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10.4: Lactase Persistence Colwin Yee

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  • Think for a minute about how many people you know are lactose intolerant. While most people think in terms of lactose intolerance, evolutionarily, lactose intolerance is the ancestral state. In mammals, the ability to digest lactose has been selected for in infants. In humans, some people also have the ability to digest lactose as an adult. This is called "lactose persistence."There are four different forms of lactase "deficiency": primary, secondary, developmental, and congenital. Primary lactase deficiency is the loss of lactase from childhood into adulthood, this is common among humans with about 70% of the world's adult population unable to digest lactose. Secondary lactase deficiency is the loss of lactose digestion due to injury to the body (most commonly, the intestines). Developmental deficiency is the lack of lactase due to premature birth, and congenital is the lack of lactase from birth onward. The focus of this article will be on primary lactase deficiency.

    Lactose tolerance

    Lactose tolerance considers the presence of lactase within the small intestine. It is located on the brush border of the small intestine enterocyte. Lactase is an enzyme that is responsible for breaking up lactose into glucose and galactose, which would be used for glycolysis and energy production in the body. However if lactase is absent in the small intestine, lactose ends up being processed in the large intestine, allowing bacteria to consume it, produce gases and acid, causing traditional symptoms of lactose intolerance such as bloating, flatulence, and diarrhea (Figure 1).

    Figure 1: Lactose Processing. Lactose is processed in the small intestine by lactase, it is broken down into two simple sugars and exported from the gut. If lactase is not present, lactose moves through the gut to the large intestine, where it is fermented by bacteria. The side products of this fermentation are gas and acids.

    Understanding the genetics of lactase persistence is vital to knowing how it is inherited between populations. Lactose intolerance is inherited in an autosomal recessive pattern, that means that one copy of the lactase persistence allele is enough to confer the ability to digest lactose as an adult. The lactose enzyme is encoded by the LCT gene. This gene has a set of protein-binding regions that help regulate it's expression. On the same chromosome is the MCM6 gene, encoding a helicase. Within MCM6 is an additional enhancer region for the LCT gene. Mutations in this enhancer region can confer lactase persistence. The common mutations are named after their distance upstream of the LCT start codon and the nucleotide at that location: -13907*G, -13910*T, -13915*G, -14009*G, and -14010*C.

    Figure 2: Mutations in the MCM6 gene that affect Lactase expression. This chromosome map incrementally zooms in on the chromosome. (a) Distribution of 123 SNPs; (b) map of the LCT and MCM6 gene region; (c) map of the MCM6 gene; and (d) location of lactase persistence-associated SNPs within introns 9 and 13 of the MCM6 gene in African and European populations. This figure is from Deng et al, 2015 and was published under a CC BY 4.0 license.

    Figure 3: A common mutation in a lactase enhancer region. The -13910 mutation creates a binding site for the transcription factor Oct1. Oct 1 can form a complex with HNF1⍺, a transcription factor with a binding site just upstream of the LCT coding region. This binding bends the DNA and helps to initiate transcription of LCT. This mutation allows lactase to be produced past childhood and into adulthood, allowing consumption and processing of lactose without repercussions to the body.

    The evolution and development of lactose intolerance

    Lactose intolerance usually begins between childhood and early adulthood. It is measured by comparing sucrase and lactase concentrations in small intestine biopsies. Sucrase processes sucrose (table sugar) in the small intestine and is present throughout a persons lifetime, it's concentration is used to normalize lactase concentration. Figure 3 compares lactase:sucrose concentration in different age groups. In infancy, lactase and sucrase levels are around the same concentrations in most individuals, indicating that there is an abundant amount of lactase present. This is vital during infancy as babies require milk from their mothers for nutrition and energy. At older ages, lactase levels slowly wane compared to sucrase. This is the period where children are weaning off their mother’s milk and will no longer need the lactase to digest this source of lactose. In children 5-17 years old, there is a wide spread of lactase concentrations, with many individuals exhibiting very low levels. In many people, the body has turned off the transcription and formation of lactase as it is no longer naturally needed to digest mother's milk. While the exact mechanisms pertaining this change in expression is not known, it is possible that epigenetic modifications are affecting the MCM6 gene. This data is important in demonstrating that humans naturally lose lactose persistence as they grow out of infancy, similar to other mammals.


    Figure 4: Lactase concentration over time. Distribution of sucrose:lactose concentration in four different age groups. The ratios are shown along the x axis and the numbers of individuals in each class are on the y-axis. All four histograms are to the same scale along the x axes, although the y axes are on different scales. The scale of the end of the xaxis is condensed from the position marked (6.5 and above); the highest ratio group contains all with ratios above 20. In our previous studies, ratios of >10 have been considered diagnostic of lactase nonpersistence. This figure is from Wang et al, 1998 and is used with permission.


    Lactase persistence has evolved several times in humans (see Table to the left from Silanikove et al, 2015, published under a CC BY 4.0 license. This is associated with ruminant domestication. Not all populations with domestic ruminants (for example sheep and goats in Southern Europe and water buffalos and yaks in Asia) have high rates of lactose tolerance, however. This may be due to the prevelance of cheese, yogurt, and butter production in these populations. Cheese, yogurt, and butter are all low in lactose. The convergent evolution of lactase persistence has been driven by different mutations in enhancer regions. The most common is the European 13910*T mutation (Figure 3). This mutation is seen at the highest levels in Northern Europe and at lower levels in Southern Europe, Africa and the Middle East (Figure 5). The spread of the mutation is thought to be due to migration of populations from the North. However, it is suspected that the population in India is due to the British colonizing and reproducing with the Indian population. Other mutations (Figure 5) are more regionally localized and are all thought to be associated with pastoralism (livestock domestication).

    Figures used with permission.

    Future directions

    As of right now, there’s no complete hypothesis for the development of lactase persistence. It's commonly thought that persistence evolved due to a change in food preservation and diet. Especially seen for the 13910*T mutation, a change in climate may have favored adaptations for changes in diet. As people migrated North from the Fertile Crescent, the climate got colder, presenting an environment not suitable for growth of some of their crops. However, the colder environment allowed for further preservation of milk from domesticated cows. The lack of available food and the readily resource of milk favored people who had the ability to digest milk. Milk is nutritious in proteins, fats, and sugars, giving people additional calories and nutrients.

    Most data on lactase persistence is from the Old World where populations are more homogenous. However in the New World, populations found in the USA and Latin America may be more diverse, with many people of mixed racial descent. This presents the possibility of developing some form of tolerance no longer on a binary scale but more on a gradient. It is possible that while some populations would still become intolerant as adults, the period of childhood tolerance could be longer than current data shows. This research will not only guide people into further understanding their ability to process lactose, but also allows people to be more aware of how their current diet might affect the genes and traits they pass on.

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