Africa’s genetic diversity revealed by full genomes of a Bushman and a Tutu

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Meet !Gubi, the tribal elder of a group of Bushmen (or Khoisan), one of the oldest known human lineages. He lives the life of a hunter-gatherer in the Namibian part of the Kalahari Desert. But he also has a strange connection to James Watson, the British American scientist who helped to discover the structure of DNA. For a start, they’re both around 80 years old. But more importantly, they are two of just 11 humans to have their entire genomes sequenced.

Along with Archbishop Desmond Tutu, !Gubi is one of two southern Africans, whose full genomes have been sequenced by Stephan Schuster and an international team of scientists . Schuster’s team also analysed the genes of three other Bushmen – G/aq’o, D#kgao and !Aıˆ (see footnote for pronunciation guide) – focusing on the parts of their genome that codes for proteins. Like, !Gubi, these men are tribal elders and all are around 80 years old. Despite the fact that the four Bushmen come from neighbouring parts of the Kalahari, their genetic diversity is astounding. Pick any two and peer into their genomes and you’d see more variety than you would between a European and an Asian. 

This diversity reveals just how important it is to include African people in genome sequencing projects. Until now, the nine complete human genomes have included just one African – a Yoruban man from Nigeria. The rest have hailed from Europe, America, China, Korea and, most recently, Greenland circa 4,000 years ago. This is a major oversight. Africa is the birthplace of humanity and its people are the most genetically diverse on the planet. To understand human genetics without understanding Africa is like trying to learn a language by only looking at words starting with z.

The Bushmen certainly provide a glimpse into this diversity. Desmond Tutu was also selected because his ancestry covers the two largest of southern Africa’s Bantu groups – the Tswama and the Nguni – making him an excellent representative for many southern Africans. Vanessa Hayes, who worked on the study, says, “This work is very expensive so we wanted to maximise the amount of diversity we could get in one individual.” The team had other reasons for sequencing the bishop.”He’s a voice for southern Africans and for his people. He’s a chairman of the Global Elders. He provides a genome with a lot of medical history behind it, having survived prostate cancer, polio and Tb, diseases that affect many southern Africans.” But most importantly, Hayes says, “He wanted to participate. He himself wanted to study medicine so this for him was a personal endeavour.”

The researchers hope that their new data will allow medical research to become more inclusive. Vanessa Hayes, who led the study, says that she found HIV research in South Africa to be very difficult because most genetic databases are severely Eurocentric, which rules out a lot of Africans from medical research. Without this knowledge, for example, we have no way of knowing if a drug that was developed and tested in Western patients will have the same benefits and risks in African ones.

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Schuster and Hayes compared the two new African genomes to the reference version (a composite of several anonymous people) and looked for “single nucleotide polymorphisms” – places that differed by a single DNA letter. He found these “SNPs” in their hundreds of thousands. Both !Gubi and Tutu have around a million unique SNPs that they don’t share with each other or any of the other fully sequenced humans. Likewise, the proteins of the five Africans had over 27,000 amino acids that differed from the reference sequence, around half of which are unique to them.

Some of these differences are easily explained by the Bushmen’s lifestyle, reflecting adaptations to hunting and gathering in a hot, dry climate. Being dark-skinned hunter-gatherers, all of them lack genetic variant that give Europeans light-coloured skin and allow them to cope with eating dairy products.

All of the Bushmen had a version of the vitamin D receptor that is associated with denser bones and three of them have a variant linked to better sprinting performance. Some of the SNPs grant the carrier the ability to taste bitter plant chemicals, and hunter-gatherers would certainly find it useful to avoid toxic plants. One of !Gubi’s variants could allow him to break down foreign substances or resist parasites. Another might make his kidneys better at reaborsbing vital chloride ions and reduce the loss of salt and water, an important skill when you live in the scorching desert.

Other differences are perhaps more surprising – the five Africans all lack a genetic variant that is specific to Africa and that grants resistance against malaria. It’s possible that the Bushmen may not need such resistance. But that could well change as their populations dwindle and they become forced into agricultural lifestyles, which carry higher risks of disease. Again, these newfound genetic markers could allow scientists to watch how they adapt to such challenges at a genetic level.

Most surprising of all, many of their unique SNPs are actually fairly recent developments. The Bushmen are one of the oldest human groups on the planet and you might expect their genes to reflect humanity’s most ancestral state. But not the SNPs – Schuster found that only 6% of !Gubi’s newfound SNPs matched the equivalent sequences in the chimpanzee genome; by comparison, the same positions in the human reference genome are an 87% match for the chimp one. They can’t be ancestral sequences. They must have turned up after the Bushmen dynasty diverged from other human populations, and they provide hints about the history of this most ancient of human lineages.

The south African genomes will also make geneticists re-evaluate what they know about how our genes affect our health and risk of disease. Our current knowledge in this area is incredibly biased towards Western societies and the results of studies in such populations don’t always translate to other continents. For example, one of the Bushmen had a SNP that is reputedly linked to Wolman’s syndrome, a disease that prevents people from storing fat properly and kills at a young age. Try telling that to the eighty-something gentleman! Hayes says, “!Gubi is a very fit and healthy man and much better skipper on a skipping rope than I am

Reference: Schuster, S., Miller, W., Ratan, A., Tomsho, L., Giardine, B., Kasson, L., Harris, R., Petersen, D., Zhao, F., Qi, J., Alkan, C., Kidd, J., Sun, Y., Drautz, D., Bouffard, P., Muzny, D., Reid, J., Nazareth, L., Wang, Q., Burhans, R., Riemer, C., Wittekindt, N., Moorjani, P., Tindall, E., Danko, C., Teo, W., Buboltz, A., Zhang, Z., Ma, Q., Oosthuysen, A., Steenkamp, A., Oostuisen, H., Venter, P., Gajewski, J., Zhang, Y., Pugh, B., Makova, K., Nekrutenko, A., Mardis, E., Patterson, N., Pringle, T., Chiaromonte, F., Mullikin, J., Eichler, E., Hardison, R., Gibbs, R., Harkins, T., & Hayes, V. (2010). Complete Khoisan and Bantu genomes from southern Africa Nature, 463 (7283), 943-947 DOI: 10.1038/nature08795

A note on names: The Bushman language Bushmen languages includes a variety of clicks, which explains the strange characters in their names. The # is an alveolar click, made by pulling the tip of the tongue down sharply from the roof of the mouth to make the sound of a popping cork. The ! is a palatal click, which is a softer version of the alveolar one and made with a flat tongue. The / is a dental click, which is made by sucking air through the front teeth and sounds like an English tsk!

Another note on names: I’m aware that there’s controversy over the use of the term “Bushmen” in some circles. I’m using it because it’s by far the most commonly used term in the paper, which also mentions San or Khoisan. Note the captial B to denote an actual group of people rather than a colloquial descriptor.

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