Lactose Intolerance. Evolutionary Genetics.

Introduction

Lactose intolerance is one of the most, if not the most, researched food intolerances in the world. It occurs when the body is unable to digest lactose, a sugar found in milk and other dairy products, leading to uncomfortable symptoms such as bloating, gas, and diarrhea.

Lactose intolerance has played a vital role in the evolution of human populations, shaping their dietary habits, cultural practices, and genetic makeup. In this article, we explore among other things, lactose intolerance from an evolutionary standpoint, diving into the mechanisms that have influenced its frequency and distribution across populations, and examining its impact on human evolution.

Before doing that, it is of great importance to explain and simplify some basic concepts surrounding the topic. These include: (a) what exactly is lactose and how our body absorbs it, (b) the pathophysiology of lactose intolerance, the mechanisms behind uncomfortable symptoms and (c) the genetic factors that determine intolerance, including the related genetic mutations.

It's important to note that the information presented on this article are not based on proper, rigorous, acaedemic research. Rather, they are intended to provide a general overview of the topic and shall not be taken either as a citation source or a substitute for professional advice. 

Lactose

Lactose makes up approximately 6% of the milk, and it’s one of the main ingredients in dairy products [1]. It is a relatively large sugar (disaccharide – double sugar) and cannot be absorbed by our body. In order to be absorbed, mammals developed a mechanism, in which they break it to smaller sugars (monosaccharides – single sugars), galactose and glucose; sugars that can be then absorbed and used as an energy source from the cells of our body. This “breaking process” is a consequence of the action of a certain enzyme-protein, lactase, which is encoded-produced by the lactase gene (LCT) [2].

Lactose Intolerance Pathophysiology

In the majority of humans (2/3), the activity of lactase declines rapidly right after the end of the weaning phase, a trait known as lactase non-persistence (LNP). On the contrary, the remaining 1/3 maintains the ability to produce lactase, a trait known as lactose persistence (LP). [2]

Individuals with the trait LNP experience the following pathophysiological process: Most of the lactose passing through the GI, cannot be broken down to its monosaccharides due to insufficient lactase present. Thus, it continues down the GI tract and enters the colon [3]. Inside the colon, where the presence of bacteria is most notable, the following processes happen: (a) Bacteria ferment-process the excess lactose, creating a mixture of gases including hydrogen, carbon dioxide and methane, all resulting in various abdominal symptoms such as gas and bloating. (b) The fermentation products (ex. acetate, butyrate, propionate) along with the unabsorbed lactose decrease water absorption (osmotic pressure), resulting in symptoms such as diarrhea. [3]

Note that the individuals with the trait LNP vary in the amounts of lactose they can tolerate before symptoms develop; this being one of the main reasons the number of individuals actually being diagnosed is significantly lower than the 2/3 of the population. [1]

Lactose Intolerance Genetics

This segment may prove challenging for individuals who lack a foundational understanding of genetics. Therefore, to ensure catholic comprehension, an attempt was made to concisely demonstrate some core concepts. If you are already familiar with these, feel free to skip the following four paragraphs.

Genes are segments of DNA that control the production-expression of proteins, which in turn perform various functions in our bodies. Usually, the produced proteins of a specific gene are inter-related and control certain traits in our body. For instance, eye colour is determined by a set of proteins, only expressed by certain genes. 

Humans have two copies of each gene, called alleles, one from each parent. These copies-alleles can be the same, or they can be different. If the alleles are different, the individual is termed hetero-zygous for the specific gene and if they are the same, the individual is termed homo-zygous. Let's consider a simplified example of the gene controlling eye color. You can inherit two black-eye alleles from your parents (homozygous), or you can inherit one black-eye allele from your mother and one brown-eye allele from your father (heterozygous). As you may have imagined, in case of inheriting two black alleles (homozygous), you'll end up having black eyes. However, things get a little more complicated in heterozygous inheritance. In that case, you'll end up having brown eyes. That is because the brown allele is stronger and dominates the expression, and that's why we cal it the dominant allele. The black allele is completely silenced and that's why we call it the recessive allele. 

