The Geographically Biased Emergence of Lactase Persistence due to Natural Selection

By Nitya Gupta

Milk is the most essential component of a young mammal’s diet and lactose is its primary carbohydrate. The lactase-phlorizin hydrolase (LPH) enzyme is largely expressed in the small intestine where it is responsible for the hydrolysis of lactose into glucose and galactose, sugars that are easily absorbed into the bloodstream. LPH is fundamental to the early development of mammals but its expression rapidly declines after weaning, leading to an inability to digest lactose. However, some individuals have the ‘lactase persistence’ trait and maintain the ability produce LPH and digest milk and other dairy products into adulthood. (Tishkoff, 2006) Individuals that lose this ability, on the other hand, are lactose intolerant, and milk consumption can lead to bloating, flatulence, cramps and nausea. (Gerbault, 2011) 

Lactase persistence is a dominant trait observed in 35% of adults but its prevalence varies drastically among human populations both between and within continents. The frequency is highest in northern Europe (>90% in Swedish, British and Danish populations), slightly lower across southern Europe and the Middle East (∼50% in Spanish, French and pastoralist Arab populations) and low in certain Asian populations (∼1% in Chinese, ∼20% in South Indians). The distribution across Africa is patchy: lactase persistence is common in pastoralist populations (∼90% in Tutsi, ∼50% in Fulani), but low in those that are agriculturalists (∼5%–20% in West Africa). The distribution of this trait around the world has been correlated with whether a population has descended from people who traditionally practiced cattle domestication. (Tishkoff, 2006) Faunal remains and dairy fats associated with archaeological pottery found in these regions provides evidence of dairying activities that took place 7,500–9,000 years ago, and the LP trait is hypothesized to have emerged around the same time. (Gerbault, 2011)

Adult expression of the gene encoding LPH (LCT), located on 2q21, is thought to be regulated by cis-acting elements, and the LP trait has been associated with certain single nucleotide polymorphisms (SNPs). The C/T-13910 SNP located ∼14 kb upstream of LCT within the thirteenth intron of a neighbouring gene, MCM6, has found to be ∼86%–98% associated with LP across European populations. In vitro studies indicate that this specific SNP affects lactase promoter activity and is functionally important for lactase expression. The allele leads to an increased production of LPH in the intestinal mucosa. Another LP-associated SNP found particularly in Finland is G/A-22018, located ∼22 kb upstream of LCT. (Tishkoff, 2006; Itan, 2010)

Though the T-13910 allele explains the distribution of LP in Europe, it is absent from African populations and cannot explain the distribution of LP outside of Europe. Genotype-phenotype association studies have identified three SNPs (G/C-14010, T/G-13915 and C/G-13907) associated with lactase persistence in African and Middle Eastern populations. These alleles significantly enhance transcription at the LCT promoter, and coincidentally are located within 100 nucleotides of −13910*T in the same intron of the MCM6 gene. These SNPs have originated on different haplotype backgrounds (genes inherited together from a single parent), not just from the European C/T-13910 SNP but also from each other. This indicates that lactase persistence is an example of convergent evolution as it has independently evolved multiple times due to strong selective pressure resulting from shared cultural traits—animal domestication and adult milk consumption. (Tishkoff, 2006)

Changes in allele frequency occur slowly and in a directionless manner by genetic drift, and thus the emergence of new alleles is rare; however, the LP persistence trait has managed to attain high population frequencies due to the ‘kick’ of natural selection. There are many theories as to why natural selection favoured the lactose persistence trait. The simplest one is that milk is a good source of calories, proteins and fat. Cows produce large amount of milk; even when the milk necessary for the raising calves is subtracted, 150–250 kg remains, which is almost equivalent to the calorie gain from the meat of a whole cow. Hence, dairying enabled populations to make economic use of livestock. (Gerbault, 2011)

Strong episodic selective pressures on LP may have occurred under certain extreme circumstances, such as drought, epidemic or famine in arid climates. Between harvesting periods or during crops failure, milk would have represented an alternative food source and LP individuals would have had an advantage. (Herring, 1998) Additionally, in regions where water was scarce or heavily contaminated by pathogens, milk would have been used by pastoralist groups as fluid. Lactase non-persistent individuals, on the other hand, would be at risk from the potentially dehydrating effects of diarrhoea upon consuming fresh milk, leading to selection favouring LP individuals. (Cook, 1975)

In Europe, the arid climate hypothesis is less likely, and the calcium assimilation hypothesis is favoured. Calcium is essential for bone health and vitamin D promotes its absorption in the gut. Populations who live in equatorial regions produce the majority of their vitamin D photochemically in the skin through the action of UVB. However, UVB exposure is limited at high latitudes which was likely to have been a problem for pre-Neolithic European agriculturalists. Additionally, a fibre-rich diet of cereal grains, can lead to a reduction in plasma 25-hydroxyvitamin D3. Milk contains small quantities of vitamin D and large quantities of calcium, and is a valuable supplement at low-sunlight latitudes. Thus, milk consumption has been suggested to have been an advantage to early LP farmers in the Baltic/North Sea area. (Flatz, 1973; Gerbault, 2011)

The spread of lactase persistence is an example of niche construction, the process by which organisms construct important components of their local environment in ways that introduce novel selection pressures. Human groups who first began to drink milk modified their selection pressure, generating an evolutionary feedback that advantaged certain individuals against others. The practice of milk drinking has continued into modern day, and the coevolution of LP and dairying illustrates how culture can affect the genetic diversity of human populations. (Gerbault, 2011) 

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Cook, G.C. & al-Torki, M.T. 1975, “High intestinal lactase concentrations in adult Arbs in Saudi Arabia”, British Medical Journal, vol. 3, no. 5976, pp. 135-136. 

Flatz, G. & Rotthauwe, H.W. 1973, “Lactose nutrition and natural selection”, Lancet (London, England), vol. 2, no. 7820, pp. 76-77.

Gerbault, P., Liebert, A., Itan, Y., Powell, A., Currat, M., Burger, J., Swallow, D.M. & Thomas, M.G. 2011, “Evolution of lactase persistence: an example of human niche construction”, Philosophical transactions. Biological sciences, vol. 366, no. 1566, pp. 863-877.

Herring, D.A., Saunders, S.R. & Katzenberg, M.A. 1998, “Investigating the weaning process in past populations”, American Journal of Physical Anthropology, vol. 105, no. 4, pp. 425-439.

Itan, Y., Jones, B.L., Thomas, M.G., Swallow, D.M. & Ingram, C.J. 2010, “A worldwide correlation of lactase persistence phenotype and genotypes”, BMC Evolutionary Biology, .

Tishkoff, S.A., Reed, F.A., Ranciaro, A., Voight, B.F., Babbitt, C.C., Silverman, J.S., Powell, K., Mortensen, H.M., Hirbo, J.B., Osman, M., Ibrahim, M., Omar, S.A., Lema, G., Nyambo, T.B., Ghori, J., Bumpstead, S., Pritchard, J.K., Wray, G.A. & Deloukas, P. 2006, “Convergent adaptation of human lactase persistence in Africa and Europe”, Nature genetics, vol. 39, no. 1, pp. 31-40.

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