Hubbry Logo
Lactase persistenceLactase persistenceMain
Open search
Lactase persistence
Community hub
Lactase persistence
logo
7 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Lactase persistence
Lactase persistence
Lactase persistence
View on Wikipedia
from Wikipedia

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.[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.[3] Lactase persistence is very high among northern Europeans. Worldwide, most people are lactase non-persistent,[1] and are affected by varying degrees of lactose intolerance as adults. However, lactase persistence and lactose intolerance can overlap.[clarification needed]

Global distribution of the phenotype

[edit]
Percentage of adults that can digest lactose in the indigenous population of Eurasia, Africa and Oceania.

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, with frequencies ranging from 15–54% in the south-east to 89–96% in the north-west.[4] 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.[5] 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.[6][7]

High frequencies of lactase persistence are also found in some places in Sub-Saharan Africa[8][9] and in the Middle East.[10][11] But the most common situation is intermediate to low lactase persistence: intermediate (11–32%) in Central Asia,[12] low (≤5%) in Native Americans, East Asians, most Chinese populations[2] and some African populations.[4][5][12]

In Africa, the distribution of lactase persistence is "patchy":[13][14][4] high variations of frequency are observed in neighbouring populations, for example between Beja and Nilotes from Sudan.[15] This makes the study of lactase persistence distribution more difficult.[5] High percentages of lactase persistence phenotype are found in traditionally pastoralist populations like Fulani and Bedouins.[4][16]

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.[17][16][18][19][20][excessive citations]

Genetics

[edit]
Percentage of adults with a known lactase persistence genotype in the indigenous population of the Old World

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.[21][22]

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.[23] The enzyme lactase is encoded by the gene LCT.[21]

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.[21] Only one high-activity allele is required to be lactase persistent.[21][22] 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.[21][22] 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.[24] 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]

At least six mutations (single-nucleotide polymorphisms – SNPs) have been associated with lactase expression.[25] 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.[26][27][28] The first identified genetic variant associated with lactase persistence is C/T*−13910.[29] 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.[citation needed]

Other alleles associated with lactase persistence have been identified: G/C*-14010,[16] C/G*-13907,[16][14][30] and T/G*-13915.[31] This variant is described as part of a compound allele with T/C*3712 in.[28] These three variants are widespread in some populations. Rare variants were reported in a few studies, like the G/A*14107 in the Xhosa[32] and the Fulani (from Mali);[25] the C/T*13906 in the Fulani (from Mali).[25]

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).[citation needed]

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.[citation needed]

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.[33] The C/G*13907 allele was described in Sudan and Ethiopia.[16][30][34] The "European" allele T*13910 allele is also found in some populations from Africa, including the Fulani (from Mali,[25] Sudan,[35] and Cameroon[30]) and the Khoe from South Africa.[19][20] This allele has also been found in Central Asia.[12]

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.[36] 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,[37] although not enough evidence is found to prove that lactase persistence is only caused by C−13910→T−13910.[21]

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.[21]

Evolutionary advantages

[edit]

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.[21] However, the specific reasons as to why lactase persistence confers a selective advantage "remain open to speculation".[38]

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;[39] the strength of selection is similar to that estimated for the resistance to malaria.[2] Haplotype inferences were performed on data from Central Asia populations; selection was detected there as well – though less strong than in European populations.[12] 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).[16]

The compound allele G*-13915 and C*-3712 was proved to be located on a long stretch of homozygosity (1.1 Mb[16] to 1.3 Mb[28]).

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.[40] 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.[40] When these enzymes are produced in low quantities, lactase non-persistence (LNP) results.[35]

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.[41] 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.[4] 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,[4] while the reverse-cause hypothesis argues that dairy consumption was embraced by the societies which were already high in LP frequency.[4]

Cultural adaptation

[edit]

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.[2][16] Individuals who expressed lactase-persistent phenotypes would have had a significant nutritional advantage,[35] meaning they would have had less competition for resources by deriving a secondary food source, milk.[42]

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.[43]

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.[1]

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.[44]

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%.[16]

Benefits of being lactase persistent in adulthood

[edit]

The consumption of lactose has been shown to benefit humans with lactase persistence through adulthood. For example, the 2009 British Women's Heart and Health Study[45] 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.[46] They also were on average 4–6 mm shorter than the other women, as well as slightly lighter in weight.[46] In addition, factors such as metabolic traits, socioeconomic status, lifestyle, and fertility were found to be unrelated to the findings, indicating that health improvements for these women were due to dairy products consumption and exhibited lactase persistence.[citation needed]

Calcium absorption hypothesis

[edit]

Another possibility is the calcium absorption hypothesis.[14][46] Lactose favors the intestinal absorption of calcium; it helps maintaining it in a soluble form. This can be advantageous in regions of low sunlight exposure where Vitamin D, necessary for the transport of calcium, is a limiting factor. The lactase persistence gene has been shown to correlate with higher levels of Vitamin D.[47]

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.[48]

Increased calcium absorption helps to prevent rickets and osteomalacia.[1]

Arid climate hypothesis

[edit]

A hypothesis specific to arid climate was proposed:[49] 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.[50] An individual's capacity to absorb milk is widespread under three conditions.[citation needed]

  1. Higher latitudes where insufficient ultraviolet-B radiation causes deficiencies of calcium and vitamin D.
  2. Arid areas where the fresh water scarcity turns milk into a welcomed source of hydration.
  3. Pastoral environments where cattle herding provides abundant milk supplies.[50]

Lactase persistence and malaria resistance

[edit]

One study suggested that lactase persistence was selected for parallel to malaria resistance in the Fulani from Mali.[25] 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

[edit]

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.[14] 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.[15]

Evolutionary history

[edit]

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,[51][52] 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.[53][2] This correlates with the beginning of animal domestication, which occurred during the Neolithic transition. Therefore, lactase persistence is often cited as an example of both recent human evolution[16] 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.[54]

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,[55] 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 lactase persistence has multiple origins in different parts of the world (i.e. it is an example of convergent evolution). In particular, it has been hypothesized[56] 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.[citation needed]

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.[57]

Some hypotheses regarding the evolutionary history of lactase persistence in given regions of the world are described below.

Europe

[edit]

Concerning Europe, the model proposed for the spread of lactase persistence combines selection and demographic processes.[45][33][4][14] Some studies used modelling approaches to investigate the role of genetic drift.[4] According to some models, the spread of lactase persistence in Europe can be attributed primarily to a form of genetic drift.[45] Evidence can also come from other fields, for example written historical records: 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.[38] The lower tolerance in southern Europe can be explained by genetic drift alone but the higher tolerance in northern Europe may be a result of positive selection.[4] 2017 reports, by 23AndMe, indicated 40.4% of its customers, who self identified as European, carried a single copy of the mutated 13910C/T allele and a further 42% carried two copies of the lactase persistence allele.[58]

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.[59]

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.[60]

Central Asia

[edit]

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.[12]

It is indicated that the allele responsible for lactase persistence (T*13910) 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.[12] This, in turn, could also be an indirect genetic proof of early domestication of horses for milk products as recently attested from archaeological remains.[12][61] 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.[12]

South Asia

[edit]

