Lactase persistence or lactose tolerance is the continued activity of the lactase enzyme in adulthood, allowing the digestion of lactose in milk. In most mammals, the activity of the enzyme is dramatically reduced after weaning. In some human populations though, lactase persistence has recently evolved as an adaptation to the consumption of nonhuman milk and dairy products beyond infancy. Lactase persistence is very high among northern Europeans. Worldwide, most people are lactase non-persistent, and are affected by varying degrees of lactose intolerance as adults. However, lactase persistence and lactose intolerance can overlap.
Global distribution of the phenotype
The distribution of the lactase persistence (LP) phenotype, or the ability to digest lactose into adulthood, is not homogeneous in the world. Lactase persistence frequencies are highly variable. In Europe, the distribution of the lactase persistence phenotype is clinal (geographically variable), with frequencies ranging from 15–54% in the south-east to 89–96% in the north-west. For example, only 17% of Greeks and 14% of Sardinians are predicted to possess this phenotype, while around 80–100% of people in northern and central Europe are predicted to be lactase persistent. Similarly, the frequency of lactase persistence is clinal in India: a 2011 study of 2,284 individuals identified a prevalence of LP in the Ror community, of Haryana, in the North West, of 48.95%, declining to 1.5% in the Andamanese, of the South East, and 0.8% in the Tibeto-Burman communities, of the North East.
High frequencies of lactase persistence are also found in some places in Sub-Saharan Africa and in the Middle East. But the most common situation is intermediate to low lactase persistence: intermediate (11–32%) in Central Asia, low (≤5%) in Native Americans, East Asians, most Chinese populations and some African populations.
In Africa, the distribution of lactase persistence is "patchy": high variations of frequency are observed in neighbouring populations, for example between Beja and Nilotes from Sudan. This makes the study of lactase persistence distribution more difficult. High percentages of lactase persistence phenotype are found in traditionally pastoralist populations like Fulani and Bedouins.
Lactase persistence is prevalent in Nguni and certain other pastoralist populations of South Africa as a result of the dairy they consume in their diet. Lactase persistence amongst Nguni people is, however, less common than in Northern European populations because traditionally, their consumption of dairy came primarily in the form of amasi (known as Maas in Afrikaans), which is lower in lactose than fresh, raw milk as a result of the fermentation process it goes through.
Genetics
Multiple studies indicate that the presence of the two phenotypes "lactase persistent" (derived phenotype) and "lactase nonpersistent" (hypolactasia) is genetically programmed, and that lactase persistence is not necessarily conditioned by the consumption of lactose after the suckling period.
The lactase persistent phenotype involves high mRNA expression, high lactase activity, and thus the ability to digest lactose, while the lactase nonpersistent phenotype involves low mRNA expression and low lactase activity. The enzyme lactase is encoded by the gene LCT.
Hypolactasia is known to be recessively and autosomally inherited, which means that individuals with the nonpersistent phenotype are homozygous and received the two copies of a low lactase-activity allele (the ancestral allele) from their parents, who may be homozygous or at least heterozygous for the allele. Only one high-activity allele is required to be lactase persistent. Lactase persistence behaves as a dominant trait because half levels of lactase activity are sufficient to show significant digestion of lactose. Cis-acting transcriptional silence of the lactase gene is responsible for the hypolactasia phenotype. Furthermore, studies show that only eight cases were found where the parents of a child with lactase persistence were both hypolactasic. While a variety of genetic, as well as nutritional, factors determine lactase expression, no evidence has been found for adaptive alteration of lactase expression within an individual in response to changes in lactose consumption levels. The two distinct phenotypes of hypolactasia are: Phenotype I, characterized by reduced synthesis of precursor LPH, and phenotype II, associated with ample precursor synthesis, but reduced conversion of the protein to its mature molecular form. The lactase enzyme has two active sites which break down lactose. The first is at Glu1273 and the second is at Glu1749, which separately break down lactose into two separate kinds of molecules.
At least six mutations (single-nucleotide polymorphisms – SNPs) have been associated with lactase expression. They are all located in a region of the gene MCM6 upstream of LCT. This region is considered as an enhancer region for the transcription of LCT. The first identified genetic variant associated with lactase persistence is C/T*−13910. The ancestral allele is C and the derived allele – associated with lactase persistence – is T. In the same study, another variant was found to also correlate with the phenotype in most of the cases: G*/A-22018.
Other alleles associated with lactase persistence have been identified: G/C*-14010, C/G*-13907, and T/G*-13915. This variant is described as part of a compound allele with T/C*3712 in. These three variants are widespread in some populations. Rare variants were reported in a few studies, like the G/A*14107 in the Xhosa and the Fulani (from Mali); the C/T*13906 in the Fulani (from Mali).
