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Lactase persistence

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Lactase persistence is the continued activity of the enzyme lactase in adulthood. Since lactase's only function is the digestion of lactose in milk, in most mammal species, the activity of the enzyme is dramatically reduced after weaning.[1] In some human populations, though, lactase persistence has recently evolved[2] as an adaptation to the consumption of nonhuman milk and dairy products beyond infancy. The majority of people around the world remain lactase nonpersistent,[1] and consequently are affected by varying degrees of lactose intolerance as adults. However, not all genetically lactase nonpersistent individuals are noticeably lactose intolerant, and not all lactose-intolerant individuals have the lactase nonpersistence allele.

Genetics

Multiple studies indicate that the presence of the two phenotypes "lactase persistent" and "lactase nonpersistent (hypolactasia)" is genetically programmed, and that lactase persistence is not necessarily conditioned by the consumption of lactose after the suckling period.[3][4]

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.[5] The enzyme lactase is encoded by the gene LCT.[3]

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 the lactase gene from their parents, who may be homozygous or at least heterozygous.[3] Also, only one active lactase gene is required to be lactase persistent, because lactase persistence is dominant to hypolactasia.[3][4] Lactase persistence behaves as a dominant trait because half levels of lactase activity are sufficient to show significant digestion of lactose.[1] Cis-acting transcriptional silence of the lactase gene is responsible for the hypolactasia phenotype.[3][4] Furthermore, studies show that only eight cases were found where the parents of a child with lactase persistence were both hypolactasic.[1] 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.[1] 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.[6] 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.[1]

Two mutations (single-nucleotide polymorphisms – SNPs) have been associated with lactase expression. C−13910 (C at position −13910 upstream of the gene LCT) and G−22018 (G at position −22018) are related to lactase nonpersistence, while T−13910 and A−22018 are related to lactase persistence.[7]

Lactase-persistent alleles vary in their geographic distributions. Within European and descendent populations, they are almost entirely correlated with the presence of the −13,910 C/T mutation of the lactase gene (LCT). This differs from LP allelic distributions in East African and Middle Eastern, as well as Northern African, populations. Amongst East African and Middle Eastern groups, the −13915 T/G mutation is the most prominent allelic contributor to lactase persistence. In Northern Africa, the −14010 G/C allele variant is most closely correlated to the trait’s expression.[8]

In addition, the lactase gene has a higher expression when T−13910 and A−22018 are present and a lower expression when C−13910 and G−22018 are present.[3] 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 mutation is thought to be responsible for the differences in lactase expression,[9] although not enough evidence is found to prove that lactase persistence is only caused by C−13910→T−13910.[3]

In one study involving a Finnish population, a CT SNP at −14 kb was found in all lactase-persistent individuals and absent in all hypolactasia individuals. A second SNP (G-22 kbA) was concordant with phenotype in all but a few rare individuals. Both SNPs being located in the same gene has led to a genetic means of testing lactase expression in individuals. Outside of the Finnish study, a separate study also confirmed that the CT SNP at −14kb is an indicator of lactase persistence, with the exception of two individuals.[1]

Global spread

Lactase persistence was due to the presence of a haplotype composed of more than 1 million nucleotide base pairs, including the lactase gene.[2] The presence of this gene is the cause of lactase persistence. Today, this haplotype can be found in 80% of Europeans and those of European ancestry, though the percentage of the population who are lactase persistent in sub-Saharan Africa and Southeast Asia is very low. It is absent in the Bantu of South Africa and most Chinese populations.[2] These geographical distributions strongly correlate with the spread of domesticated cattle. About 5,000 to 10,000 years ago,[10] this haplotype came under very strong selective pressure. This period matches the rise of dairy farming. As dairy farming originated in Europe, Europeans were exposed to increased lactose nutrition provided by dairy products, resulting in positive natural selection.[11] The additional nutrition provided by the dairy foods was very important for survival in the recent history of Europe; therefore, the supply of fresh milk leads to the favoring of the lactase-persistent trait. As dairy farming spread across the globe, after the separation of European-derived populations from Asian- and African-derived populations, and after the colonization of Europe,[2] the strong positive selection occurred in a large region, leading to the global spread of lactase persistence.

Evolutionary advantages

Lactase expression persistence is largely due to natural selection, which is a component of evolution by which a trait affects the chances of the survival of organisms, and consequently, the trait becomes more prevalent in the population over time.

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.[12] This is evident in examining the mammalian lactase gene (LCT), which decreases in expression after the weaning stage, resulting in a lowered production of lactase enzymes.[12] When these enzymes are produced in low quantities, lactose non-persistence (LNP) results.[13]

The ability to digest fresh milk through adulthood is genetically coded for by LCT variants, which differ amongst populations. Individuals who expressed lactase-persistent phenotypes would have had a significant advantage in nutritional acquisition.[13] This is especially true for societies in which the domestication of milk-producing animals and pastoralism became a main way of life.