In South Asia, the dominant causal polymorphism for lactase persistence is the same as in Europe (T*13910, rs4988235), suggesting genetic diffusion between the two geographical regions. A 2012 study, of 2284 individual across the region, identified an average frequency of 10.3% for the allele, though varying in prevalence from 0.8% among the Tibeto-Burman speakers to 18.4% among Indo-European speakers; the west of India hosting the highest incidents of the derived allele. Additionally approximately 3.4% of the population possessed one of the other known alleles.[62]

Africa

[edit]

The situation is more complex in Africa, where all five main lactase persistence variants are found.[63][16][18][19]

The presence of T*13910 alleles among the Khoe pastoralists is ascribed to gene flow from Europe. However, the presence of other alleles signals gene flow from East Africa.[18]

It has been hypothesized that the G*13915 variant dispersed from the Middle East,[63] in association with the domestication of the Arabian camel.[28]

The G-14009 variant is based in Ethiopia.[64]

The G*13907 variant is concentrated among Afroasiatic speakers in Northeast Africa.[63]

The C*14010 allele is today most common among pastoralist groups inhabiting eastern Africa, from where it is thought to have spread along with pastoralism into parts of southern Africa.[63][18][19][65] 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).[66]

The evolutionary processes driving the rapid spread of lactase persistence in some populations are not known.[1] Among some populations inhabiting East Africa, lactase persistence has gone from negligible to near-ubiquitous frequencies in just 3000 years, suggesting a very strong selective pressure.[16] Some studies also proposed that selection for lactase persistence is not as strong as supposed (soft selective sweep), and that its strength varies a lot depending on particular environmental conditions.[14] Post animal domestication, individuals gained the ability to tolerate lactose after weaning from infancy. This offered a crucial advantage to humans through natural selection by creating genetic variances.[67]

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.[68] 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.[68] 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.[68] 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.[68]

Other mammals

[edit]

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.[69] 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.[70] While nearly all humans can normally digest lactose for the first 5 to 7 years of their lives,[69] most mammals stop producing lactase much earlier. Cattle can be weaned from their mothers' milk at 6 months to a year of age.[71] Lambs are regularly weaned around 16 weeks old.[72]

Confounding factors

[edit]

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, yogurt).[73] 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.[73][74]

Lactose tolerance testing

[edit]

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.[20]

A hydrogen breath test is often used to detect lactose intolerance.[75]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Lactase persistence

View on Grokipedia
from Grokipedia
Lactase persistence is a genetic adaptation in humans that enables the continued production of the enzyme lactase into adulthood, allowing the digestion of lactose—the primary sugar in fresh/raw milk—long after weaning. In contrast to the typical mammalian pattern, where lactase activity declines post-infancy leading to lactose intolerance in most adult humans, this trait permits continued consumption of raw milk without digestive difficulties. From an evolutionary perspective, adult humans are not universally adapted to consume raw milk. This trait affects approximately 35% of the global adult population and is most prevalent in populations with histories of dairy farming and pastoralism. The genetic basis of lactase persistence primarily involves single nucleotide polymorphisms (SNPs) in an enhancer region of the MCM6 gene, which regulates the expression of the nearby LCT gene encoding lactase. In populations of European descent, the most common variant is -13910C>T (rs4988235), an autosomal dominant allele that emerged around 7,500 years ago and spread rapidly due to positive selection. Independent mutations have arisen elsewhere, such as -14010C>G in East African pastoralists and -13915G in some African and Middle Eastern groups, illustrating convergent evolution driven by local dairy consumption. These variants enhance LCT transcription in intestinal cells, preventing the onset of lactose intolerance that affects the majority of humans worldwide. Lactase persistence exemplifies gene-culture coevolution, as its rise coincided with the Neolithic domestication of lactating animals like cattle and goats around 10,000 years ago. Archaeological and proteomic evidence indicates that milk consumption sometimes predated the genetic adaptations for lactase persistence, likely through fermentation to reduce lactose content, thereby providing initial nutritional access for non-persistent individuals before strong selection for the trait. This provided advantages such as additional calories, nutrition during famines, and a relatively safe fluid source, driving strong natural selection in regions with dairying traditions. Prevalence varies dramatically by region: it reaches 89–96% in Northern Europeans (e.g., Scandinavians and British Isles populations) and certain African herding groups like the Sudanese Beni Amer (64%), but is rare (<5%) in East Asians and Native Americans without dairy traditions. Ancient DNA evidence confirms its absence in early Neolithic Europeans, underscoring its status as one of the strongest and most recent signals of natural selection in human evolution.

Overview and Physiology

Definition and Phenotype

Lactase persistence (LP) is a genetic trait characterized by the continued activity of the lactase enzyme into adulthood, enabling the hydrolysis of lactose—the primary sugar in milk—into its constituent monosaccharides, glucose and galactose. This sustained enzymatic function contrasts with the ancestral mammalian condition, where lactase expression is typically downregulated after weaning, resulting in the inability to efficiently digest lactose in later life. Phenotypically, individuals with LP can consume dairy products containing unfermented milk without experiencing common symptoms of lactose maldigestion, such as abdominal bloating, flatulence, diarrhea, or cramping, as the lactose is properly broken down in the small intestine and absorbed. In contrast, lactase non-persistence (LNP), the default physiological state in most humans, leads to a sharp decline in lactase production post-infancy—often to 5-10% of infantile levels—causing undigested lactose to ferment in the gut and trigger these gastrointestinal symptoms upon dairy intake. This distinction manifests as lactose tolerance in LP individuals versus lactose intolerance in those with LNP. Globally, LP affects approximately 35% of adults, while LNP predominates in about 65% of the human population, reflecting the trait's uneven distribution shaped by historical and cultural factors. The emergence of LP is a relatively recent evolutionary adaptation, arising around 10,000 years ago in conjunction with the domestication of dairy animals and the onset of pastoralism in regions like Southwest Asia and Europe.

Lactose Digestion Mechanism

Lactase, formally known as β-galactosidase or lactase-phlorizin hydrolase, is a glycoside hydrolase enzyme embedded in the brush border membrane of enterocytes in the small intestine. It catalyzes the hydrolysis of lactose, the primary disaccharide in mammalian milk, by cleaving the β-1,4-glycosidic bond between its glucose and galactose moieties, yielding absorbable monosaccharides. The digestion of lactose begins in the duodenum and jejunum, where dietary lactose is broken down into equimolar amounts of glucose and galactose through lactase activity. These monosaccharides are then efficiently absorbed, whereas in lactase non-persistence (LNP), insufficient enzyme leads to undigested lactose reaching the colon. There, colonic microbiota ferment the osmotically active lactose, producing short-chain fatty acids, hydrogen, methane, and carbon dioxide gases, which draw water into the lumen and trigger gastrointestinal symptoms such as bloating, flatulence, and osmotic diarrhea. Absorption of the liberated glucose and galactose occurs via secondary active transport across the apical membrane of enterocytes, primarily mediated by the sodium-glucose linked transporter 1 (SGLT1), which couples monosaccharide uptake to a sodium electrochemical gradient established by the Na+/K+-ATPase. These sugars then diffuse across the basolateral membrane through the facilitative transporter into the portal bloodstream, where they contribute metabolic energy at approximately 4 kcal per gram, equivalent to other dietary carbohydrates. Lactase expression is tightly regulated by transcription factors that drive high levels during infancy to support milk-based nutrition, but in LNP individuals, enzyme activity declines sharply after weaning due to progressive epigenetic silencing of the lactase gene, resulting in reduced mRNA and protein production without altering the DNA sequence itself.

