Genetically, culturally and ethically the Khoe-San have something special to add to this world. The largest genomic study ever conducted among Khoe and San groups reveals that these groups from southern Africa are descendants of the earliest diversification event in the history of all humans -- some 100,000 years ago, well before the 'out-of-Africa' migration of modern humans.
Some 220 individuals from different regions in southern Africa participated in the research that led to the analysis of around 2.3 million DNA variants per individual -- the biggest ever.
The research was conducted by a group of international scientists, including Professor Himla Soodyall from the Human Genomic Diversity and Disease Research Unit in the Health Faculty at the University of the Witwatersrand in Johannesburg.
Entitled Genomic variation in seven Khoe-San groups reveals adaptation and complex African history, the study has been selected for early online publishing in the scientific journal, Science, on September 20, 2012.
"The deepest divergence of all living people occurred some 100,000 years ago, well before modern humans migrated out of Africa and about twice as old as the divergences of central African Pygmies and East African hunter-gatherers and from other African groups," says lead author Dr Carina Schlebusch, a Wits University PhD-graduate now conducting post-doctoral research at Uppsala University in Sweden.
Soodyall, from National Health Laboratory Services in South Africa, has a long standing relationship with Khoe and San communities and said that the findings are a "phenomenal tribute to the indigenous Khoe and San people of southern Africa, and through this magnificent collaboration, we have given the peoples of Africa an opportunity to reclaim their place in the history of the world."
Besides the publication of the study, the authors will also be visiting the San groups in the Kalahari, in the Askam area in South Africa on the 24th of September 2012 for the country's Heritage Day celebrations. "We are excited that together with some of our colleagues from Uppsala University, we will be able to join in the celebrations with the San groups in the Kalahari who participated in our research and to acknowledge their contribution in making our research possible."
The researchers are now making the genome-wide data freely available: "Genetic information is getting more and more important for medical purposes. In addition to illuminating their history, we hope that this study is a step towards Khoe and San groups also being a part of that revolution," says Schlebusch. Another author, Professor Mike de Jongh from University of South Africa adds, "It is important for us to communicate with the participants prior to the genetic studies, to inform individuals about the nature of our research, and to also go back to not only to share the results with them, but also to explain the significance of the data for recapturing their heritage, to them."
According to Assistant-Professor Mattias Jakobsson from Uppsala University, these deep divergences among African populations have important implications and consequences when the history of all humankind is deciphered.
The deep structure and patterns of genetic variation suggest a complex population history of the peoples of Africa. "The human population has been structured for a long time," says Jakobsson, "and it is possible that modern humans emerged from a non-homogeneous group."
The study also found surprising stratification among Khoe-San groups. For example, the researchers estimate that the San populations from northern Namibia and Angola separated from the Khoe and San populations living in South Africa as early as 25,000 -- 40,000 years ago.
"There is astonishing ethnic diversity among the Khoe-San group, and we were able to see many aspects of the colorful history that gave rise to this diversity in their DNA," said Schlebusch.
The study further indicates how pastoralism first spread to southern Africa in combination with the Khoe culture. From archaeological and ethnographic studies it has been suggested that pastoralism was introduced to the Khoe in southern Africa before the arrival of Bantu-speaking farmers, but it has been unclear if this event had any genetic impact.
The Nama, a pastoralist Khoe group from Namibia showed great similarity to 'southern' San groups. "However, we found a small but very distinct genetic component that is shared with East Africans in this group, which may be the result of shared ancestry associated with pastoral communities from East Africa," says Schlebusch.
With the genetic data the researchers could see that the Khoe pastoralists originate from a Southern San group that adopted pastoralism with genetic contributions from an East African group -- a group that would have been the first to bring pastoralist practices to southern Africa.
The study also revealed evidence of local adaptation in different Khoe and San groups. For example, the researchers found that there was evidence for selection in genes involved in muscle function, immune response, and UV-light protection in local Khoe and San groups. These could be traits linked with adaptations to the challenging environments in which the ancestors of present-day San and Khoe were exposed to that have been retained in the gene pool of local groups.
The researchers also looked for signals across the genome of ancient adaptations that happened before the historical separation of the Khoe-San lineage from other humans. "Although all humans today carry similar variants in these genes, the early divergence between Khoe-San and other human groups allowed us to zoom-in on genes that have been fast-evolving in the ancestors of all of us living on the planet today," said Pontus Skoglund from Uppsala University.
Among the strongest candidates were genes involved in skeletal development that may have been crucial in determining the characteristics of anatomically modern humans.
The obesity crisis has given prehistoric dining a stardom not known since Fred Flintstone introduced the Bronto Burger. Last year, “Paleo diet” topped the list of most-Googled weight loss searches, as modern Stone Age dieters sought the advice of bestsellers like The Paleo Solution or The Primal Blueprint, which encourages followers to “honor your primal genes.”