The combination of pastoralism and LP genes would have allowed individuals the advantage of niche construction, meaning they would have had less competition for resources by deriving a secondary food source, milk.[14] Milk as a nutrition source may have been more advantageous than meat, as it is renewable. Rather than having to raise and slaughter animals, one cow or goat could repeatedly serve as a resource with fewer time and energy constraints. The competitive advantage conferred on lactose-tolerant individuals would have given rise to strong selective pressures for this genotype, especially in times of starvation and famine, which in turn gave rise to higher frequencies in lactase persistence within the populations.

In contrast, for societies which did not engage in pastoral behaviors, no selective advantage exists for lactase persistence. Mutations which may have developed allelic variations which code for lactase production into adulthood are simply neutral mutations. They seemingly confer no fitness benefit to individuals. As a result, no selection has perpetuated the spread of these allelic variants, and the LP genotype and phenotype remains rare.[1] For example, in east Asia, historical sources also attest that the Chinese did not consume milk, whereas the nomads who lived on the 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. The nomads also make an alcoholic beverage, called airag or kumis, from mare's milk, although the fermentation process reduces the amount of lactose present.

Indeed, the consumption of lactose has been proven to benefit humans through adulthood. For example, the 2009 British Women's Heart and Health Study[11] 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.[15] They also were on average 4–6 mm shorter than the other women, as well as slightly lighter in weight.[15] In addition, factors such as metabolic traits, socioeconomic status, lifestyle, and fertility were found to be unrelated to the findings, thus it can be concluded that the lactase persistence benefited the health of these women.

Evidence that lactase persistence has been favored by natural selection was found in a 2006 study.[16] The analysis process consisted of plotting extensive linkage disequilibrium of ancestral and current alleles. The score did in fact reflect positive selection of lactase persistence. Lactase persistence has also been reported to present stronger selection pressure than any other known human gene.[3]

Evolutionary history

The ability to digest lactose into adulthood (lactase persistence) would have only been useful 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,[17][18] as are modern hunter-gatherers. Genetic studies suggest that the oldest mutations associated with lactase persistence only reached appreciable levels in human populations in the last 10,000 years.[2][19] Therefore, lactase persistence is often cited as an example of both recent human evolution[20][21] and, as lactase persistence is a genetic trait but animal husbandry a cultural trait, gene-culture coevolution in the mutual human-animal symbiosis initiated with the advent of agriculture.[22] In Northern European populations, the spread of the lactase-persistence allele is most closely correlated with positive selection due to added vitamin D into the diet. 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.[2]

Several genetic markers for lactase persistence have been identified, and these show that the allele has multiple origins in different parts of the world (i.e. it is an example of convergent evolution).[1] The version of the allele most common amongst 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 Linearbandkeramik and Starčevo cultures. From there, it most probably spread eastwards as far as India. Likewise, one of the four alleles associated with lactase persistence in African population is also probably of European origin.[23] Since North Africans also possess this version of the allele, it probably originated earlier, in the Near East, but the earliest farmers did not have high levels of lactase persistence and, subsequently, did not consume significant amounts of unprocessed milk.[24] Lactase persistence in sub-Saharan Africa almost certainly had a separate origin, probably more than one,[25] and it is also likely that there was a separate origin associated with the domestication of the Arabian camel.[26] None of the mutations 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.[27]

The evolutionary processes driving the rapid spread of lactase persistence in some populations are not known.[1] In some East African ethnic groups, lactase persistence has gone from negligible to near-ubiquitous frequencies in just 3000 years, suggesting a very strong selective pressure,[20][21] but some models for the spread of lactase persistence in Europe attribute it primarily to a form of genetic drift.[28] Competing theories on why the ability to digest lactose might be selected for include nutritional benefits, milk as a water source in times of drought, and increased calcium absorption helping to prevent rickets and osteomalacia in low-light regions.[1]

Roman authors recorded that the people of northern Europe, particularly Britain and Germany, drank unprocessed milk. This corresponds very closely with modern European distributions of lactose intolerance, where the people of Britain, Germany, and Scandinavia have a high tolerance, and those of southern Europe, especially Italy, have a lower tolerance.[29]

Lactase persistence in nonhumans

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.[30] 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 aged from five to 18 days, it lost 67% of its lactose absorption ability.[31] While nearly all humans can normally digest lactose for the first 5 to 7 years of their lives,[30] most mammals stop producing lactase much earlier. Cattle can be weaned from their mothers' milk at 6 months to a year of age.[32] Lambs are regularly weaned around 16 weeks old.[33] Such examples suggest that lactase persistence is a uniquely human phenomenon.

