Lactase persistence

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:

• 6% to 15% in white Americans and Northern Europeans
• 18%, 30%, and 47% in Mexican Americans
• 25%, 45%, and 60% in black South Africans
• approximately 10%, 20%, and 25% in Chinese and Japanese
• 30–55%, 90%, and >90% in Mestizos of Peru^[60][61]

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]

References

1. Swallow, D. M. (2003). "Genetics of lactase persistence and lactose intolerance". Annual Review of Genetics 37: 197–219. doi:10.1146/annurev.genet.37.110801.143820. PMID 14616060.
2. Bersaglieri, T.; Sabeti, P. C.; Patterson, N.; Vanderploeg, T.; Schaffner, S. F.; Drake, J. A.; Rhodes, M.; Reich, D. E.; Hirschhorn, J. N. (2004). "Genetic Signatures of Strong Recent Positive Selection at the Lactase Gene". The American Journal of Human Genetics 74 (6): 1111–1120. doi:10.1086/421051. PMC: 1182075. PMID 15114531.
3. Troelsen JT (May 2005). "Adult-type hypolactasia and regulation of lactase expression". Biochim. Biophys. Acta 1723 (1–3): 19–32. doi:10.1016/j.bbagen.2005.02.003. PMID 15777735.
4. Wang Y, Harvey CB, Hollox EJ, Phillips AD, Poulter M, Clay P, Walker-Smith JA, Swallow DM (June 1998). "The genetically programmed down-regulation of lactase in children". Gastroenterology 114 (6): 1230–6. doi:10.1016/S0016-5085(98)70429-9. PMID 9609760.
5. Harvey CB, Wang Y, Hughes LA, Swallow DM, Thurrell WP, Sams VR, Barton R, Lanzon-Miller S, Sarner M (January 1995). "Studies on the expression of intestinal lactase in different individuals". Gut 36 (1): 28–33. doi:10.1136/gut.36.1.28. PMC: 1382348. PMID 7890232.
6. Lloyd M, Mevissen G, Fischer M, Olsen W, Goodspeed D, Genini M, Boll W, Semenza G, Mantei N (February 1992). "Regulation of intestinal lactase in adult hypolactasia". J. Clin. Invest. 89 (2): 524–9. doi:10.1172/JCI115616. PMC: 442883. PMID 1737843.
7. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I (February 2002). "Identification of a variant associated with adult-type hypolactasia". Nature Genet. 30 (2): 233–7. doi:10.1038/ng826. PMID 11788828.
8. Gerbault, Pascale; Moret, Céline; Currat, Mathias; Sanchez-Mazas, Alicia; O'Rourke, Dennis; Volm, M; Lorenz, WJ (24 July 2009). "Impact of Selection and Demography on the Diffusion of Lactase Persistence". PLoS ONE 4 (7): e6369. doi:10.1371/journal.pone.0006369. PMC: 2711333. PMID 19629189.
9. Troelsen JT, Olsen J, Møller J, Sjöström H (December 2003). "An upstream polymorphism associated with lactase persistence has increased enhancer activity". Gastroenterology 125 (6): 1686–94. doi:10.1053/j.gastro.2003.09.031. PMID 14724821.
10. Hussin J, Nadeau P, Lefebvre JF, Labuda D (2010). "Haplotype allelic classes for detecting ongoing positive selection". BMC Bioinformatics 11 (1): 65. doi:10.1186/1471-2105-11-65. PMC: 2831848. PMID 20109229.
11. Itan Y, Powell A, Beaumont MA, Burger J, Thomas MG (August 2009). Tanaka, Mark M., ed. "The origins of lactase persistence in Europe". PLoS Comput. Biol. 5 (8): e1000491. doi:10.1371/journal.pcbi.1000491. PMC: 2722739. PMID 19714206.
12. Burger, J.; Kirchner, M.; Bramanti, B.; Haak, W.; Thomas, M. G. (2007). "Absence of the lactase-persistence-associated allele in early Neolithic Europeans". Proceedings of the National Academy of Sciences 104: 3736–3741. doi:10.1073/pnas.0607187104.
13. Enattah, N. S.; Kozlov, A.; Sajantila, A.; Jarvela, I.; Shaat, N.; Groop, L.; et al. (2007). "Evidence of still-ongoing convergence evolution of the lactase persistence T-13910 alleles in humans". The American Journal of Human Genetics 81 (3): 615–625. doi:10.1086/520705. PMC: 1950831. PMID 17701907.