Lactase-persistence alleles vary in their geographic distributions. Within European and populations of European ancestry, they are almost entirely correlated with the presence of the −13,910 C/T variant in the enhancer region of the lactase gene (LCT).
This differs from lactase persistence allelic distributions in the rest of the world, particularly in Africa and in the Middle East, where several alleles coexist.
The T/G*-13915 allele is found mostly in populations from East and North Africa and the Middle East. The allele G/C*-14010 was identified in East Africa. The C/G*13907 allele was described in Sudan and Ethiopia. The "European" allele T*13910 allele is also found in some populations from Africa, including the Fulani (from Mali, Sudan, and Cameroon) and the Khoe from South Africa. This allele has also been found in Central Asia.
It is not known how exactly the different variants described above regulate LCT expression. None of the variants so far identified have been shown to be exclusively causal for lactase persistence, and it is possible that there are more alleles to be discovered. If we focus on the "European variant", the position −13910 has an enhancer function on the lactase promoter (the promoter facilitates the transcription of the LCT gene). T−13910 is a greater enhancer than C−13910, so this variant is thought to be responsible for the differences in lactase expression, although not enough evidence is found to prove that lactase persistence is only caused by C−13910→T−13910.
In addition, it was shown in one study involving a Finnish population that the lactase gene has a higher expression when G−22018 is combined with T-13910.
Evolutionary advantages Lactase persistence is a textbook example of natural selection in humans: it has been reported to present stronger selection pressure than any other known human gene. However, the specific reasons as to why lactase persistence confers a selective advantage "remain open to speculation".
Several pieces of evidence for positive selection acting at the T*-13910 allele were given: it is located in a stretch of homozygosity of c. 1 Mb; the strength of selection is similar to that estimated for the resistance to malaria. Haplotype inferences were performed on data from Central Asia populations; selection was detected there as well – though less strong than in European populations. Thus, even if T*13910 may not be causative for lactase persistence, it was selected during human evolutionary history.
The other variants were also proved to be under selection. The C*-14010 allele is located on a particularly long stretch of homozygosity (> 2 Mb).
The compound allele G*-13915 and C*-3712 was proved to be located on a long stretch of homozygosity (1.1 Mb to 1.3 Mb).
The ability to digest lactose is not an evolutionary novelty in human populations. Nearly all mammals begin life with the ability to digest lactose. This trait is advantageous during the infant stage, because milk serves as the primary source for nutrition. As weaning occurs, and other foods enter the diet, milk is no longer consumed. As a result, the ability to digest lactose no longer provides a distinct fitness advantage. This is evident in examining the mammalian lactase gene (LCT), whose expression decreases after the weaning stage, resulting in a lowered production of lactase enzymes. When these enzymes are produced in low quantities, lactase non-persistence (LNP) results.
The ability to digest fresh milk through adulthood is genetically coded for by different variants which are located upstream of the LCT gene and which differ among populations. Those variants are found at very high frequencies in some populations and show signatures of selection. There are two notable hypotheses with dissimilar theories which try to explain why lactase persistence phenotype has been positively selected. The first one, known as the cultural-historical hypothesis, states that the main reason for LP is the introduction of dairy-based food products into the diet, while the reverse-cause hypothesis argues that dairy consumption was embraced by the societies which were already high in LP frequency.
Cultural adaptation Pastoralist populations often present high levels of lactase persistence. According to one hypothesis, there is a nutritional advantage of being lactase persistent in pastoralist populations, as milk has high calorific and nutritional density. Individuals who expressed lactase-persistent phenotypes would have had a significant nutritional advantage, meaning they would have had less competition for resources by deriving a secondary food source, milk.
Milk as a nutrition source may have been more advantageous than meat, as it can be produced more quickly than meat. Milk is also generally less contaminated than water, which decreases exposure to pathogens or parasites.
By contrast, for societies which did not engage in pastoral behaviors, no selective advantage exists for lactase persistence, and the lactase persistence genotype and phenotype remains rare.
For example, in East Asia, historical sources also attest that the Chinese did not consume milk, whereas the nomads who lived on the northern and western borders did. This reflects modern distributions of intolerance. China is particularly notable as a place of poor tolerance, whereas in Mongolia and the Asian steppes, milk and dairy products are a main nutrition source. However, modern East Asian steppe people mainly consume fermented milk, kumis, which has almost no lactose, as the lactose is almost completely destroyed during the fermentation process, which makes the product safe to drink for anyone who is lactose intolerant.
Two scenarios have been proposed for this hypothesis: either lactase persistence developed and was selected after the onset of pastoralist practices (culture-historical hypothesis); or pastoralism spread only in populations where lactase persistence was already at high frequencies (reverse-cause hypothesis). There are exceptions to the hypothesis like the hunter-gatherers Hadza (Tanzania), who have a prevalence of lactase persistence phenotype of 50%.
Benefits of being lactase persistent in adulthood