Confounding factors

Some examples exist of factors that can cause the appearance of lactase persistence in the absence of the alleles. 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, yogurt).[34] 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.[34]

Distribution

Human group Individuals examined Intolerance (%) Reference Allele frequency[35]
Dutch N/A 1 [36] N/A
Danes N/A 4 [37] N/A
Europeans in Australia 160 4 [38] 0.20
Swedes N/A 5–7 [39][40] N/A
Basques 85 8.3 [41] N/A
British N/A 5–15 [42] 0.184–0.302[43]
Germans 1805 6–23 [44] N/A
Swiss N/A 10 [38] 0.316
European Americans 245 12 [38] 0.346
Tuareg N/A 13 [42] N/A
Ukrainians N/A 13 [45] N/A
Finns N/A 14–23 [46] N/A
Austrians N/A 15–20 [42] N/A
Belarusians N/A 15 [45] N/A
Spaniards (non-Basque) N/A 15 [47] N/A
Russians N/A 16 [45] N/A
Northern French N/A 17 [42] N/A
Central Italians 65 19 [48] N/A
Mexicans (nationwide) N/A 16–33 [49] N/A
Indians N/A 20 [50][51] N/A
African Tutsi N/A 20 [38] 0.447
African Fulani N/A 23 [38] 0.48
Bedouins N/A 25 [42] N/A
Portuguese adults 102 25 [52] N/A
Saami (in Russia and Finland) N/A 25–60 [53] N/A
Southern Italians 51 41 [48] N/A
Jews, Yemenite N/A 44 [54] N/A
African American Children N/A 45 [50] N/A
Northern Italians 89 52 [48] N/A
North American Hispanics N/A 53 [42] N/A
Balkans N/A 55 [42] N/A
Mexican American Males N/A 55 [50][51] N/A
Cretans N/A 56 [50] N/A
African Maasai 21 62 [55] N/A
Jews, Sephardic N/A 62 [54] N/A
Southern French N/A 65 [42] N/A
Greek Cypriots N/A 66 [50][51] N/A
Jews, Ashkenazi N/A 68.8 [50][51] N/A
Sicilians 100 71 [56][57] N/A
Rural Mexicans N/A 73.8 [50][51] N/A
African Americans 20 75 [38] 0.87
Lebanese 75 78 [58] N/A
Alaskan Inuit N/A 80 [50][51] N/A
Australian Aborigines 44 85 [38] 0.922
Jews, Mizrahi (Iraq, Iran, etc.) N/A 85 [54] N/A
African Bantu 59 89 [38] 0.943
Asian Americans N/A 90 [50][51] N/A
Mestizos of Peru N/A 90< [42] N/A
Northeastern Han Chinese 248 92.3 [59]
Chinese 71 95 [38] 0.964
Southeast Asians N/A 98 [50][51] N/A
Thais 134 98 [38] 0.99
Native Americans 24 100 [38] 1.00

The statistical significance of these figures varies greatly depending on number of people sampled.

Lactose intolerance levels also increase with age. At ages 2 – 3 yr, 6 yr, and 9 – 10 yr, the amount of lactose intolerance is, respectively:

Chinese and Japanese populations typically lose between 20 and 30% of their ability to digest lactose within three to four years of weaning. Some studies have found that most Japanese can consume 200 ml (8 fl oz) of milk without severe symptoms.[62] Milk tolerance is about 81% in Japanese adults.[62] The relatively low prevalence of lactose malabsorption among the Kazakhs suggests that lactose persistence may be frequent in herding pastoralist populations of southwest Asia.[63]

The −13910*T allele, which is widespread in Europe, was found to be located on an extended haplotype of 500 kb or more.[64] In Central Asia, the causal polymorphism for LP is the same as in Europe (−13.910C > T, rs4988235; Heyeretal., 2011), suggesting genetic diffusion between the two geographical regions.[65]

It is indicated that the allele responsible for lactose persistence (13.910*T) may have arisen in Central Asia, based on the higher frequency of lactase persistence among Kazakhs who have the lowest proportion of "western" gene pool inferred from admixture analysis from autosomal microsatellite data.[66] This, in turn, could also be an indirect genetic proof of early domestication of horses for milk products as recently attested from archaeological remains.[66][67] In Kazakhs, traditionally herders, lactose persistence frequency is estimated to 25–32%, of which only 40.2% have symptoms and 85–92% of the individuals are carriers of the −13.910*T allele.[66]

The allele frequencies associated with lactase persistence (T-13910) were 10.9% in ancient groups of Hungary, 35.9% in modern-day Hungarians and 40% in Hungarian Seklers of Transylvania, respectively.[68]

Of the 10% of the Northern European population who develop lactose intolerance, it is a gradual process spread out over as many as 20 years.[69]

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