In a more generalized fashion, heterozygous inheritance consists of one dominant and one recessive allele. However, there can be cases of intermediate inheritance (incomplete dominance). In intermediate inheritance, the alleles are not expressed as dominant or recessive; rather, the dominant allele is expressed in a reduced ratio. To help you understand this, let's imagine that the gene for eye color was following intermediate inheritance. In this case, you could have dark brown or light black eyes, or anything in-between black and brown. 

Another important term you should know is single nucleotide polymorphism (SNP). SNPs are frequently occurring DNA variations (variation and mutation are used somewhat interchangeably). SNPs are like typos in a book, small changes in the letters that can alter the meaning of a word or sentence. In the case of DNA, these small changes can impact genomic function and alter the end-result, protein formation. SNPs are often used as genetic markers in research studies to track the inheritance of genes or to identify genetic variations associated with specific traits or diseases. 

In the case of lactose intolerance, several SNPs had been found on the LCT gene. However, none of them consistently correlated with the production of lactase. That is to say, scientists could not calculate whether an individual’s trait was LP or LNP, simply by looking at the behavior of those SNPs [3]. In a recent study however, two relevant SNPs have been found. One SNP in particular, known as SNP -13910C/T, has been found to be strongly linked to an individual's ability to digest lactose. This SNP describes the presence of two alleles on a certain gene, termed "T" and "C", which influence how much lactase an individual's body can produce at any moment. This directly translates into whether the individual is lactose intolerant or not [4].

Alleles (Genotype)	Lactase Production	Trait (Phenotype)	Lactose Intolerance
C/C	Low	LNP	Yes
T/T	High	LP	No
C/T or T/C	Intermediate	LP or LNP	Probably NO

As you can observe from the above table, if the individual is homozygous for the "C" allele (C/C), the production of lactase will be at a minimum and thus the individual will most probably be lactose intolerant (LNP). On the contrary, if the individual is homozygous for the "T" allele (T/T), the production of lactase will be sufficient enough for the individual to be deemed lactose tolerant (LP). However, when an individual is heterozygous for the specific gene, a bizarre phenomenon is observed (incomplete dominance). It seems that if the individual inherits both "T" and "C" alleles (T/C), the production of lactase is moderate. And not just moderate, but moderate enough for the individual to probably be considered lactose tolerant (LP). Concluding, lactose intolerance in cases of heterozygosity has an intermediate character, in which no clearly dominant or recessive allele is obvious. Nevertheless, a weak pattern of dominance is observed by the "T" allele [4].

It's worth noting that the existence of two different alleles ("C" and "T") is solely due to the presence of the SNP in question. Without this SNP, there would only be one allele present, resulting in either universal homozygosity for the "T" allele or the "C" allele. This directly translates into humanity being either universally lactose tolerant or intolerant. And to determine that, one should note that humans are the only species that consume milk from other species. This being the case, we can deduce that almost certainly, if the SNP didn't exist, the prevailing scenario would have been universal homozygosity for the "C" allele, resulting in total human lactose intolerance.

Evolutionary Genetics of Lactase Persistence

As stated, the T allele of the specific SNP tilts towards domination. It has been shown that in cases of heterozygosity, the T allele prevails and causes the production of moderate amounts of lactase. The result is an individual with minimal-to-none signs of lactose intolerance. Several questions arise here. Why is this the case? Why nature facilitated the prevalence of lactose tolerant individuals?

Apparently, it has been elicited that the "T" allele originating from specific SNP, has a positive natural selection [2]. That means that individuals who inherit at least one "T", have a greater likelihood of surviving and reproducing, leading to an increase in the frequency of the allele within the population over time. As a matter of fact, some authors have estimated that the specific selection has been shown to exist as far as twenty thousand years ago. Its strength is also estimated to be extremely high, even surpassing the powerful selection mechanism for malaria resistance [2][4]. Strong positive natural selection means that the advantage conferred by LP is strong enough, to generate a rapid increase in the frequency of lactose tolerant individuals within the population. Nevertheless, the question remains: Why has nature facilitated this phenomenon?

