Lactose Tolerance: a Recent Adaptive Selection at Work

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According to prevailing but unsubstantiated sociobiological theory, humans have remained essentially the same since the emergence of modern man around 100,000 years ago. Most of the changes that have occurred since this time have been attributed to cultural evolution. Recent progress in molecular genetics when applied to populations is beginning to convey a different story, however.

The gene for the persistence of lactase is an example of a recent adaptive evolutionary process at work that challenges conventional ideas that humanity has stopped evolving (Meisenberg 2008). Lactase, an enzyme located in the brush border of mammalian small intestines, is essential for the digestion of lactose, which is a disaccharide comprised of one glucose molecule and one galactose molecule. Lactose is essential for body and brain development in infants, and it also provides essential nutrition for adults who can digest it.

Humans are the only species of mammals who have been found to have lactase in their small intestinal brush border post weaning. The ability of some humans to retain functionality of the enzyme lactase into adulthood is known as lactase persistence or lactose tolerance. Its recent evolution during the past 10,000 years and apparent co-evolution with the agricultural revolution makes it a keen research interest in evolutionary biology. The discovery of a recent adaptive trait such as lactose tolerance serves as evidence that positive selective pressures remain at work in human populations.

Lactose, the predominant sugar in milk, can only be digested after hydrolysis to its monosaccharides by the enzyme lactase-phlorizin hydrolase, better known as lactase. The lactase (LCT) gene has a single locus on the q arm of chromosome 2, and its expression is limited to the enterocytes in the small intestine, primarily the jejunum. Reduced to simple Mendelian genetics, the phenotypic trait that is responsible for lactose tolerance has dominant inheritance. Yet the the allele for lactase is inherited as a recessive “loss of function” allele. Tolerance to lactose or persistence of lactase is actually the mutational phenotype.

The gene for lactase is regulated at the level of transcription by a cis-acting nucleotide located in an enhancer region upstream from the lactose gene (Liebert).Lactase activity in most mammals and also in the majority of humans, declines after weaning. When lactase is present in the small intestine, the enzyme cleaves lactose into its constituent monosaccharides of glucose and galactose which are then absorbed into the bloodstream.

Lactose intolerant individuals, however, lack a sufficient concentration of lactase in the brush border of the small intestine to metabolize lactose. Instead of being broken down into digestible sugars, the lactose moves from the small intestine to the large intestine, where it is fermented by bacteria to fatty acids and gases such as hydrogen. This results in side effects of diarrhea, gas, and vomiting.

Studies of DNA changes and allelic frequencies in early human populations suggest that the persistence of lactase has co-evolved with increases in farming and agriculture. The lactose non-persistent phenotype is assumed to be the ancestral form since lactose tolerance disappears after weaning in other mammals. Similar to their ancient ancestors, approximately 70 percent of the world’s population loses lactase activity after weaning.

Unlike earlier humans, however, the other 30 percent maintains lactase production throughout adulthood, allowing them to consume fresh dairy products (storhaug). Distinct subgroups of the population, however, have much higher and much lower lactose tolerance. Up to 90 percent of the Danish and Swedish retain lactase activity, and in pastoral Africa the Tutsi have about 90 percent tolerance and the Fulani, about 50 percent. Non-pastoralist populations in Asia and Africa show only one to five percent persistence of lactase.

Several hypotheses have been proposed to answer the question of why lactose tolerance evolved in prehistoric human populations, but the most plausible and well-supported hypothesis is the gene-culture coevolution model (Aoki 1986). This hypothesis supports the emergence of lactose tolerance in humans during the same time period as the first agricultural revolution.

As humans began to shift from the hunter-gatherer lifestyle to a more sedentary agricultural lifestyle, individuals who were able to successfully utilize milk as a food source were more likely to survive and pass their mutations on to their offspring. The persistence of lactase conferred a distinct advantage to survival of the individual and in the populations that continued to display it, particularly in times of famine. The populations with significant lactose tolerance can trace their lineage back to ancestors that traditionally practiced cattle domestication and thus had milk availability (Deloukas, Panos, et al. 2007).

The agricultural revolution represents one of the clearest examples of humans rearranging their own environment with ecological and evolutionary consequences (Gerbault, Pascale, et al.). In Europe, Africa, and Central Asia, a single trait separated a select few populations from other humans. The meteoric rise in genes for lactase regulation can be attributed to several factors. Initially, the culture shifted from hunting and gathering to agriculture and herding.

This marked the opportunity for humans to utilize carbohydrates and other nutrients found in milk. Previously unavailable, milk represented a niche opportunity to individuals who could digest lactose without adverse effects. The shift in culture from hunting to farming caused a complete upheaval in diet for the populations that practiced animal domestication and crop cultivation. A diet that consisted of animal meats and various fruits and tubers was quickly replaced by grains, meat from domesticated cattle, and the milk that these cattle produced.