Genetics

Molecular Basis and Gene Regulation

The LCT gene, which encodes the enzyme lactase-phlorizin hydrolase (LPH) responsible for lactose digestion, is located on the long arm of chromosome 2 at position 2q21.3. This gene spans approximately 50 kilobases (kb) and consists of 17 exons, with its transcription producing a messenger RNA of about 6.3 kb that translates into the mature LPH protein primarily expressed in the brush border of intestinal enterocytes. LPH functions as a β-galactosidase, hydrolyzing lactose into glucose and galactose, but its expression is tightly regulated during development, declining post-weaning in most mammals, including humans without lactase persistence. The primary regulatory control of LCT expression occurs through an enhancer element located approximately 14 kb upstream in intron 13 of the neighboring MCM6 gene, which encodes a DNA replication factor but harbors this tissue-specific regulatory sequence. This enhancer directs LCT transcription in the intestine while preventing expression in other tissues, and it contains multiple single nucleotide polymorphisms (SNPs) that modulate its activity; for instance, the -13910C>T SNP serves as a well-studied example of a variant altering enhancer function. In individuals with lactase non-persistence (LNP), the enhancer's default activity allows for the developmental silencing of LCT, whereas persistence-associated alleles enhance binding, such as to the HNF1α protein, thereby maintaining expression into adulthood. Epigenetic mechanisms further fine-tune LCT regulation, with at CpG sites in the promoter and enhancer regions, along with repressive modifications like , contributing to post-weaning silencing in LNP phenotypes. These modifications accumulate with age in non-persistent individuals, effectively repressing transcription, while lactase persistence alleles disrupt this process by reducing susceptibility and promoting active marks, such as , to sustain enhancer-promoter interactions.

Key Genetic Variants and Alleles

Lactase persistence (LP) is primarily conferred by single nucleotide polymorphisms (SNPs) in an enhancer region approximately 14 kb upstream of the LCT gene, located within an of the neighboring MCM6 gene, which modulate LCT transcription in intestinal cells. These variants arose independently in different populations and exhibit dominant inheritance, allowing sustained production into adulthood. The most well-characterized LP-associated variant in populations of European descent is the -13910C>T SNP (rs4988235), where the derived T disrupts a transcriptional , leading to increased LCT expression. Functional assays demonstrate that this T enhances transcriptional activity of the LCT promoter by approximately 2- to 3-fold compared to the ancestral C , with the effect mediated through improved binding of transcription factors such as Oct-1. The T acts in a dominant manner, with heterozygotes maintaining sufficient levels for digestion. In African populations, multiple independent LP alleles have been identified in the same enhancer region, including -14010G>C (rs145946881), -13915T>G (rs41380347), and -13907C>G (rs41525747), each originating separately and conferring similar enhancer effects by altering binding to sustain LCT expression. These variants show variable but collectively explain a portion of LP variation in pastoralist groups, with functional studies confirming their role in upregulating activity comparably to the European allele. A distinct variant associated with LP in some Middle Eastern and South Asian populations is -13907C>G (rs41525747), which exhibits partial dominance and enhances LCT transcription through modifications in the enhancer sequence, though with potentially lower than the European . Overall, LP inheritance follows an autosomal dominant pattern at the LCT locus, where heterozygotes typically retain 50-80% of lactase activity relative to homozygotes, sufficient for effective lactose ; additional polygenic factors contribute minimally to the . A 2023 review highlights that over 10 such LP alleles have now been identified globally across diverse ancestries, with varying degrees of and functional strength.

Global Prevalence

Regional Distributions

Lactase persistence (LP) shows marked geographic variation, with prevalence strongly associated with historical dairy pastoralism in different regions of the world. In , LP frequencies are highest in northern and western populations, ranging from 70% to 100%, such as approximately 96% among Scandinavians and groups. Frequencies decline southward, reaching as low as 15-22% in southern European populations like those in . These European patterns are primarily driven by the -13910*T genetic variant. In , LP distribution is patchy and largely confined to pastoralist groups, with frequencies of 20-40%, including approximately 43% among the Fulani of . In contrast, non-pastoralist populations in East and exhibit very low prevalence, typically under 5%. In the , LP is generally uncommon but varies by lifestyle; a 2024 study in reported 16% prevalence in urban populations compared to 30% in rural farming communities, with even higher rates observed among pastoralists. Across , LP is rare in East Asian populations at less than 5%. Prevalence rises to 20-40% in northwestern regions like parts of and , linked to local traditions, while remaining low in . In the and , indigenous populations show low LP rates under 20%, reflecting limited historical use, though admixed groups with European ancestry exhibit higher frequencies due to . Globally, about one-third of adults are lactase persistent, with distributions varying markedly according to regional histories of milk consumption.

Demographic and Environmental Influences

Population movements have significantly influenced the distribution of lactase persistence (LP) alleles across continents. In , the primary LP-associated allele spread through the migrations of Neolithic farmers from the around 8,000 years ago, introducing pastoralism and selecting for LP in subsequent generations. Additionally, from the Eurasian steppes during the further disseminated these alleles westward into , contributing to higher LP frequencies in northern and central regions. In , distinct LP alleles, such as the -14010C>G variant, expanded southward with the Bantu migrations starting approximately 3,000–5,000 years ago, integrating into populations practicing and herding in sub-Saharan regions. Admixture events following colonial-era population mixing have reshaped LP prevalence in the Americas. In Latin American countries, LP frequencies range from 30% to 50%, largely attributable to European genetic input during the colonial period, which introduced high-LP alleles into predominantly non-persistent indigenous populations. In contrast, indigenous Native American populations exhibit very low LP rates (typically 10-20%), reflecting their historical absence of and minimal pre-colonial exposure to LP-conferring alleles. Lifestyle differences between urban and rural settings can modulate observed LP patterns. A 2024 study in found LP incidence at 16% among urban residents compared to 30% in rural farmers, with indicating variation linked to historical pastoralist ancestry in these communities. Environmental factors indirectly influence LP distribution without altering the underlying . Dairy consumption patterns show a strong positive with LP allele frequencies globally, as pastoralist societies with historical use exhibit higher persistence rates, though this reflects cultural selection pressures rather than causation. Similarly, LP is indirectly linked to levels, as persistent individuals in high-latitude populations consume more milk—a fortified source of the —leading to elevated serum concentrations independent of exposure. Recent ancestry modeling supports the role of pastoralist migrations in LP dissemination. A 2025 analysis using genetic ancestry components and polygenic risk scores predicted that LP alleles propagated primarily through ancient herder movements across and , aligning observed modern distributions with migration routes rather than local de novo evolution.