The assumption is that America has a weight problem because human metabolism runs on ancient genes that are ill equipped for contemporary eating habits. In this line of thinking, a diet true to the hunter-gatherers we once were — heavy on protein, light on carbs — will make us skinny again. While the fad has attracted skepticism from those who don’t buy the idea whole hog, there’s still plenty of acceptance for one common premise about the evolution of obesity: Our bodies want to stockpile fat.
For most of human history, the theory goes, hunter-gatherers ate heartily when they managed to slay a fleeing mastodon. Otherwise, prehistoric life meant prolonged stretches of near starvation, surviving only on inner reserves of adipose. Today, modern humans mostly hunt and gather at the drive-thru, but our Pleistocene genes haven’t stopped fretting over the coming famine.
The idea that evolution favored calorie-hoarding genes has long shaped popular and scientific thinking. Called the “thrifty gene” hypothesis, it has arguably been the dominant theory for evolutionary origins of obesity, and by extension diabetes. (Insulin resistance and diabetes so commonly accompany obesity that doctors have coined the term “diabesity.”) However, it’s not that difficult to find scientists who call the rise of the thrifty gene theory a feat of enthusiasm over evidence. Greg Gibson, director of the Center for Integrative Genomics at Georgia Tech in Atlanta, calls the data “somewhere between scant and nonexistent — a great example of crowd mentality in science.”
Support for the thrifty gene theory may be eroding in scientific circles, even while it’s still going strong on the Internet. One analysis published in February in the American Journal of Human Genetics found no consistent association between 65 variations in possible thrifty genes and survival. Another study published in January inBiology Letters concluded that prehistoric hunter-gatherers actually ate more often, not less, than later societies that grew their own food. In describing the results, anthropologists from the University of Roehampton and University of Cambridge wrote that their finding challenges popular assumptions about the evolution of diet and today’s epidemic of obesity and diabetes.
It’s not that obesity has nothing to do with genetics, Gibson says. Of the 21,000 or so genes that make up the human genome, he estimates that perhaps hundreds influence body weight. Where the genetics get controversial, he says, is with the assumption that the overriding influence is a throwback to starvation — leaving humans at the mercy of genes that encourage overeating and the rapid accumulation of fat.
Instead, thrifty genes, if they exist, are just part of a complex genetic picture that contributes to the obesity epidemic, says Hertzel Gerstein, director of endocrinology and metabolism at McMaster University in Hamilton, Canada. The interaction between any one person’s predisposition and the calorie-dense Western smorgasbord is still not well understood. “People are looking for an explanation,” he says. “The thrifty gene hypothesis might be a piece of an explanation. However, if you accept it too uncritically, you close your mind and thinking to possibly better explanations.”
And there are plenty of lesser-known theories that address the origins of obesity, including those rooted in the complex nature of evolution, the migration patterns of early humans and changes in gene function that don’t involve mutations. Some explanations even stand out for their creativity, such as one from a team of researchers in India who propose that obesity is a consequence of declining human aggression.
For all its recent fame, the thrifty gene hypothesis isn’t new. Geneticist James Neel of the University of Michigan Medical School proposed it in 1962 in the American Journal of Human Genetics. “It must be remembered,” he wrote, “that during the first 99 percent or more of man’s life on Earth, while he existed as a hunter and gatherer, it was often feast or famine.” The human who gorged and then held an extra pound or two in reserve when food was scarce was better able to survive. Thus, he concluded, the development of insulin resistance (a propensity for diabetes) conferred some physiological advantage that continues to exert itself.
In the five decades since its debut, the theory has “gone off in all sorts of directions,” says Andrew Prentice, who studies international nutrition at the London School of Hygiene & Tropical Medicine. Prentice supports the general concept Neel proposed — that the genetic influences on body weight are the product of natural selection from lean times — but not in the way people commonly interpret it. For one, he doesn’t think the advantage of fatness had much to do with mortality.
His research, particularly focused on women in Gambia, in West Africa, suggests that food shortage affects fertility, and that women with the highest body weight have greater reproductive success. (Alternatively, women who become dangerously thin cease to ovulate.) Once human societies became agricultural, they went through periods of both blight and plenty — much like the population Prentice studies today. He’s found that plumpness is an advantage not because thinner members of a population are more likely to die, but because they are less likely to bear children and pass their genes to the next generation.
