For a baby, digesting milk is a piece of cake. But the same can't be said of adults. Infants have the ability to digest milk’s essential sugar, lactose, thanks to an enzyme called lactase, which breaks it up into two smaller sugars, glucose and galactose. As we get older, many people stop producing lactase and lose this ability. Others don’t.
Scientists have been trying to decipher the how, the when, and the why of lactose tolerance in humans for a while. People with lactose tolerance (or lactase persistence, in scientific speak) tend to come from northern Europe, the Middle East and Africa. The general hypothesis: in some people, mutations naturally arose nearby the gene for lactase and kept production of the enzyme going into adulthood, and because of something going on in the environment, adults with lactase had a survival advantage over the lactose intolerant. "Whatever it was, it was really, really beneficial because it rapidly spread," explains Sarah Tishkoff, a geneticist at the University of Pennsylvania in Philadelphia.
Scientists disagree over what drove the adaptation in different regions, but they have identified a handful of mutations that may be linked to lactose tolerance. It's hard to tell, though, which mutations are the most important and how much that varies from one region to another.
Tishkoff and her colleagues published a new study today in the American Journal of Human Genetics—the largest study of lactose tolerance across Africa today—that takes another step in identifying the most relevant mutations, and hints at an evolutionary cause of them. The work confirmed that previously identified genetic mutations are indeed linked to lactase persistence in Africans. By demonstrating that these genes show up in disproportionately high frequencies in African pastoral groups, the findings also put genetic data behind the idea that the domestication of animals is inextricably linked to the spread of lactose tolerance.
In 2007, Tishkoff's lab found three mutations that roughly correlated with lactase persistence in smaller groups of east Africans, and other groups have found other mutations associated with lactase persistence in select African populations, such as communities in Ethiopia. But, within these studies, "there are people who can digest milk, who don't have these [mutations]," says Tishkoff, "So, we thought there might be something else out there."
In their new work, the researchers wanted to use a wider lens to look at lactase persistence. The team took blood samples and sequenced DNA from 819 Africans (representing 63 different populations) and 154 non-Africans (representing nine populations in Europe, the Middle East and Central and East Asia). They focused on three regions of the human genome near the lactase gene: a promoter region (which turns the gene on or off, causing lactase production to occur) and two enhancer regions (involved in keeping the gene on or increasing production of lactase). When they sequenced these regions, they found five mutations known to be associated with lactase persistence, and measured their frequencies across all of the different populations.
To match the genetic data with lactose tolerance, they needed to test for the condition in the field, including remote areas across Africa. They gave participants sweet lactose powder equivalent to one to two liters of milk. “It kind of tastes like orange Cool-Aid,” says Tishkoff.
Then, using a portable diabetic testing kit, researchers measured glucose blood levels every 20 minutes over the course of an hour. An increase in blood glucose meant the person’s body was breaking down lactose. "Based on that we can categorize people as tolerant, partially tolerant, or intolerant," says Alessia Ranciaro, a research scientist in Tishkoff's lab who conducted most of the field work.
Comparing the genetic data to field data, they confirmed the connection between the three enhancer region mutations they previously discovered and lactase persistence. Two other mutations, one in the promoter and one in an enhancer region, were also associated with lactase persistence, but those are less common and less clear cut in their correlation with the trait.
To get a sense of where these mutations might have originated geographically, they looked at mutation patterns (called haplotypes) on the chromosomes of participants where the lactase genes were located. Different haplotypes are known to have historically originated in different geographic regions, so by looking at the correlation between different haplotypes in Africa today and the presence or absence of mutations in the lactase gene, the researchers were able to retrace the geographic spread of these mutations across Africa.
The data suggest that the spread of the lactase mutations coincided with the spread of people and livestock domestication across Africa. The evolutionary history of the mutations lines up with known migration patterns and archaeological evidence for the beginnings of livestock domestication, the authors found. In particular, a mutation that spread from the Middle East to northern Africa is about 5,000 to 12,300 years old, putting it at about the same age as cattle domestication in Northern Africa and the Middle East, which occurred around 10,000 years ago. Another variant, prevalent on the Arabian Peninsula, corresponds in age to archaeological evidence of camel domestication in that region around 5,000 years ago.
"When those groups migrate into other regions, they’re bringing that mutation with them, and if they intermarry with the local group, whoever they run into, it's beneficial in them too, so it’s also going to increase in frequency," says Tishkoff.
In another example, a specific mutation prevalent in Tanzania, Kenya, and South Africa, is believed to be only 2,700 to 6,800 years old, based on previous studies. That coincides with the timing of pastoralist migrations down from northern Africa to east Africa. How it showed up in southern Africa is a little more complicated, but it may have something to do with the spread of the Bantu people in east Africa and their intermixing with local pastoralists as they moved south.
It's not totally surprising that genetic variants which cause the lactase persistence trait would be associated with pastoralism. In fact, scientists have known of the association of the trait for a long time, notes geneticist Dallas Swallow of University College London. The new study backs up a lot of previous work, including her own. But, "the correlation with lifestyle [is] far from absolute," she says.
Ranciaro and Tishkoff acknowledge that their study doesn't answer all the questions surrounding lactase persistence in Africa. Not having cattle does not necessarily mean a population can't digest milk or vice versa. Additionally, it seems that there are other as-yet unidentified mutations involved in lactase production. For example, some members of the hunter-gatherer Hadza people in Tanzania don’t have genetic traces of lactase persistence, but it appears that some can digest milk without a problem.
Lactase can also play a role in breaking down proteins in plants, so that could explain why some groups that don't have cattle might still produce lactase as adults. Alternatively, some researchers have hypothesized that gut bacteria might be helping some digest milk when they lack the mutation.
What does this all mean for the average milk drinker? If you're of African descent, it explains the evolutionary journey behind your lactase-related mutations pretty well. In the arid environments of Africa, milk is a key source of liquid when water is scarce, so the evolutionary advantage of lactase persistence is clear.
But if you're of European descent—another region with a tradition of livestock domestication and common lactase persistence—the story remains a mystery. Scientists have proposed various theories for the evolutionary pressures that propelled lactase persistence across Europe, but the hard genetic evidence still needs to be discovered.