14. Gerbault, P.; Liebert, A.; Itan, Y.; Powell, A.; Currat, M.; Burger, J.; et al. (2011). "Evolution of lactase persistence: an example of human niche construction". Philosophical Transactions of the Royal Society B: Biological Sciences 366 (1566): 863–877. doi:10.1098/rstb.2010.0268.
15. Smith GD, Lawlor DA, Timpson NJ, Baban J, Kiessling M, Day IN, Ebrahim S (March 2009). "Lactase persistence-related genetic variant: population substructure and health outcomes". Eur. J. Hum. Genet. 17 (3): 357–67. doi:10.1038/ejhg.2008.156. PMC: 2986166. PMID 18797476.
16. Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, Powell K, Mortensen HM, Hirbo JB, Osman M, Ibrahim M, Omar SA, Lema G, Nyambo TB, Ghori J, Bumpstead S, Pritchard JK, Wray GA, Deloukas P (January 2007). "Convergent adaptation of human lactase persistence in Africa and Europe". Nat. Genet. 39 (1): 31–40. doi:10.1038/ng1946. PMC: 2672153. PMID 17159977.
17. Swaminathan, N. 2007. Not Milk? Neolithic Europeans Couldn't Stomach the Stuff. Scientific American.
18. Malmstrom H., Linderholm A., Liden K., Stora J., Molnar P., Holmlund G., Jakkobson M., Gotherstrom A. (2010). "High frequency of lactose intolerance in a prehistoric hunter-gatherer population in northern Europe". BMC Evolutionary Biology 10: 89. doi:10.1186/1471-2148-10-89.
19. Coelho M., Luiselli D., Bertorelle G., Lopes A. I., Seixas S., Destro-Bisol G., Rocha J. (2002). "Microsatellite variation and evolution of human lactase persistence". Human Genetics 117 (4): 329–339. doi:10.1007/s00439-005-1322-z. PMID 15928901.
20. Wade, N. Study Detects Recent Instance of Human Evolution. The New York Times. December 10, 2006.
21. Swaminathan, N. 2006. African Adaptation to Digesting Milk Is "Strongest Signal of Selection Ever". Scientific American.
22. Aoki K (2001). "Theoretical and Empirical Aspects of Gene–Culture Coevolution". Theoretical Population Biology 59 (4): 253–261. doi:10.1006/tpbi.2001.1518. PMID 11560446.
23. Itan Y, Powell A, Beaumont MA, Burger J, Thomas MG (2009). "The Origins of Lactase Persistence in Europe". PLoS Comput Biol 5 (8): e1000491. doi:10.1371/journal.pcbi.1000491. PMC: 2722739. PMID 19714206.
24. Myles S., Bouzekri N., Haverfield E., Cherkaoui M., Dugoujon J. M., Ward R. (2005). "Genetic evidence in support of a shared Eurasian-North African dairying origin". Human Genetics 117 (1): 34–42. doi:10.1007/s00439-005-1266-3. PMID 15806398.
25. Tishkoff S. A.; Reed, Floyd A; Ranciaro, Alessia; Voight, Benjamin F; Babbitt, Courtney C; Silverman, Jesse S; Powell, Kweli; Mortensen, Holly M; Hirbo, Jibril B; Osman, Maha; Ibrahim, Muntaser; Omar, Sabah A; Lema, Godfrey; Nyambo, Thomas B; Ghori, Jilur; Bumpstead, Suzannah; Pritchard, Jonathan K; Wray, Gregory A; Deloukas, Panos (2006). "Convergent adaptation of human lactase persistence in Africa and Europe". Nature Genetics 39 (1): 31–40. doi:10.1038/ng1946. PMC: 2672153. PMID 17159977.
26. Enattah N. S., Jensen T. G. K., Nielsen M., Lewinski R., Kuokkanen M., Rasinpera H., El-Shanti H., Kee Seo J., Alifrangis M.; et al. (2008). "Independent Introduction of Two Lactase-Persistence Alleles into Human Populations Reflects Different History of Adaptation to Milk Culture". American Journal of Human Genetics 82 (1): 57–72. doi:10.1016/j.ajhg.2007.09.012. PMC: 2253962. PMID 18179885.
27. Itan Y., Jones B. L., Ingram C. J. E., Swallow D. M., Thomas M. G. (2010). "A worldwide correlation of lactase persistence phenotype and genotypes". BMC Evolutionary Biology 10 (1): 36. doi:10.1186/1471-2148-10-36. PMC: 2834688. PMID 20144208.
28. Itan, Y.; Powell, A.; Beaumont, M. A.; Burger, J.; Thomas, M. G. (2009). "The Origins of Lactase Persistence in Europe". PLoS Computational Biology 5 (8): e1000491. doi:10.1371/journal.pcbi.1000491. PMC: 2722739. PMID 19714206.