Even before lactose tolerance developed there is evidence of cheese making and other milk processing as discerned by milk residues in ancient clay pots. This allowed dairy to be used as a calorie and protein source even before the mutation made it digestible. ( Salque 2012) There is no evidence that continued ingestion of fresh dairy led to its tolerance (Keusch et al), however. Instead, extreme selective pressure at a time when nutritional practices were changing was the impetus for this adaptive mutation.

The increased amounts of food produced by prehistoric farming societies subsequently led to an increase in the population density. Although the agricultural lifestyle greatly increased the food availability, the sedentary nature of farming made populations vulnerable to disasters like famine and plague (Barker 2006). Lactase persistence likely arose during these times of famine, as individuals who could capitalize on the nutrients in milk were able to survive while the lactose intolerant individuals either died from lack of food or complications of lactose indigestion.

This intense positive selection caused the presence of the adaptive allele to increase rapidly in European populations. According to a study performed to test for the change in allele frequencies, the allele frequency likely increased significantly from 0.05 to 0.7 within just a few hundred generations (Aoki 1986). This statistic is corroborated by genetic testing of agricultural populations on other continents. When humans were still nomadic hunter-gatherers, mutations for lactase persistence would not have been advantageous and could have been selected against due to the extra metabolic requirements for lactase production. However, after the shift to agriculture and animal husbandry, any mutation for lactase persistence would be immediately selected for and passed on to the next generation.

As research on the genetic origins of lactase persistence continues, the evolution trail becomes even more complicated. Though European and some African populations share the same mutation for lactase persistence, DNA sequencing of individuals from different parts of Africa suggest that it has convergently evolved multiple times, as evidenced by different SNPs that affect the same metabolic process. A single nucleotide polymorphism, SNP-13910 T/ C, is strongly correlated with the ability to produce lactase as an adult.

DNA evidence from various archaeological sites reveals that this SNP became common very quickly in European populations. Bone and DNA samples from fourteen individuals excavated in the Baltic region showed extremely high rates of the selective allele (T) when compared to other hunter-gatherer populations from the same time period (Malmstem, Helena, et al. 2010). In Africa, further DNA evidence from African populations such as the Fulani and the Hausa suggests that lactase persistence evolved convergently due to distinct genetic events.

A genotypic study of 470 East Africans revealed three previously undiscovered mutations that link directly to adult lactase persistence, each derived independently from the European SNP-13910 T/ C allele (Deloukas, Panos, et al. 2007). Another genotype-phenotype study conducted on 183 individuals from central Asia revealed a small proportion of their population to carry the SNP-13910 T/ C. However, some individuals exhibited lactase persistence despite lacking the T nucleotide at that position, and upon a complete genome sequence, were found to lack all known SNPs that link to lactase persistence.

Importantly, these studies reveal the likely convergence of the trait for lactase persistence, pointing to possible relationships between prehistoric populations or just reflecting different selective pressures (Tischoff) which point to deeper evolutionary themes that undergird parts of human history.There is strong Archaeological evidence for an increase in dairy practices dating back to the Neolithic period. By examining pottery from the time period, milk protein residues were detected using an immunological approach and milk lipids were identified using stable carbon isotopes.

However, archeological evidence during the same time period did not find evidence of lactose tolerance. DNA extraction from 8 early Neolithic and one Mesolithic found no evidence for lactase persistence, indicating that dairy practices were in use before the mutation for lactose tolerance arose(Burger 2007). Recently, using population genetic studies, it has been shown that the trait for lactase persistence follows the timeline for a recent selection 5 to 10 thousand years ago, which again, roughly coincides with the change in agricultural practices.

Using three methods of genetic analysis, which included looking at the length of the haplotype around the 13910T allele of the LCT gene, Bersaglieri concluded that the selection pressure for lactose tolerance is the strongest ever identified in the human genome. He pinpointed the time of selection to have occurred after the separation of the Europeans from the Asian and African populations and also concluded that it likely occurred after the colonization of Europe. (T. Bersaglieri 2004 genetic signature).In the past, adaptive mutations such as the trait for lactase persistence were thought to be rare and to spread slowly throughout the population.

Contrary to theory, cultural changes seem to have an extreme effect on natural selection. The niche created by a worldwide agricultural revolution created a need for more food, and resulting genetic changes turned lactose intolerant cultures into semi-isolated groups of lactase-persistent farmers. These recent mutations, under strong selective pressures, allowed populations that can digest lactose to evolve and thrive.

The introduction of new environments may stall some evolutionary forces, but they create new challenges to individual survival, which in turn create new opportunities for natural selection to work in humans. In concert with archeological evidence, population genetics has helped unravel the evolutionary course of lactose tolerance, which serves as an example of a significant genetic change in a short evolutionary period and makes a case for cultural changes leading to rapid phenotypic changes.


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