Although milk and dairy products are common components of the human diet, approximately 65% of the world’s population cannot completely digest them due to lactose intolerance (Malik & Panuganti, 2023). Lactose intolerance is a heritable trait that typically emerges in individuals around weaning. Previously, the enzyme lactase is produced in the infant’s small intestinal lining to digest breast milk. Lactase consists of four identical polypeptide subunits encoded by the LCT gene on chromosome 2 (Juers et al., 2012). After independent synthesis in the ribosome, each polypeptide folds into its secondary and tertiary structures. Through hydrophobic interactions, the subunits assemble into the quaternary structure of lactase, which consists of two enzymatic active sites. The β-galactosidase site can bind to lactose, a disaccharide in milk, and hydrolyze it into glucose and galactose, its monomer components (Forsgård, 2019). Only the monomer forms of carbohydrates can be efficiently absorbed by the small intestine, transferred throughout the body via the circulatory system, and transformed into readily available energy sources within cells. However, the activity of the LCT gene is downregulated around weaning, which permanently lowers lactase production. Insufficient levels of lactase in the small intestine cause failure to digest lactose; lactose molecules are instead digested by intestinal bacteria as they enter the large intestine, resulting in the production of hydrogen gases. Excessive gas in the intestines, as well as excessive water drawn to lactose through osmosis, induces symptoms such as bloating, abdominal pain, and diarrhea. Yet, a minority of individuals continue to produce lactase after weaning, maintaining the ability to digest lactose. Their trait, known as lactose tolerance or lactase persistence, is due to a point mutation that enhances LCT gene transcription. The emergence of this new heritable trait in human populations would allow for natural selection in living environments where it provided a selective advantage. Based on extensive genetic and evolutionary studies, it can be concluded that some people are lactose tolerant, while others are not, due to the gene-culture coevolution led by human milk consumption, which results in differential genetic regulation of lactase production.
Humans’ varying abilities to digest lactose involve a genetic basis. Researchers generally agree that transcription repressors of the LCT gene cause a decline in lactase production. The PDX-1 transcriptional factor is one possible repressor, as it is found to repress the LCT promoter activity through indirect, inhibitory interactions with the RNA polymerase binding site (Wang et al., 2004). Several independent point mutations have been discovered to maintain lactase production into adulthood by creating alternative regulatory pathways of the LCT gene; the new pathways involve a different set of transcriptional factors, which can upregulate LCT gene expression, from the original inhibitory pathways. For instance, a common mutation 13910 base pairs upstream from the start of the LCT gene, where cytosine (C) is replaced by thymine (T), accounts for lactose tolerance among Northern Europeans (Regulation of the Lactase Gene, 2011). It is located in the LCT enhancer region MCM6, which modulates the expression of LCT, and thus the production of lactase, at the transcriptional level. A study in 2004 concludes that the mutation creates a new local binding site for Oct-1, an activator for LCT; therefore, Oct-1 may bind more strongly to MCM6 (Lewinsky et al., 2005). Interactions between the enhancer-bound Oct-1 and transcriptional factors at the LCT promoter region—HNF1-ɑ, GATA, andCTX-2—activate transcription of the gene by RNA polymerase. As a result of upregulated transcription, more lactase is synthesized to digest lactose in the small intestine, constituting the lactose tolerance phenotype. However, another study in 2018 argues that the genetic variation at MCM6 is “not completely predictive of the phenotype” unless DNA methylation levels at MCM6 and the LCT promoter region are also considered (Leseva et al., 2018). Still, the study discovers a negative correlation between the mutation and methylation, which indicates that DNA methylation is likely not regulated by a different mechanism. Lactose tolerance is dominant over lactose intolerance: individuals with one or two copies of the 13910*T-allele express lactose tolerance, while those with two copies of the -13910*C-allele express lactose intolerance. Since the LCT gene is located in an autosome, the lactose intolerance trait is inherited in an autosomal recessive pattern among Northern Europeans, such as the Finnish family in Figure 3. Lactose-intolerant parents, such as III-8 and III-9, must have lactose-intolerant offspring, such as IV-7 and IV-8. Nevertheless, lactose-tolerant parents, such as III-5 and III-6, may give birth to a lactose-intolerant offspring, such as IV-6, if both of them are heterozygous: they must carry exactly one copy of each allele, while both passing down the 13910*T-allele to their child. Ancient DNA study reveals that the -13910*T allele was “very rare or absent” among early Neolithic central Europeans, which strongly suggests that, in an evolutionary process, certain selective pressures increase its allele frequency over time. Other point mutations at MCM6 are also known to independently upregulate LCT gene expression in non-European populations. An example is the 14010G>C mutation, also inherited in a dominant pattern among Africans (Regulation of the Lactase Gene, 2011). The existence of multiple variants for lactose tolerance exemplifies convergent evolution, the independent development of the same trait in different populations.