29. "Lactose tolerance/intolerance". Gene Expression. January 19, 2004. Retrieved 2008-01-31.
30. Kretchmer N (October 1989). "Expression of lactase during development". Am. J. Hum. Genet. 45 (4): 487–8. PMC: 1683494. PMID 2518796.
31. Murray RD, Ailabouni AH, Powers PA, McClung HJ, Li BU, Heitlinger LA, Sloan HR (July 1991). "Absorption of lactose from colon of newborn piglet". Am. J. Physiol. 261 (1 Pt 1): G1–8. PMID 1907103.
32. Menéndez-Buxadera A, Carleos C, Baro JA, Villa A, Cañón J (February 2008). "Multi-trait and random regression approaches for addressing the wide range of weaning ages in Asturiana de los Valles beef cattle for genetic parameter estimation". J. Anim. Sci. 86 (2): 278–86. doi:10.2527/jas.2007-0252. PMID 17998432.
33. Bickell S, Poindron P, Nowak R, Chadwick A, Ferguson D, Blache D (November 2009). "Genotype rather than non-genetic behavioural transmission determines the temperament of Merino lambs". Animal Welfare 18 (4): 459–466.
34. Ingram, C. J., Mulcare, C. A., Itan, Y., Thomas, M. G., & Swallow, D. M. (January 1, 2009). "Lactose digestion and the evolutionary genetics of lactase persistence". Human Genetics 124 (6): 588. doi:10.1007/s00439-008-0593-6.
35. for the C (lactase non-persistence) allele
36. Flatz G (1987). "Genetics of lactose digestion in humans". Adv. Hum. Genet. 16: 1–77. doi:10.1007/978-1-4757-0620-8_1. PMID 3105269.
37. Timo Sahi. "Genetics and epidemiology of adult-type hypolactasia with emphasis on the situation in Europe". Scandinavian Journal of Nutrition/Naringsforskning.
38. Kretchmer N (1972). "Lactose and lactase". Sci. Am. 227 (4): 71–8. doi:10.1038/scientificamerican1072-70. PMID 4672311.
39. Almon, R; Engfeldt, P; Tysk, C; Sjöström, M; Nilsson, TK (2007). "Prevalence and trends in adult-type hypolactasia in different age cohorts in Central Sweden diagnosed by genotyping for the adult-type hypolactasia-linked LCT −13910C > T mutation". Scandinavian journal of gastroenterology 42 (2): 165–70. doi:10.1080/00365520600825257. PMID 17327935.
40. Torniainen, S.; Hedelin, M.; Autio, V.; Rasinpera, H.; Balter, K. A.; Klint, A.; Bellocco, R.; Wiklund, F.; et al. (2007). "Lactase Persistence, Dietary Intake of Milk, and the Risk for Prostate Cancer in Sweden and Finland". Cancer Epidemiology Biomarkers & Prevention 16 (5): 956–61. doi:10.1158/1055-9965.EPI-06-0985. PMID 17507622.
41. Enattah, N; Trudeau, A; Pimenoff, V; Maiuri, L; Auricchio, S; Greco, L; Rossi, M; Lentze, M; et al. (2007). "Evidence of Still-Ongoing Convergence Evolution of the Lactase Persistence T-13910 Alleles in Humans". The American Journal of Human Genetics 81 (3): 615–25. doi:10.1086/520705. PMC: 1950831. PMID 17701907.
42. de Vrese M, Stegelmann A, Richter B, Fenselau S, Laue C, Schrezenmeir J (2001). "Probiotics—compensation for lactase insufficiency". Am. J. Clin. Nutr. 73 (2 Suppl): 421S–429S. PMID 11157352.
43. Smith, G.D.; Lawlor, Debbie A; Timpson, Nic J; Baban, Jamil; Kiessling, Matt; Day, Ian N M; Ebrahim, Shah; et al. (2008). "Lactase persistence-related genetic variant: population substructure and health outcomes". European Journal of Human Genetics 17 (3): 357–67. doi:10.1038/ejhg.2008.156. PMC: 2986166. PMID 18797476.
44. Flatz, G.; Howell, J.N.; Doench, J.; Flatz, S.D. (1982). "Distribution of physiological adult lactase phenotypes, lactose absorber and malabsorber, in Germany". Human Genetics 62 (2): 152–7. doi:10.1007/BF00282305. PMID 6819221.
