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Accounting for Lactase Mutants

    hands with a global overlay. By studying lactose tolerance worldwide, scientists have discovered much about human migration and the genetic mutation of T-13910

    Written by: Anna Petherick, Ph.D. | Issue # 43 | 2015

    • About two-thirds of adult humans around the world are lactose intolerant.
    • The ability to digest lactose after weaning occurs in many northern Europeans, but also in many populations in the Middle East and in Africa.
    • Recently, researchers have started to use new data about the genes behind the ability to digest lactose to uncover new details about human migratory history.

    Back in the 50s and 60s, work on lactose intolerance was often published under cringeworthy and blunt racial titles. A Nature article from 1969 sums it up with ‘Can Asians Digest Milk?’ It was also probably a subliminal non-accident that ‘lactose intolerance’—which is the typical condition for adult humans—became common parlance for a trait for which those with northern European ancestry are the real mutants. Many decades on, the genetic basis of the ability to digest lactose has been largely pinned down. As it turns out, there are different genetic reasons for the mutants’ lactose tolerance in the various populations that drink milk without intestinal incident, and the gene that confers mutant power in Europeans is only part of the story. That research history is discussed below, along with recent work that has extended the field’s reach beyond genetics. Investigations of the transcontinental basis of lactose tolerance are now providing insights into mankind’s cultural, as well as biological evolution.

    Lactose digestion mutants fail to ‘turn off’ a gene that lies on chromosome 2. Early in life, human beings need to digest the lactose in their mother’s milk. The enzyme required to break it down is called lactase (full name, lactase-phlorizin hydrolase), which is produced in cells that line the small intestine. Lactase extracts the simpler sugars, glucose and galactose, from a milky meal by breaking lactose in half, ready for absorption into the blood. Without it, lactose continues on towards the large intestine, where bacteria feast on it—and it is these bacteria’s waste products that deliver the symptoms of lactose intolerance.

    While they were naïve in their categorizations, the correlations of the early studies threw up strong patterns; genetic ancestry does matter for lactose tolerance. The blunt answer to the question set out in that Nature article was “No, Asians Cannot Digest Milk.” A researcher called Welsh measured lactose intolerance among Native Americans [1]. Then, he set out to compare its frequency among, as he describes, American blacks, Africans, Asians, Greek Cypriots, Australian Aborigines and South American Indians [2].

    All the while, explanations for lactose intolerance that focused on nurture—in this case, food preferences that aligned with racial categories—also seemed to be plausible reasons for lactose intolerance. After all, the lac operon model of gene regulation, proposed in 1961, inferred a use-it-or-lose-it logic to the functioning of the lactase gene. The way to convince the field of the pre-eminence of inherited genetic differences was to find groups of people with differing racial profiles, and tell them what to eat. A study on incarcerated Americans—20 white, 20 black—demonstrated the link between intestinal lactase activity and milk intolerance [3]. Then, given that result, the way to figure out whether the gene responsible is dominant or recessive, was to test the lactose tolerance of a group of people with one lactose-tolerant parent and one lactose-intolerant parent; studies of mixed race people in the early 1970s [4] suggested that tolerance—the persistence into adulthood of the ability to digest lactose—is a dominant Mendelian trait.

    Shoot forward to the era of the Human Genome Project, and all the new-fangled genome-scouring technologies that developed as a consequence. In 2002, researchers in Finland found a mutation in a region of the genome upstream of the lactase gene that was common to all lactose-digesting Finns in their study (almost all Finns can digest lactose) [5]. Termed ‘T-13910’, this single nucleotide mutation sitting in an intron (a non-protein coding section of the genome – specifically in this case, a transcription factor binding site), appeared to explain why some people, including the vast majority of northern Europeans, are able to digest milk as adults.

    It seemed like an elegantly neat and simple answer. The problem was that it only worked for Europeans. Lactose-tolerant people whose ancestors hail from the Middle East and Africa, rarely share this mutation. Enter Sarah Tishkoff, a geneticist who studies ethnically diverse African populations and an expert in human evolution.

    In 2006, Tishkoff and her team published a paper detailing three mutations that appeared to be the reason why their study participants from Kenya, Tanzania and Sudan happily consume milk [6]. To hammer home the point, they also found no link between T-13910 and the lactose digestion abilities of pastoralists in Sudan. The obvious challenge was then to make sense of how the known lactose tolerance mutations spread through human migrations over millennia.

    Recently, the team sequenced the intron in which T-13910 lies, and another intron nearby, in over 800 people—from 63 African populations and 9 non-African populations (from Europe, Asia and the Middle East) [7]. Aside from adding to the list of mutations associated with lactose tolerance, these data enabled the researchers to date each of its various genetic causes and to map their population frequency (see Figure

    Putting the data together with what is known about human migrations over the relevant period, led to a number of insights into human evolution. Among them, the team found that the !Xhosa, who live mainly in southeast South Africa, share the same lactose persistence mutation as Kenyan and Tanzanian populations. This, in turn, suggests that the gene somehow flowed south from eastern Africa prior to the Bantu expansion, which began about 3,000 years ago, when the Bantu family of languages is thought to have spread.

    There were additional surprises. A few African populations—the Mozabite from Algeria, the Fulani from Cameroon, and the Bulala from Chad—for example, did indeed have the T-13910 mutation, suggesting it was introduced from outside, perhaps during key historical moments, such as the spread of the Roman Empire into North Africa. Another mutation that confers lactose tolerance was found in 47% of volunteers belonging to the Hazda, a Tanzanian hunter-gather group—even though they have no known history of dairy production. Being able to digest milk seems to be a side effect in this case. The lactase enzyme performs a second, different enzymatic job in breaking down phlorizin, a bitter plant product that occurs in bark and the stems of fruit trees of the Rosaceae family, and a known traditional remedy for treating malaria. It was likely this lesser-known job of lactase that promoted the spread of lactose tolerance among the Hazda.

    By evolutionary genetics standards, the evolution of lactase tolerance is a high-speed thriller. Few other genes are known to have experienced such strong positive selection in human history. But there are still many unanswered questions. Tishkoff, for one, wants to integrate the genetic data with microbiome studies, to try to get a better handle on human history.


    1. Welsh, J. D et al (1967) Isolated lactase deficiency: correlation of laboratory studies and clinical data.Arch. Intern. Med. 120: 261-269.
    2. Welsh, J. D. (1970) Isolated lactase deficiency in humans: report on 100 patients. Medicine 49: 257-277.
    3. Bayless, T. M., Rosensweig, N. S. (1967) A racial difference in incidence of lactase deficiency: a survey of milk intolerance and lactase deficiency in healthy adult males. JAMA 197: 968-972.
    4. Kretchmer, N. (1972) Lactose and lactase.Sci. Am. 227(4): 70-78.
    5. Enattah N.S. et al. (2002) Identification of a variant associated with adult-type hypolactasia. Nat Genet 30:233–237
    6. Tishkoff, S. A. et al. (2006) Convergent adaptation of human lactase persistence in Africa and Europe. Nature Genet. doi:10.1038/ng1946
    7. Ranciaro, A. et al. (2014) Genetic Origins of Lactase Persistence and the Spread of Pastoralism in Africa. AJHG.94(4), 496-510