’s work, we might have continued on for many more years thinking that the miniscule sample of Africa’s population that we had in the gene libraries several years ago was sufficiently representative of this profoundly diverse nation, and of humanity as a whole.

And according to Hayes, we’ve only scratched the surface when it comes to understanding human genetic diversity. Most of the individuals who have had their genome sequenced have been of European descent, with a smaller sample of others from around the world.

Yet Africa, the birthplace of humanity, remains a frontier for genetics, with many populations yet to be added to databases such as the International HapMap Project or the 1000 Genomes Project.

With her recent appointment as the head of genomic medicine at the J Craig Venter Institute (JCVI), Hayes intends to continue exploring the broad landscape of the human genome globally with the hope of gaining a better insight into how variations in genotypes link to variations in phenotypes.

Genetics in reverse

A decade ago, Vanessa Hayes was frustrated. While working in her native South Africa on genetic susceptibility to HIV/AIDS, she realised we were doing genetics in reverse.

“We did genetics on white people and tried to extrapolate back into Africa. But because we all come out of Africa, I felt that we need to do our studies in Africa, and then extrapolate out to the rest of the world.”

Large scale genome studies, like the pioneering Human Genome Project, were conducted mainly on Americans of European descent – people like J. Craig Venter and James Watson – which is understandable given America is where the money is, and these studies had bills in the billions.

But in terms of gaining an understanding into what makes us who we are, they weren’t necessarily the ideal starting point. “I remember thinking at the time about the Human Genome Project: why didn’t they sequence an African? It would have given us more information,” says Hayes.

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Even looking at only 13 relevant genes during her HIV study – in the days before affordable whole genome sequencing – she could plainly see the diversity in southern African people. But it would take another 10 years before she would have the opportunity to explore this diversity in greater depth.

That opportunity arrived while she was stationed at the Children’s Cancer Institute Australia, when she teamed up with Professor Stephan Schuster from Pennsylvania State University in the US, and headed back to Africa to finally begin doing genetics the right way around. “This had been a very long dream of mine. I believed that we needed to have a southern African genome for the gene databases.”

For their study, they chose two southern African populations that had been overlooked in previous sequencing endeavours, which had only included one African people: the Yoruba from Nigeria.

The first group was a Bantu speaker, represented by none other than Archbishop Desmond Tutu, who agreed to participate in the study. There are around 500 different Bantu speaking peoples, covering around one third of Africa’s population, making them a significant and highly diverse population in themselves.

The other population chosen for the study was the Bushmen of the Kalahari desert. “The Bushman, or the click-speaking people, are hunter-gatherers, and they really represent who we all were. The theory was that these were the oldest living decedents of all of us.

To me these were the obvious people to sequence.” Four Bushmen were chosen to participate in the study, each the oldest member of their community, although only one had his entire genome sequenced, to a 10.2-fold coverage.

Besides being the oldest living descendents of the rest of humanity, the Bushmen were also fascinating subjects because they still live a hunter-gatherer lifestyle, and exhibit many adaptations to that environment. “There are many phenotypic adaptations and characteristics of the Bushman that we don’t have in Western society today,” says Hayes.

“This is a great way to learn about phenotype. Genotype is something we’ve looked at pretty well with all the new sequencing technologies, even before next generation sequencing. But what we’ve done poorly is connecting that with phenotype, with real characteristics. So the Bushman were an obvious choice to help us do this.”

Read part II of this feature: Genetic diversity and human evolution.