Evolutionary Origins

Selection Pressures and Timeline

Lactase persistence (LP) first emerged in human populations approximately 7,000 to 10,000 years ago, shortly following the of animals such as and sheep in the around 9,000 BCE. From an evolutionary perspective, adult humans are not universally adapted to consume raw milk. Like most mammals, humans typically lose lactase enzyme production after weaning, leading to lactose intolerance in adulthood. Initial milk consumption in early dairying populations was therefore likely via fermented products (such as yogurt, cheese, or kefir) to reduce lactose content through bacterial fermentation, allowing intake by lactose-intolerant individuals before independent genetic mutations for lactase persistence enabled digestion of fresh/raw milk. This temporal alignment indicates that the genetic adaptations enabling adult lactose digestion arose in response to the increasing availability of milk as a dietary resource after the transition to . The evolution of LP has been driven by exceptionally strong positive selection, among the most intense documented in , with estimated selection coefficients ranging from 0.04 to 0.097 per generation, facilitating a rapid rise in frequencies over a few thousand years. This selective pressure is evidenced by the swift spread of LP-associated s, such as the European -13910*T variant, which transitioned from rarity to prevalence in pastoralist groups within millennia. A primary driver appears to be the nutritional value of post-weaning consumption, providing a critical source during famines, promoting enhanced childhood growth through increased energy intake from glucose and , and offering a relatively safe fluid source in environments where water may be scarce or contaminated. Archaeological and genetic evidence from supports this timeline, with LP alleles first detectable in European samples dating to around 5,000 BCE, coinciding with the expansion of dairying practices. In , convergent evolution of distinct LP variants occurred independently around 3,000 BCE, linked to local pastoral traditions, though evidence indicates milk consumption predated these genetic changes in some cases. Recent analysis of ancient genomes further ties LP to nutritional advantages, revealing that carriers of the LP allele exhibited increased stature by 0.20 standard deviations in prehistoric populations, underscoring the role of milk-derived in driving selection for and .

Gene-Culture Coevolution

Lactase persistence (LP) exemplifies gene-culture coevolution, where the cultural practice of dairy farming—initially relying on fermentation to make milk accessible despite widespread lactose intolerance—exerted selective pressure favoring the spread of LP alleles, while these alleles in turn facilitated more intensive consumption of fresh/raw milk and the development of pastoral economies. In populations adopting animal and milk use around 10,000 years ago, the nutritional availability of fresh created an environment where individuals with LP variants gained a advantage, particularly during periods of food scarcity or , thereby increasing the frequency of these alleles over generations. This reciprocal dynamic is a hallmark of niche , as the cultural transmission of dairying practices amplified genetic selection for LP. A key feedback loop in this process involves serving as a reliable weaning food that reduced infant and rates among LP carriers, enabling herder communities to thrive and expand. Successful pastoralists not only passed on LP alleles genetically but also disseminated dairying knowledge culturally through social learning and migration, accelerating the allele's propagation beyond what alone could achieve. Simulations from the 2000s demonstrate this effect: cultural transmission of milk consumption increased the spread of the primary European LP allele (-13910*T) by 5-10 times compared to scenarios relying solely on genetic drift and selection, with models estimating origins around 7,500 years ago in . Illustrative cases highlight this coevolution in diverse contexts. Among herders like the (circa 3300–2500 BCE), the adoption of dairying—evidenced by proteomic analysis of dental calculus showing widespread consumption—coincided with expansions, laying the groundwork for subsequent LP selection despite its initial rarity in these groups. Independently, African pastoralists such as the Fulani developed high LP frequencies linked to their nomadic , driven primarily by the Eurasian-derived -13910*T , with Africa-specific variants like -14010G present at low frequencies, underscoring parallel gene-culture interactions in non-overlapping regions where milk use sometimes predated LP via fermentation. Updated models from 2023 incorporating multiple alleles across continents confirm that such coevolutionary processes occurred repeatedly, reinforcing LP's role as a adaptive response to pastoralism in varied environments.

Regional Evolutionary Histories

Europe and Central Asia

In Europe, the primary genetic variant associated with lactase persistence (LP), the -13910T allele in the MCM6 gene, is estimated to have arisen around 7,500 years ago in , likely among early populations practicing . This allele's emergence coincided with the spread of introduced by Linearbandkeramik (LBK) culture farmers, who migrated from the and into around 5500 BCE, facilitating the initial dissemination of LP through pastoral economies reliant on cattle herding. evidence confirms the allele's absence in pre- hunter-gatherers across , underscoring its novelty in the context of early agricultural expansions. By the , the -13910T appeared at low frequencies in populations such as the (circa 2900–2350 BCE), which spanned much of Northern and and incorporated Indo-European pastoralist elements from the Eurasian steppes. This presence, though rare (less than 10% in sampled individuals), marks an early phase of diffusion amid broader migrations and cultural shifts toward intensified dairying. In medieval , from a 12th-century site in Dalheim, , and other regions reveals a sharp increase, with LP frequencies exceeding 70% by around 1200 CE, reflecting ongoing strong positive selection in northern latitudes where dairy formed a dietary staple. Archaeogenetic analysis of Britain (circa 800 BCE–43 CE) further illustrates rapid regional , with the -13910T rising markedly during this period—reaching levels not seen on the continental mainland until over a later—likely driven by local intensification of practices among Celtic populations. This acceleration predates Roman influence and highlights Britain's insular dynamics in LP evolution. Within Europe, the frequency of lactase persistence exhibits a north-south gradient, with higher prevalence in Northwestern Europe compared to the Balkans and southern regions. This pattern is attributed to differences in historical dairy consumption practices and environmental factors. In northern latitudes characterized by low sunlight, the consumption of fresh milk provided a significant source of vitamin D, potentially enhancing selective pressure for the LP allele. In contrast, in warmer southern and southeastern Europe, including the Balkans, dairy traditions predominantly involved fermented products such as cheese and yogurt, which have reduced lactose content due to bacterial fermentation, thereby allowing consumption by lactase non-persistent individuals and diminishing the selective advantage of the LP allele. Additionally, the warmer climate in these regions led to faster spoilage of fresh milk, favoring preservation methods like fermentation over direct consumption. In , the -13910T allele spread via from the Pontic-Caspian , beginning around 4000–3000 BP, as Yamnaya-related herders moved eastward, introducing and facilitating allele transmission among horse- and cattle-rearing groups. Among modern Central Asian populations with Indo-European linguistic ties, such as and Mongolians, LP frequencies range from 12% to 30%, attributed in part to historical reliance on fermented milk products that mitigated while enabling gradual genetic . This pattern contrasts with higher European prevalences but underscores the allele's Eurasian-wide dispersal through shared migratory and dairying networks.

Africa and Middle East

In , lactase persistence (LP) has evolved independently through multiple genetic variants, with the -14010C>G allele (rs145946881) being prominent among East African pastoralists. This variant emerged approximately 3,000 to 7,000 years ago, coinciding with the intensification of practices in the region. Among Nilo-Saharan and Afro-Asiatic speaking groups, such as the Maasai in and the in and , LP frequencies range from 20% to 80%, reflecting strong selective pressure in dairy-dependent communities. Ancient evidence supports the early association of LP with in northern , where consumption is attested from around 6,000 years ago through proteomic analysis of dental calculus from northeastern African individuals, indicating milk processing during the period. from eastern African pastoralists around 3000 BCE shows low or absent LP alleles, aligning with the spread of domestication from the Valley southward, which facilitated the migration of herding economies across sub-Saharan landscapes. In the , the -13907C>G allele (rs41525747) represents a key LP variant, with origins estimated around 4,000 BCE, linked to the expansion of following the of goats, sheep, and in the and surrounding areas. This allele is particularly elevated among populations, where LP prevalence reaches 30-50%, supporting their traditional reliance on camel and as vital nutritional sources in arid environments. A 2024 study in documented a notable urban-rural gradient, with LP incidence at 16% in urban dwellers, 30% among farmers, and 62% in Bedouins, suggesting a decline in the trait's frequency with modernization and reduced pastoral lifestyles. These regional developments illustrate of LP, where distinct alleles underwent parallel positive selection despite genetic differences, driven by the nutritional demands of consuming unfermented milk from camels and goats in pastoralist societies across and the .