Furthermore, lactose-tolerant individuals are unevenly distributed across geographic regions and ethnicities, providing strong evidence that common practices across certain cultures, in addition to genetic variation, lead to phenotypic variation. Based on the collective outcomes of earlier observational studies, the average phenotypic frequency of lactose tolerance is the highest in European populations (~61.89%), followed by those in Near/Middle East (~43.83%), Africa (~43.07%), Asia (~26.90%), and Australasia (~10.00%), as shown in Figure 4. The allele frequency for lactose tolerance exhibits a similar association (Figure 5), further suggesting that certain geographic regions seem to impose a greater selective pressure for lactose tolerance on local populations than others (Figure 5). However, the location is insufficient to determine the prevalence of the lactose tolerance trait within a population. Different ethnic groups that live in the same country are found to have drastically different phenotypic and allele frequencies: in Kenya, the Maasai people are mostly lactose-tolerant (~88.46% of the population) with a high allele frequency for the trait (~84.38%), few Sengwer people are lactose-tolerant (~16.67% of the population), and the lactose tolerance allele was relatively rare (~12.50%) (Demographic Data). Thus, a typical evolutionary model, where the selective pressure originates from environmental differences across regions alone, fails to account for the development of lactose tolerance in certain populations. Notably, these populations—the British, the Saudi Arabians, the Kenyan Maasai people, the Sudanian Beni Amer people, etc.—share a pastoralist or nomadic culture (Pastoralist Map, 2022). As a tradition, they raise milk-producing livestock and feed on their milk. Therefore, persistent dairying practices across these populations may have also contributed to a selective pressure favoring those who are lactose tolerant.
A gene-culture coevolutionary model best describes the joint effects of environmental conditions and cultural practices on the development of lactose tolerance. In prehistoric times, dairying provided a strong selective advantage to populations. Milk is a high-calorie and nutritious food source, especially in its raw form. Raw milk contains free amino acids such as glutamic acid, tyrosine, and glycine, which are crucial components of functional human proteins (Landi et al., 2021); carbohydrates, primarily lactose, that serve as humans’ primary source of energy; and abundant fats, which allow for long-term energy storage in the human body (Itan et al., 2009). Milk supply was more consistent than crop yield, which is seasonal and vulnerable to droughts. Meanwhile, milk was one of the few sources of healthy, relatively uncontaminated fluids. Therefore, the mutant lactose tolerance trait was favored within populations that practice dairying: those who could drink milk without adverse symptoms while effectively deriving energy from it were more likely to survive and reproduce. More alleles for lactose tolerance were inherited by the following generations, increasing both the allele frequency and the phenotypic frequency of the trait within the population. Through natural selection, populations underwent convergent evolution with the lactose tolerance trait becoming more prevalent. Chemical analyses, which use δ13C isotope signatures to detect milk fats on prehistoric pottery, reveal milk use in Northern Europe, Africa, and the Near/Middle East, as early as the 7th to 8th millennia BC; dating techniques further confirm that earliest dairying activities were concurrent with the initial spread of lactose tolerance mutations in local populations (biointeractive, 2014; Evershed et al., 2008). As mapped in Figure 6, demographic research has also detected lactose tolerance alleles in central Europe as early as 4000-3000 BP, again concurrent with dairying practices by early farmers in the same region (Casanova et al., 2022). Results from these studies strongly support that dairying practices select for the lactose tolerance trait. In other populations that do not practice dairying, a similar evolutionary process did not take place because alternative lifestyles had created other selective advantages. It is noteworthy, though, that the distribution of lactose-tolerant and intolerant individuals worldwide is far more complex. Migration of individuals from one population to another may have introduced alleles for lactose tolerance to a mostly lactose-intolerant population, or vice versa; the establishment of a new population by a small group of individuals, or a disaster that narrows the gene pool, can also change the allele and phenotypic frequencies of the two traits. Overall, the development of lactose tolerance among humans is a unique example of evolution, demonstrating how humans’ daily practices can have significant impacts on their evolutionary development.
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