The most widely accepted theory is that the LP trait provided an evolutionary advantage by allowing lifetime access to nutrient-rich milk in societies that traditionally practiced cattle domestication. While this theory serves as the best explanation for the majority of scenarios, there are regions and cultures where it simply does not apply. For example, some cultures in the Middle East, although heavily relying on pastoralism, exhibit low frequencies of LP. This, along with other discrepancies, have puzzled evolutionary biologists. However, some counter-explanations have been proposed [2]:

One theory proposes that a variety of factors influence the willingness and the ability of a said population to process and ferment milk in order to produce dairy products [2]. Note that the fermentation of milk results in the breakdown of lactose. For instance, a population that prefers dairy products, over consuming milk by itself, would have been less exposed to lactose, leading to an increase in lactose intolerant individuals, over time.

Another theory proposes that the mixing of pastoral and non-pastoral populations may have reduced the effectiveness of natural selection [2]. This can be explained as follows: hat has relied on domesticated cattle as their primary food source for generations. Now, imagine this population moving to a new region where people have other sources of food and do not depend on cattle. After several years and interbreeding between these populations, a mixture of genes may result in the formation of traits that do not correspond to the new environment.

In conclusion, the fact that the specific SNP(s) underwent strong positive natural selection, shaped the evolution of human populations. However, while LP provided an evolutionary advantage in societies that practiced cattle domestication, there are exceptions and they can be challenging to our understanding. 

Conclusion

Diving into the complex world of lactose intolerance has been nothing short of amazing. From examining its pathophysiological mechanisms, to studying cultural and genetic factors that contributed to its occurrence and distribution. I hope this article provided a clear and manageable picture as my goal has always been to make scientific concepts accessible and understandable to everyone. 

While there is still much to learn and explore, our understanding of this condition highlights the importance of genetic and cultural diversity in human evolution. Ultimately, further research on the evolutionary aspects of lactose intolerance can provide valuable insights into the complex interplay between genetic, cultural, and environmental factors that shape our understanding of human health.

References

1. Gerrit M. Westhoff, Ben F.M. Kuster, Michiel C. Heslinga, Hendrik Pluim, Marinus Verhage (2014). ‘Lactose and Derivatives.’Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH. pp. 1-9 DOI: 1002/14356007.a15_107.pub2
2. Augusto Anguita-Ruiz, Concepción M. Aguilera, and Ángel Gil (2020). ‘Genetics of Lactose Intolerance: An Updated Review and Online Interactive World Maps of Phenotype and Genotype Frequencies’ Nutrients DOI: 3390/nu12092689
3. Praveen K Roy, Sarah D Komanapall, Homayoun Shojamanesh (2019) ‘Lactose Intolerance’ Gastroenterology< Drug & Diseases, Medscape. URL: https://emedicine.medscape.com/article/187249-overview
4. Nabil Sabri Enattah, Tine G.K. Jensen, Mette Nielsen, Rikke Lewinski, Mikko Kuokkanen, Heli Rasinpera, Hatem El-Shanti, Jeong Kee Seo, Michael Alifrangis, Insaf F. Khalil, Abdrazak Natah, Ahmed Ali, Sirajedin Natah, David Comas, S. Qasim Mehdi, Leif Groop, Else Marie Vestergaard, Faiqa Imtiaz, Mohamed S. Rashed, Brian Meyer, Jesper Troelsen, and Leena Peltoneo (2008). ‘Independent Introduction of Two Lactase-Persistence Alleles into Human Populations Reflects Different History of Adaptation to Milk Culture’ American Journal of Human Genetics 1 to 109; 1949 to 2022 DOI: 10.1016/j.ajhg.2007.09.012
5. Rejane Mattar, Maria do Socorro Monteiro, Cibele Aparecida Villares, Aníbal Ferreira dos Santos, Flair José Carrilho (2008). ‘Single nucleotide polymorphism C/T(-13910), located upstream of the lactase gene, associated with adult-type hypolactasia: validation for clinical practice’ Clinical Biochemistry DOI: 1016/j.clinbiochem.2008.01.006