South Asia and Other Regions

In , lactase persistence (LP) is characterized by the presence of specific genetic variants, including the -13907C>G allele (rs41525747), which emerged approximately 4,000 years ago, likely linked to the introduction of and Steppe migrations. This variant, along with others such as -13910C>T shared with European populations, shows elevated frequencies in northwestern regions associated with historical herding practices. Among Punjabi herders in northwest and , LP prevalence ranges from 20% to 40%, reflecting adaptation to consumption in agro-pastoral communities, while it remains low (often below 10%) in southern and eastern populations. The overall lower LP across much of South Asia is attributed to cultural practices emphasizing fermented products like and , which reduce content and diminish selective pressure for persistence alleles. In the , LP was rare among pre-Columbian indigenous populations, with frequencies below 5% and no evidence of local alleles or widespread use prior to European contact in 1492. Post-colonial admixture with Europeans introduced the -13910C>T , leading to increased LP proportional to European ancestry; for instance, admixed populations in and exhibit LP rates of 50-60%. Among US Hispanics, particularly those of Mexican descent, LP reaches approximately 50% due to varying degrees of European genetic contribution, though gastrointestinal symptoms persist in non-persistent individuals consuming . LP prevalence in Oceania and Australia is low among indigenous groups, typically 0-10%, with near absence of known persistence alleles in Aboriginal Australians, consistent with the lack of historical dairy pastoralism. European descendants in these regions show higher rates mirroring global patterns for that ancestry.

Hypotheses for Evolutionary Advantages

Nutritional and Developmental Benefits

Unlike most mammals and the majority of adult humans worldwide, who experience a decline in lactase production after weaning leading to lactose intolerance in adulthood, lactase persistence (LP) enables adults to digest lactose in fresh/raw milk, the primary carbohydrate in milk, into glucose and galactose, providing a significant source of energy. A standard cup (approximately 240 ml) of cow's milk contains 100-150 kcal, with lactose contributing about 12 grams of carbohydrates that yield roughly 48 kcal upon hydrolysis, making milk an efficient calorie source in environments where other foods may be scarce. Individuals with LP derive up to 70% more calories from equivalent volumes of milk compared to those without, as undigested lactose in non-persistent individuals passes unabsorbed, reducing net energy gain. This caloric advantage from fresh milk consumption has been proposed as a key driver for the evolution of LP, particularly during periods of nutritional stress in early childhood when growth demands are high, and especially during famines or subsistence crises when milk provided additional calories and nutrition critical for survival. While milk consumption, often in fermented forms that reduce lactose content through bacterial action, likely predated the genetic adaptation for LP in some populations by several thousand years, LP enabled the digestion of fresh/raw milk, thereby maximizing caloric yield and nutritional benefits without reliance on processing. Developmental benefits of LP include enhanced childhood growth metrics, such as increased and weight, linked to sustained intake. Studies in modern populations show that children with the LP and higher consumption exhibit greater body , with associations persisting into . In dairy-reliant groups, LP correlates with accelerated linear growth and improved weight-for-age, supporting overall physical development during critical periods. Ancient DNA analyses further confirm these effects, revealing that carriers of the LP in prehistoric populations had statures approximately 0.20 standard deviations taller than non-carriers, indicating a substantial genetic contribution to independent of other factors. LP also promotes bone health by facilitating greater intake of milk-derived calcium and , essential for mineralization and skeletal integrity. is a primary dietary source of bioavailable calcium, with LP allowing persistent consumption that enhances absorption efficiency compared to lactose-intolerant individuals who may limit . This benefit is particularly relevant in regions with limited sunlight, such as northern Europe, where reduced UVB exposure limits endogenous vitamin D synthesis; here, milk consumption provided a key dietary source of calcium (and limited natural vitamin D), aiding absorption and contributing to stronger selection pressures for LP compared to southern regions with more abundant sunlight. Overall, these nutritional pathways underscore LP's role in optimizing developmental outcomes through dairy utilization.

Environmental and Pathogen Resistance Hypotheses

One hypothesis posits that lactase persistence (LP) evolved to facilitate vitamin D-independent calcium absorption in regions with limited sunlight, such as northern s, where low UVB exposure impairs endogenous synthesis essential for calcium uptake. This "calcium assimilation hypothesis," originally proposed in the 1970s, suggests that digesting enhances calcium bioavailability from , mitigating risks of and in early dairy-consuming populations reliant on low-calcium cereal-based diets. Computational models simulating LP spread in indicate stronger selective pressures at higher latitudes (selection coefficients of 0.8–1.8%), correlating with archaeological evidence of dairying from around 8500 BP. However, empirical studies in Iberia reveal that while LP alleles show positive selection, latitude alone does not fully explain their distribution, suggesting calcium absorption was influential but not the sole driver. In arid environments, LP may have provided adaptive advantages through milk's role in hydration and nutrient delivery for pastoralist groups facing and climate variability. African pastoralists, such as the Fulani (~50% LP frequency) in and the Tutsi (up to 90%) in , exhibit high LP frequencies, coinciding with the adoption of herding practices in semi-arid regions where milk serves as a reliable source of fluids and calories during dry seasons or droughts. Genetic and isotopic evidence from ancient remains supports this, showing LP alleles emerging alongside around 3000–5000 years ago in response to environmental shifts toward drier conditions, enabling sustained mobility and survival in resource-limited landscapes. Additionally, fresh milk provided a relatively safe fluid source compared to potentially contaminated water sources, reducing risks of dehydration and waterborne diseases in such environments. For instance, migrations of herders through to carried LP variants, linking genetic to arid adaptations in Khoe populations. A proposed link between LP and pathogen resistance involves heterozygote advantages against in endemic areas, where LP alleles might confer partial protection via milk's immunomodulatory effects or nutrient competition with parasites. Preliminary studies from the early 2000s in Mali's Fulani population, known for both high intake and innate resistance, found lower asymptomatic parasitemia (18% vs. 24%) among LP individuals compared to non-persistent genotypes, though differences were not statistically significant (P=0.29). This suggests potential benefits from consumption, such as para-aminobenzoic acid (PABA) deficiency impairing parasite growth, but the data remain inconclusive and require larger-scale validation. Recent reviews critique these environmental hypotheses, emphasizing that nutritional energy gains and growth promotion better explain LP selection than latitude-specific calcium needs or arid hydration alone. A 2023 analysis argues that lactose digestion yields substantial caloric benefits (up to 20% more from milk), driving rapid allele fixation in dairying populations beyond what vitamin D limitations predict. Similarly, pathogen resistance models, including malaria links, show weaker selective signals compared to famine or growth-related pressures. Counterexamples, such as low LP prevalence among Mongolian herders (despite heavy reliance on fermented dairy like airag, which reduces lactose content via bacterial action), highlight that cultural processing mitigates needs for genetic persistence in some arid, milk-dependent groups.