45. Prevalence of the lactase deficiency among the population of the northwestern region of Russia
46. Heli Rasinperä (April 2006). "ADULT-TYPE HYPOLACTASIA: Genotype-phenotype correlation" (PDF).
47. http://yannklimentidis.blogspot.com/2007/03/monday-maps-lactase-persistence-in.html
48. Cavalli-Sforza LT, Strata A, Barone A, Cucurachi L (1987). "Primary adult lactose malabsorption in Italy: regional differences in prevalence and relationship to lactose intolerance and milk consumption" (PDF). Am. J. Clin. Nutr. 45 (4): 748–54. PMID 3565303.
49. Report published by the Mexican institute of social security
50. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I (2002). "Identification of a variant associated with adult-type hypolactasia". Nat. Genet. 30 (2): 233–7. doi:10.1038/ng826. PMID 11788828.
51. "Lactose Intolerance: The Molecular Explanation". UC Davis Nutritional Genomics.
52. Maria do Céu Salgado (2007). "Intolerência à lactose" (PDF) (in Portuguese). Archived from the original (PDF) on August 15, 2010.
53. Kozlov A, Lisitsyn D (1997). "Hypolactasia in Saami subpopulations of Russia and Finland". Anthropol Anz 55 (3–4): 281–7. PMID 9468755.
54. Ernest L. Abel (August 2001). Jewish Genetic Diseases: a Layman's Guide. McFarland & Company, Inc., Publishers. ISBN 978-0-7864-0941-9.
55. Jackson RT, Latham MC (1979). "Lactose malabsorption among Masai children of East Africa". Am. J. Clin. Nutr. 32 (4): 779–82. PMID 581925.
56. Burgio GR, Flatz G, Barbera C, et al. (1984). "Prevalence of primary adult lactose malabsorption and awareness of milk intolerance in Italy" (PDF). Am. J. Clin. Nutr. 39 (1): 100–4. PMID 6691285.
57. Vesa TH, Marteau P, Korpela R (2000). "Lactose intolerance". J Am Coll Nutr 19 (2 Suppl): 165S–175S. doi:10.1080/07315724.2000.10718086. PMID 10759141.
58. Nasrallah SM (1979). "Lactose intolerance in the Lebanese population and in "Mediterranean lymphoma"" (PDF). Am. J. Clin. Nutr. 32 (10): 1994–6. PMID 484518.
59. Wang YG, Yan YS, Xu JJ, et al. (1984). "Prevalence of primary adult lactose malabsorption in three populations of northern China". Hum. Genet. 67 (1): 103–6. doi:10.1007/BF00270566. PMID 6235167.
60. Sahi T (1994). "Genetics and epidemiology of adult-type hypolactasia". Scand. J. Gastroenterol. Suppl. 202: 7–20. doi:10.3109/00365529409091740. PMID 8042019.
61. Woteki CE, Weser E, Young EA (1976). "Lactose malabsorption in Mexican-American children" (PDF). Am. J. Clin. Nutr. 29 (1): 19–24. PMID 946157.
62. Yoshida Y, Sasaki G, Goto S, Yanagiya S, Takashina K (1975). "Studies on the etiology of milk intolerance in Japanese adults". Gastroenterol. Jpn. 10 (1): 29–34. PMID 1234085.
63. Wang; et al. (1984). "Prevalence of primary adult lactose malabsorption in three populations of northern China". Hum Genet 67 (1): 103–6. doi:10.1007/BF00270566. PMID 6235167.
64. (Anagnostou et al., 2009).
65. Jackson, Fatimah L.C. (2014). "Gene-environment Interactions in Human Health: Case Studies and Strategies for developing new paradigms and research methodologies". Frontiers in Genetics 5. doi:10.3389/fgene.2014.00271.
66. Heyer; et al. (2011). "Lactase Persistence in Central Asia: Phenotype, Genotype, and Evolution" (PDF). Human Biology 83 (3): 379–392. doi:10.3378/027.083.0304.
67. (Outram et al. 2009
68. Nagy, D.; Tömöry, G.; Csányi, B.; Bogácsi-Szabó, E.; Czibula, Á.; Priskin, K.; Bede, O.; Bartosiewicz, L.; Downes, C.S.; Raskó, I. (2011). "Comparison of lactase persistence polymorphism in ancient and present-day Hungarian populations.". American Journal of Physical Anthropology 145 (2): 262–9. doi:10.1002/ajpa.21490. PMID 21365615.
69. Matthews SB, Waud JP, Roberts AG, Campbell AK (2005). "Systemic lactose intolerance: a new perspective on an old problem". Postgrad Med J 81 (953): 167–73. doi:10.1136/pgmj.2004.025551. PMC: 1743216. PMID 15749792.