Lactase persistence

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. 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 This makes the study of lactase persistence distribution more difficult. 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. 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. 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, and T/G*-13915. This variant is described as part of a compound allele with T/C*3712 in. and the Fulani (from Mali); 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, 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. 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. 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. 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. 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. 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%. investigated the effects on women's health of the alleles that coded for lactase persistence. Where the C allele indicated lactase nonpersistence and the T allele indicated lactase persistence, the study found that women who were homozygous for the C allele exhibited worse health than women with a C and a T allele and women with two T alleles. Women who were CC reported more hip and wrist fractures, more osteoporosis, and more cataracts than the other groups. They also were on average 4–6 mm shorter than the other women, as well as slightly lighter in weight. The correlation between lactase persistence frequencies and latitude in 33 populations in Europe was found to be positive and significant, while the correlation between lactase persistence and longitude was not, suggesting that high levels of lactose assimilation were indeed useful in areas of low sunlight in northern Europe. Increased calcium absorption helps to prevent rickets and osteomalacia. here, milk is not only a source of nutrients, but also a source of fluid, which could be particularly advantageous during epidemics of gastrointestinal diseases like cholera (where water is contaminated). Human populations differ in the prevalence of genotypic lactase persistence, phenotypic lactose tolerance, and habitual milk consumptions. Lactase persistence and malaria resistance One study suggested that lactase persistence was selected for parallel to malaria resistance in the Fulani from Mali. Proposed mechanisms are: nutritional advantage of milk; low content of p-aminobenzoic acid compared to non-milk diets; intake of immunomodulators contained in milk. Lactase non-persistence in milk reliant populations Although the selective advantages of lactase persistence have been discussed, there have been studies of ethnic groups whose populations, despite relying heavily on milk consumption, currently have a low frequency of lactase persistence. A study of 303 individuals from the Beja tribe and 282 individuals from various Nilotic tribes in Sudan discovered a sharp difference between the distribution of lactase phenotypes of the two populations. Lactase persistence was determined with hydrogen breath tests. The frequency of lactose malabsorbers was 18.4% in members of Beja tribes over the age of 30, and 73.3% in members of Nilotic tribes over the age of 30. == Evolutionary history ==

According to the gene-culture coevolution hypothesis, the ability to digest lactose into adulthood (lactase persistence) became advantageous to humans after the invention of animal husbandry and the domestication of animal species that could provide a consistent source of milk. Hunter-gatherer populations before the Neolithic Revolution were overwhelmingly lactose intolerant, as are modern hunter-gatherers. Genetic studies suggest that the oldest alleles associated with lactase persistence only reached appreciable levels in human populations in the last 10,000 years. Depending on the populations, one or the other hypothesis for the selective advantage of lactase persistence is more relevant: In Northern Europe, the calcium absorption hypothesis might be one of the factors leading to the strong selection coefficients, whereas in African populations, where vitamin D deficiency is not as much of an issue, the spread of the allele is most closely correlated with the added calories and nutrition from pastoralism. that the T*13910 variant appeared at least twice independently. Indeed, it is observed on two different haplotypes: H98, the more common (among others in the Finnish and in the Fulani); and H8 H12, related to geographically restricted populations. The common version is relatively older. The H98 variant – most common among Europeans – is estimated to have risen to significant frequencies about 7,500 years ago in the central Balkans and Central Europe, a place and time roughly corresponding to the archaeological Linear Pottery culture and Starčevo cultures. The T*13910 variant is also found in North Africans. Thus it probably originated earlier than 7500 ya, in the Near East, but the earliest farmers did not have high levels of lactase persistence and did not consume significant amounts of unprocessed milk. Some hypotheses regarding the evolutionary history of lactase persistence in given regions of the world are described below. Europe Concerning Europe, the model proposed for the spread of lactase persistence combines selection and demographic processes. A 2015 genome-wide scan for selection using DNA gathered from 230 ancient West Eurasians who lived between 6500 and 300 BCE found that the earliest appearance of the allele responsible for lactase persistence occurred in an individual who lived in central Europe between 2450 and 2140 BCE. A 2021 archaeogenetics study found that lactase persistence rose swiftly in early Iron Age Britain, a thousand years before it became widespread in mainland Europe, which suggests that milk became a very important foodstuff in Britain at this time. Central Asia In Central Asia, the causal polymorphism for lactase persistence is the same as in Europe (T*13910, rs4988235), suggesting genetic diffusion between the two geographical regions. In Kazakhs, traditionally herders, lactase persistence frequency is estimated to 25–32%, of which only 40.2% have symptoms and 85–92% of the individuals are carriers of the T*13910 allele. Africa The situation is more complex in Africa, where all five main lactase persistence variants are found. The G*13907 variant is concentrated among Afroasiatic speakers in Northeast Africa. Ultimately, the C*14010 lactase persistence variant is believed to have arrived from the Sahara in areas that were previously inhabited by Afroasiatic-speaking populations. This was deduced from the existence of animal husbandry- and milking-related loanwords of Afroasiatic origin in various Nilo-Saharan and Niger-Congo languages, as well as from the earliest appearance of processed milk lipids on ceramics which were found at the Tadrart Acacus archaeological site in Libya (radiocarbon-dated to c. 7,500 BP, close to the estimated age of the C*14010 variant). The evolutionary processes driving the rapid spread of lactase persistence in some populations are not known. Neolithic agriculturalists, who may have resided in Northeast Africa and the Near East, may have been the source population for lactase persistence variants, including –13910*T, and may have been subsequently supplanted by later migrations of peoples. The Sub-Saharan West African Fulani, the North African Tuareg, and European agriculturalists, who are descendants of these Neolithic agriculturalists, share the lactase persistence variant –13910*T. While shared by Fulani and Tuareg herders, compared to the Tuareg variant, the Fulani variant of –13910*T has undergone a longer period of haplotype differentiation. The Fulani lactase persistence variant –13910*T may have spread, along with cattle pastoralism, between 9686 BP and 7534 BP, possibly around 8500 BP; corroborating this timeframe for the Fulani, by at least 7500 BP, there is evidence of herders engaging in the act of milking in the Central Sahara. ==Other mammals==

Lactose malabsorption is typical for adult mammals, and lactase persistence is a phenomenon likely linked to human interactions in the form of dairying. Most mammals lose the ability to digest lactose once they are old enough to find their own source of nourishment away from their mothers. After weaning, or the transition from being milk-fed to consuming other types of food, their ability to produce lactase naturally diminishes as it is no longer needed. For example, in the time a piglet in one study aged from five to 18 days, it lost 67% of its lactose absorption ability. While nearly all humans can normally digest lactose for the first 5 to 7 years of their lives, Lambs are regularly weaned around 16 weeks old. ==Confounding factors==

Some examples exist of factors that can cause the lactase persistence phenotype in the absence of any genetic variant associated with LP. Individuals may lack the alleles for lactase persistence, but still tolerate dairy products in which lactose is broken down by the fermentation process (e.g. cheese, yoghurt). Also, healthy colonic gut bacteria may also aid in the breakdown of lactose, allowing those without the genetics for lactase persistence to gain the benefits from milk consumption. == Lactose tolerance testing ==

A lactose tolerance test may be conducted by asking test subjects to fast overnight, then sampling blood to establish a baseline glucose level. Lactose solution is then given to the subjects to drink, and blood glucose levels are checked at 20 minute intervals for an hour. The subjects who show a substantial rise in their blood glucose level are considered lactose tolerant. ==References==