Health Implications

Modern Nutritional Effects

Adults with lactase persistence (LP) can tolerate higher dairy consumption without experiencing lactose intolerance symptoms, leading to increased intake of calcium-rich foods compared to those with lactase non-persistence (LNP). This elevated dairy intake is associated with improved bone mineral density, particularly at the femoral neck, as demonstrated in Mendelian randomization studies linking genetically predicted milk consumption to higher bone density in middle-aged and older populations. Furthermore, higher consumption of certain dairy products like yogurt and cheese has been linked to a reduced risk of hip fractures in meta-analyses of prospective cohorts, with relative risk reductions of up to 20-30% for moderate intakes. However, excessive dairy intake enabled by LP may carry risks, including potential associations with increased incidence, where high consumption (over 400 g/day) correlates with a 25% higher risk, possibly mediated by elevated (IGF-1) levels from . Similarly, consumption has been implicated in aggravating through IGF-1-induced activity and , with meta-analyses showing a modest of 1.2-1.5 for in high- consumers. These risks are often balanced by the overall nutritional benefits of , such as contributions to protein and needs, when consumed in moderation within a varied diet. In response to varying LP prevalence globally, the market for lactose-free dairy products has surged, growing from approximately $12.9 billion in 2024 to $13.9 billion in 2025, driven by demand in regions with high LNP rates like and . Although lactase persistence is genetically determined, the severity of lactose intolerance symptoms in individuals with lactase non-persistence can vary with individual consumption habits, particularly in regions with mixed dairy traditions where fermented products like cheese and yogurt, which have reduced lactose content, are prevalent. Public health policies, such as U.S. dietary guidelines recommending for calcium, have faced scrutiny for potential racial biases, as LP is less common in African American and Asian populations, prompting calls for more inclusive alternatives to ensure equitable access. Studies in multi-ethnic U.S. adults indicate that the LP genotype correlates with higher and intake, as well as improved status of key micronutrients like calcium and , supporting better overall dietary nutrient profiles in LP individuals.

Associations with Microbiota and Disease

Lactase persistence (LP) has been associated with distinct gut microbiota compositions compared to lactase non-persistence (LNP), particularly in relation to intake levels. In healthy U.S. adults, individuals with the LP (rs4988235 AA/AG) consume higher average daily (approximately 12 g/day) than those with LNP (GG, approximately 9 g/day), influencing microbial abundances. LNP individuals with elevated intake (>12 g/day) exhibit increased relative abundances of Firmicutes families such as and , which are involved in lactate , whereas LP individuals show lower levels of these taxa, potentially due to efficient host digestion reducing undigested available for microbial utilization. Similarly, a 2025 study in a multi-ethnic U.S. cohort found that persistent activity in LP genotypes competitively excludes (e.g., and Lactococcus genera), leading to reduced abundances of these Firmicutes compared to LNP individuals with high intake (>10 g/day), who displayed enriched lactate-utilizing taxa like and Megamonas. The LP genotype also modulates microbiota diversity and function. The rs4988235 variant influences overall microbial diversity in healthy adults, with LP associated with greater beta-diversity in some cohorts, reflecting shifts in functional pathways such as beta-galactosidase activity, which is higher in LNP regardless of intake. Higher lactose consumption in LP individuals correlates with altered Firmicutes/Bacteroidetes ratios, promoting a more diverse Firmicutes profile without the pronounced lactate fermentation seen in LNP. These genotype-specific interactions highlight how LP facilitates lactose metabolism primarily in the small intestine, minimizing microbial adaptations in the colon, as evidenced by recent metagenomic analyses. Studies from 2024 and 2025 have begun addressing prior gaps in understanding post-2020 microbiota-LP dynamics, emphasizing the role of undigested lactose as a prebiotic in LNP, which enhances short-chain fatty acid production like propionate. Regarding disease associations, LP is linked to reduced risk of irritable bowel syndrome (IBS) symptoms, as LNP genotypes correlate with higher prevalence of lactose intolerance-related gastrointestinal distress, including and , which overlap with IBS phenotypes. A confirmed that maldigestion, more common in LNP, is not independently associated with IBS, but intolerance symptoms are, suggesting LP confers protection by preventing osmotic and microbial over-fermentation. A 2024 study further indicated that higher intake in LNP individuals is associated with lower risk, potentially mediated by gut microbiota effects including enrichment of species. No strong, consistent links exist between the LP genotype and cancer risks; early correlations with ovarian or cancers appear driven by dietary consumption rather than the genotype itself, as confirmed in genetic studies.

Comparative Aspects

Lactase in Other Mammals

In most mammals, activity is high at birth to facilitate the digestion of in maternal , but it undergoes a significant post-weaning decline, typically dropping to less than 10% of neonatal levels by adulthood. This downregulation, often exceeding 90-99% reduction in expression, aligns with the shift to a post-nursing diet lacking , conserving by limiting unnecessary production in the . The pattern is conserved across diverse mammalian species, from to carnivores, reflecting an adaptive response to dietary changes after infancy. Humans stand out as the only species exhibiting widespread lactase persistence (LP) into adulthood, enabling continued lactose digestion beyond —a trait absent in other mammals without exception until recent evolutionary contexts. This human-specific adaptation emerged in conjunction with animal domestication around 10,000 years ago, particularly in pastoralist societies where fresh became a dietary staple, driving strong selective pressure for LP alleles. In non-human , such as rhesus, bonnet, and owl monkeys, adult lactase levels remain low, mirroring the typical mammalian decline and confirming no natural LP in primate lineages outside humans. Rare exceptions to the mammalian norm occur in domesticated species with historical milk exposure. In dogs, LP is breed- and region-dependent, with a key adaptive (LCT-G) present in 91.7% of European breeds, 61.8% of Southeast Asian indigenous dogs, and only 6.1% of gray wolves, indicating selection for milk digestion in dairy-associated populations starting less than 6,500 years ago. Natural variants conferring LP have not been documented in wild mice or other undomesticated mammals, though lab models using human-derived mutations demonstrate retained juvenile expression. Evolutionarily, human LP represents a form of , where the pre-weaning production pattern is extended into adulthood, unlike the strict ontogenetic shutdown in other .