One of the most vocal critics of the thrifty gene hypothesis is John Speakman, who heads the Energetics Research Group at the University of Aberdeen in Scotland. If being fat offered a benefit over the course of human evolution, Speakman reasons, then even more of the population would be obese, in the same way humans have universally developed large brains and upright postures. With the thrifty gene idea and its different incarnations, “the common thread is that some time in our evolutionary history it was advantageous to be fat,” he says. If this were true, and genes for obesity conferred a survival benefit, “the real problem is to explain why so few people get fat,” he says. “Even in America, 60 to 70 percent of people are not obese. How come so many of us didn’t inherit thrifty genes?”
Speakman became disenchanted with the thrifty gene hypothesis about a decade ago, deciding that it was based on simplistic assumptions about evolutionary dynamics. He set out to test it. Among other studies, in 2013 in Disease Models & Mechanisms, he published a mathematical analysis gauging how 32 known gene variations associated with body mass index would help people survive near starvation — and found that they made only a tiny difference.
The basic problem with the thrifty gene idea, he says, is that “it’s based on a naïve view of how evolution works.” Natural selection, though powerful, isn’t the sole architect of human DNA. Nature favors genes that help survival, but genes that are simply along for the ride will also be handed down through generations. In early human history, Speakman says, being overweight was a disadvantage. When a species is subject to predators, the slower, fatter members who are prone to overheating are the unlucky ones who will be picked off first. As humans developed fire and weapons, and grew less vulnerable to being hunted, he argues, heavier individuals survived — not because being fat was good, but because upper limits on body weight didn’t matter as much any more.
He calls this idea the “drifty gene” hypothesis, a name he first proposed in 2008 in the International Journal of Obesityto reflect that obesity might not have been actively selected for, just passively allowed to float into the human genome. “If you have a mutation that happens but doesn’t create a selective advantage, its influence is not going to be strong, but it’s not going to be actively removed either,” Speakman says.
Speakman’s isn’t the only alternative to the idea that obesity is a holdover from ancient times of starvation. Elizabeth Genné-Bacon, a graduate student in genetics at Yale University, recently compiled evidence for the thrifty gene hypothesis along with other theories in a paper in the Yale Journal of Biology and Medicine.
“I see textbooks with [the thrifty gene hypothesis] all the time,” she says. “It’s elegant and it makes sense. It’s easy to understand.” However, she found the support to be surprisingly thin, writing that, “Obesity researchers are often not aware that there is, in fact, limited evidence to support the thrifty gene hypothesis.”
For example, if thrifty genes were influencing metabolism, populations that most experienced famine should be particularly prone to diabetes. She points out that Europe has a lengthy history of war, disease and frequent food shortages, but European descendants have a lower incidence of diabetes than the indigenous people of the Americas and Pacific Islands who may have had less food turmoil in their distant past.
In her article, she lists other theories that might explain the evolution of obesity and diabetes:
None of the theories could be right, or several could, says Jeffrey Friedman, the Rockefeller University geneticist best known for discovering leptin, the hormone that helps regulate appetite. When he announced the finding in 1994, many researchers thought Friedman had found a link to a long-sought thrifty gene because of leptin’s direct relationship to appetite. Friedman himself went looking into the origins of obesity by conducting genetic studies on the island of Kosrae in Micronesia, where the native population was reduced to only 300 in the late 1880s, following a typhoon and an influx of communicable diseases from the West. Such a small, confined population creates a genetic bottleneck that makes isolating specific genes easier. As the island’s eating patterns fell under Western influence, diabetes and obesity emerged as serious health threats.
So far, though, he hasn’t found the answers he would like, including insight into evolutionary influences on diabetes. One of the largest studies of the Kosrae, published by Friedman and colleagues in PLoS Genetics in 2009, found that common gene variants associated with cholesterol and insulin response could not explain why some people became diabetic while others did not.
Despite the gaps in knowledge, it’s a mistake to think that any one theory would explain an evolutionary tendency to become obese, Friedman says. He points out that humans in different parts of the world experienced different evolutionary pressures, so what’s true in one population might not apply to the next.
“People think about evolution of this sort taking place over millennia or eons. Evolution can be evident in a single generation,” he says. “Populations walk around with a spectrum of alleles, or genetic variants, and the frequency of one variant versus another can be changed dramatically even in a single generation.”
Just as being overweight might have affected survival, so would being too thin. “You could draw the lines wherever you want, but the point is if you were infinitely fat or infinitely thin it wouldn’t be good,” he says. “And there’s a biological system that’s evolved that allows you balance in a particular environment.”
The genetics of obesity has many influences, not just starvation or abundance or cold climates or warm, says obesity geneticist Claude Bouchard at Pennington Biomedical Research Center in Baton Rouge. Human DNA is a genetic soup that reflects any number of prehistoric dinner challenges. “Evolution must have been zigzagging,” he says. “That’s why it’s hard to put all the pieces together.”