Exceptions and Variations

While mammals typically express lactase-phlorizin (LPH) for digestion during infancy, non-mammalian vertebrates and generally lack this due to the absence of production in their lineages. In birds, such as chickens, homologues of the mammalian LCT gene encoding LPH have been identified through reverse transcriptase-PCR, producing transcripts similar in size and structure, including a membrane-anchoring domain. However, these avian proteins show sequence similarity to mammalian but lack confirmed functionality in hydrolyzing , as birds do not consume . Reptiles similarly exhibit no evidence of LPH expression tailored to digestion, consistent with their evolutionary divergence from milk-producing lineages. In contrast, some possess analogous β-galactosidase in their intestines that cleave β-1,4-galactosidic bonds in plant-derived , aiding breakdown; for instance, in nilotica, intestinal β-galactosidase activity is high in the juice of the upper and middle intestine, with optimal function at 5.0 and 40°C, though it primarily targets substrates like galactan rather than . Wildlife variations in lactase expression highlight adaptations to diets low in lactose, reducing selective pressures for persistence beyond weaning. In carnivorous mammals like polar bears (Ursus maritimus), adult lactase activity remains undetermined but is likely minimal, as their milk contains only about 0.49% lactose—far lower than in many herbivores—minimizing the need for sustained enzyme production in offspring or adults. Polar bear diets, dominated by high-fat seal blubber rather than milk, further alleviate any potential demand for lactose digestion in maturity, contrasting with herbivorous or omnivorous mammals under dairy-related pressures. This low-lactose profile in ursid milk exemplifies how ecological niches in carnivores can preserve the ancestral pattern of lactase decline without evolutionary retention for adult use. Laboratory models have elucidated regulatory mechanisms of lactase persistence through . Transgenic mice incorporating 3.3 kb of human LPH 5′ flanking sequence from lactase-persistent individuals express the in the during the suckling period, mirroring developmental patterns, but activity declines post-weaning, akin to murine lactase regulation. When the human lactase enhancer element is included, it drives persistent expression into adulthood in these mice, demonstrating that human regulatory variants can override the typical post-weaning silencing observed in . These knock-in models reveal key differences in enhancer-driven and transcription factors, such as Oct-1 binding, that prevent methylation-based repression in persistent humans but not in mice. In human populations with high lactase persistence, such as northern Europeans, rare cases of lactase non-persistence (LNP) arise from compound heterozygous in the LCT , leading to congenital lactase deficiency (CLD). The Finnish-major allele (c.4170T>A, p.Y1390X), a , is prevalent (carrier frequency ~1:35 in some regions) and combines with rarer variants like frameshifts (e.g., c.4998_5001delTGAG) or missenses (e.g., c.804G>C, p.Q268H) to abolish function from birth. These compound heterozygotes, documented in Finnish families, exhibit severe watery upon ingestion despite the population's ~90% adult persistence rate, underscoring how biallelic loss-of-function disrupts the dominant LP trait. Such outliers highlight the distinction between regulatory LNP (common globally) and causing outright deficiency.

Research Considerations

Confounding Factors

Research on lactase persistence (LP) is often complicated by self-reporting bias, where individuals' perceptions of lactose intolerance symptoms do not always align with their actual genetic . Symptoms such as , , and can vary widely in severity and may be influenced by individual tolerance thresholds, leading to under- or over-reporting of intolerance. In populations with high cultural emphasis on consumption, non-persistent individuals may adapt by continuing intake despite mild symptoms, masking the true prevalence of lactase non-persistence and weakening correlations between self-reports and genetic markers like the -13910C/T variant. For instance, studies have shown no strong association between self-reported milk avoidance and LP genotypes in groups accustomed to dairy, as cultural exposure encourages persistence in consumption regardless of underlying physiology. Admixture and population structure further confound genetic analyses of LP by introducing heterogeneous ancestry that can mimic or obscure selection signals. In admixed populations, such as those in or among the Fulani nomads, European or North African genetic contributions carrying the LP allele (e.g., -13910T) can inflate apparent persistence frequencies without reflecting local adaptation. This requires statistical corrections for ancestry, such as or admixture mapping, to disentangle true LP variants from background . Failure to account for these effects has led to overestimations of LP spread in regions with recent migration histories, particularly in where multiple LP alleles coexist amid complex population histories. Age and gender introduce potential confounders in LP studies, though evidence for significant effects on activity or symptom reporting is lacking. Reviews indicate no inherent susceptibility differences based on age or , with symptom responses primarily influenced by dose, body size, and rather than these demographic factors. These considerations still necessitate age- and -stratified analyses to control for possible variations in study cohorts and ensure robust phenotype-genotype correlations. Recent studies from 2023 to 2025 have increasingly highlighted the as a key confounder in LP research, mediating the relationship between and phenotypic outcomes. In lactase non-persistent individuals consuming high- diets, microbial communities adapt by enriching taxa like and lactate-utilizers (e.g., ), which ferment undigested and produce such as propionate, potentially alleviating symptoms and decoupling genetic predictions from observed tolerance. This microbial compensation can explain discordant genotype-phenotype matches, as metagenomic analyses reveal elevated β-galactosidase genes in non-persistent guts regardless of host levels. Such findings underscore the need to incorporate profiling in future LP studies to clarify environmental-genetic interactions.

Diagnostic Methods

The serves as the gold standard for diagnosing lactose malabsorption, a key indicator of non-persistence. In this , the patient ingests a standardized load, typically 25 grams dissolved in , after an overnight fast. Breath samples are then collected at baseline and at intervals (usually every 15-30 minutes) over 2-3 hours to measure exhaled (H₂) levels using a breath analyzer. Undigested reaches the colon, where it is fermented by gut bacteria, producing H₂ that is absorbed into the bloodstream and exhaled; an increase of more than 20 parts per million (ppm) above baseline indicates malabsorption. This test is preferred for its simplicity and patient comfort, though false positives can occur in cases of . Genetic testing provides a direct assessment of lactase persistence status by targeting single nucleotide polymorphisms (SNPs) in the MCM6 gene enhancer region, particularly the rs4988235 variant (also known as -13910C>T). The presence of the T allele is associated with lactase persistence in individuals of European descent, while the CC indicates non-persistence. Testing typically involves (PCR) amplification followed by genotyping via methods like assays or next-generation sequencing, often accessible through (DTC) kits such as those from . In European populations, this SNP predicts lactase persistence with approximately 90% accuracy when correlated with phenotypic tests, though sensitivity drops to around 87% and accuracy is lower in non-European groups due to population-specific variants. The blood glucose tolerance test, or oral lactose tolerance test, evaluates lactase activity through systemic glucose response but is less commonly used due to its invasive nature requiring multiple venipunctures. After , the patient consumes 50 grams of , and blood glucose levels are measured at baseline and at 30, 60, and 120 minutes post-ingestion. A rise of less than 20 mg/dL above baseline suggests , as insufficient lactase prevents glucose-galactose absorption. This method correlates well with breath tests but is avoided in favor of noninvasive alternatives, particularly in pediatric or anxious patients. Recent advancements, including 2024 studies, have begun integrating analysis to resolve ambiguous diagnoses in lactase non-persistence cases, where traditional tests yield inconclusive results. Metagenomic sequencing of fecal samples can identify microbial shifts, such as reduced levels, that influence fermentation and symptom severity, complementing genetic and breath-based assessments. European guidelines updated in recent reviews emphasize optimizing breath test protocols while exploring profiling for personalized diagnostics, particularly in diverse populations.

References

  1. https://www.nature.com/articles/s41576-023-00660-3
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC3048992/
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC7302802/
  4. https://www.nature.com/articles/s41467-020-20682-3
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC8419441/
  6. https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.696516/full
  7. https://www.sciencedirect.com/topics/medicine-and-dentistry/lactase-persistence
  8. https://medlineplus.gov/genetics/condition/lactose-intolerance/
  9. https://www.ncbi.nlm.nih.gov/books/NBK532285/
  10. https://www.sciencedirect.com/science/article/pii/S0002916523050797
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC5683963/
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC7462918/
  13. https://www.gastrojournal.org/article/S0016-5085%2803%2950016-6/fulltext
  14. https://www.mdpi.com/2072-6643/11/11/2737
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC4899171/
  16. https://www.annualreviews.org/doi/pdf/10.1146/annurev.genet.37.110801.143820
  17. https://www.ncbi.nlm.nih.gov/gene/3938
  18. https://www.sciencedirect.com/science/article/pii/S0002929707623647
  19. https://omim.org/entry/603202
  20. https://www.pnas.org/doi/10.1073/pnas.2404393122
  21. https://onlinelibrary.wiley.com/doi/10.1111/ahg.12575
  22. https://academic.oup.com/hmg/article/14/24/3945/2355865
  23. https://www.nature.com/articles/s41598-018-23957-4
  24. https://academic.oup.com/hmg/article/12/18/2333/2355640
  25. https://academic.oup.com/hmg/article/30/R1/R98/6224903
  26. https://omim.org/entry/223100
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC2722739/
  28. https://www.researchgate.net/publication/5817644_Decline_of_Lactase_Activity_and_CT-13910_Variant_in_Sardinian_Childhood
  29. https://www.annualreviews.org/doi/10.1146/annurev-genom-091416-035340
  30. https://www.sciencedirect.com/science/article/pii/S2405844024094866
  31. https://bmcecolevol.biomedcentral.com/articles/10.1186/1471-2148-10-36
  32. https://www.mdpi.com/2072-6643/12/9/2689
  33. https://www.sciencedirect.com/science/article/pii/S096098222031277X
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC3980415/
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC8493957/
  36. https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.671079/full
  37. https://www.nature.com/articles/5201297
  38. https://pubmed.ncbi.nlm.nih.gov/29799022/
  39. https://www.sciencedirect.com/science/article/pii/S0960982225014010
  40. https://historyworld.net/history/Domesticationofanimals/240
  41. https://www.science.org/content/article/how-can-you-eat-dairy-if-you-lack-gene-digesting-it-fermented-milk-may-be-key-ancient
  42. https://www.sciencedirect.com/science/article/pii/S0002929707628389
  43. https://academic.oup.com/mbe/article/41/8/msae156/7724092
  44. https://onlinelibrary.wiley.com/doi/full/10.1002/bies.202200243
  45. https://www.science.org/content/article/humans-were-drinking-milk-they-could-digest-it
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC2672153/
  47. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000742
  48. https://www.nature.com/articles/s41586-021-03798-4
  49. https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-019-6296-7
  50. https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1000491
  51. https://www.pnas.org/doi/10.1073/pnas.0607187104
  52. https://www.sciencedirect.com/science/article/pii/S0960982220311878
  53. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086251
  54. https://www.ucl.ac.uk/news/2009/aug/milk-drinking-started-around-7500-years-ago-central-europe
  55. https://www.science.org/doi/10.1126/science.aaw6275
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC4055572/
  57. https://pmc.ncbi.nlm.nih.gov/articles/PMC10557253/
  58. https://academic.oup.com/mbe/article/29/1/249/1749245
  59. https://www.uchicagomedicine.org/forefront/gastrointestinal-articles/2011/september/lactose-tolerance-in-the-indian-dairyland
  60. https://pmc.ncbi.nlm.nih.gov/articles/PMC3191413/
  61. https://pubmed.ncbi.nlm.nih.gov/3976561/
  62. https://pmc.ncbi.nlm.nih.gov/articles/PMC9910737/
  63. https://www.nature.com/articles/s41586-022-05010-7
  64. https://www.newscientist.com/article/2371243-calorie-boost-may-explain-why-adults-evolved-ability-to-digest-milk/
  65. https://pmc.ncbi.nlm.nih.gov/articles/PMC3169089/
  66. https://academic.oup.com/af/article/13/3/7/7197940
  67. https://doi.org/10.1016/j.cub.2025.10.040
  68. https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2020.578702/full
  69. https://royalsocietypublishing.org/doi/full/10.1098/rstb.2010.0260
  70. https://doi.org/10.1371/journal.pone.0006369
  71. https://pubmed.ncbi.nlm.nih.gov/24448642/
  72. https://www.npr.org/sections/thesalt/2012/12/27/168144785/an-evolutionary-whodunit-how-did-humans-develop-lactose-tolerance
  73. https://doi.org/10.1186/1475-2875-10-9
  74. https://pmc.ncbi.nlm.nih.gov/articles/PMC3031279/
  75. https://pmc.ncbi.nlm.nih.gov/articles/PMC10266752/
  76. https://www.mdpi.com/2072-6643/11/8/1860
  77. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.900109/full
  78. https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-018-5041-5
  79. https://news.llu.edu/research/new-study-associates-intake-of-dairy-milk-with-greater-risk-of-prostate-cancer
  80. https://www.sciencedirect.com/science/article/abs/pii/S0261561418301663
  81. https://www.sciencedirect.com/science/article/pii/S0002916523050724
  82. https://www.researchandmarkets.com/reports/5792808/lactose-free-dairy-global-market-report
  83. https://pmc.ncbi.nlm.nih.gov/articles/PMC2608451/
  84. https://doi.org/10.1016/j.tjnut.2023.06.025
  85. https://doi.org/10.1039/D5FO01640A
  86. https://www.researchgate.net/publication/371851794_Association_of_Estimated_Daily_Lactose_Consumption_Lactase_Persistence_Genotype_rs4988235_and_Gut_Microbiota_in_Healthy_US_Adults
  87. https://pmc.ncbi.nlm.nih.gov/articles/PMC7379306/
  88. https://doi.org/10.1038/s42255-023-00961-1
  89. https://pubmed.ncbi.nlm.nih.gov/17507622/
  90. https://pubmed.ncbi.nlm.nih.gov/15880573/
  91. https://pmc.ncbi.nlm.nih.gov/articles/PMC7551416/
  92. https://www.sciencedirect.com/science/article/abs/pii/S0304416505000346
  93. https://pubmed.ncbi.nlm.nih.gov/5003924/
  94. https://pmc.ncbi.nlm.nih.gov/articles/PMC8557436/
  95. https://pmc.ncbi.nlm.nih.gov/articles/PMC3408868/
  96. https://pmc.ncbi.nlm.nih.gov/articles/PMC1218217/
  97. https://www.jstage.jst.go.jp/article/fishsci1994/70/4/70_4_688/_article
  98. https://www.researchgate.net/publication/237974752_Polar_bear_milk_I_Gross_composition_and_fat_constitution
  99. https://nagonline.net/wp-content/uploads/2018/11/Lintzenich-et-al.-2006-Polar-Bear-Nutrition-Guidelines.pdf
  100. https://pmc.ncbi.nlm.nih.gov/articles/PMC1380240/
  101. https://pmc.ncbi.nlm.nih.gov/articles/PMC2986166/
  102. https://pubmed.ncbi.nlm.nih.gov/26095206/
  103. https://www.sciencedirect.com/science/article/pii/S0002929722000623
  104. https://pmc.ncbi.nlm.nih.gov/articles/PMC6316196/
  105. https://www.tandfonline.com/doi/abs/10.3109/03014460.2014.902992
  106. https://pubs.rsc.org/en/content/articlehtml/2025/fo/d5fo01640a
  107. https://pubmed.ncbi.nlm.nih.gov/37354976/
  108. https://journals.asm.org/doi/10.1128/msystems.00839-24
  109. https://pmc.ncbi.nlm.nih.gov/articles/PMC2659903/
  110. https://emedicine.medscape.com/article/187249-workup
  111. https://my.clevelandclinic.org/health/diagnostics/12360-hydrogen-breath-test
  112. https://karger.com/lfg/article/12/1-6/1/188174/Genetic-and-Oral-Tests-for-the-Diagnosis-of
  113. https://www.urmc.rochester.edu/encyclopedia/content?contenttypeid=167&contentid=lactose_tolerance_blood
  114. https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1395801/full
  115. https://www.mdpi.com/2072-6643/16/20/3516
Add your contribution
Related Hubs
User Avatar
No comments yet.