Lactase persistence (LP) in humans is very simply the continued production of lactase, the enzyme that allows us to metabolize the lactose that we get from eating dairy, in our intestines. The allele for this production, however, is rare amongst certain populations of the world. In China, for instance, only approximately 1% of its population continues to synthesize lactase throughout their lives versus the 90% of the Finnish, Danish, and Tutsi populations that all continue to create lactase. This percentage difference between different populations of the world makes lactase persistence an interesting problem. How can different populations so far away, Northern Europe versus Eastern Africa, have similar lactase persistence frequencies despite the huge racial, geographic, historic, and cultural differences? Why does it even exist, does it provide an advantage to survival? To find this out, the rates of lactase persistence across the globe must be considered along with the cultural and historical backgrounds of the various populations to see if there are any proximate causes for the isolated nature of lactase persistence or is there an ultimate point for humans to be able to digest dairy products after being weaned.
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Human culture has been domesticating and keeping sheep, goats, and cattle for our own personal usage for approximately 10,000 years. We know that mammals of the world in their infancy have the ability to digest lactose, the primary carbohydrate found in milk and associated dairy products. Upon weaning, most animals lose their ability to produce lactase and consequently are unable to further digest lactose. Humans are different. On average only 65% of our population lose the ability to produce lactase, the key enzyme responsible for our ability to digest lactose. For these individuals, lactose causes cramps, stomach bloating, gas, and general abdominal discomfort. The other 35% of the population then has lactose as a legitimate source of glucose. (Burger, 2007)
On a genetic level we know that carrying theÂ Tâˆ’13910Â variant 14 kb upstream of the lactase (LCT)Â gene is correlative to all populations of the world that have lactase persistence. (Enattah, 2008) Meaning that in the whole of the world, so far as we can tell as of yet, this is the gene responsible for the lactase production. This however is not the only genetic component in deciding LP. It has been found that in a wider scope, inclusive of the C/Tâˆ’13910Â variant allele, the DNA contains enhancer elements with binding sites for several transcription factorsÂ such as Oct-1 and GATA-6 (region from âˆ’13909 toÂ âˆ’13934), HNF4Î± and Fox/HNF3Î± (region âˆ’13857 toÂ âˆ’13817), andÂ Cdx-2(region âˆ’14022 to âˆ’14032). All this has an effect on the lactase regulation processes of the genes in the intestines. Any one of these variations has an effect on the length of time that lactase is produced in the body and in what amounts. This way there are varying levels of LP, some people who can handle any amount of lactose down to those who can have a little lactose but cannot handle any more than that. (Enattah, 2008)
Recent attention given to the nucleotide changes associated with LP has also made it apparent that there are multiple separately found alleles that correspond to lactase persistence. These different alleles are each part of the populations of the world that have a strong inclination towards lactase persistence, such as populations in Europe as well as certain Middle Eastern and African populations. So far there are four strong candidates for alleles that cause lactase persistence in populations, but the number of populations tested has been small making it very likely that we as of yet do not know all of the alleles responsible for lactase persistence in humans globally.
In order to find out which genotypes create individuals with LP, populations must first be found that are still producing lactase. Several non-invasive measures and examinations can be administered to discover this. One popular method is for a surveyor to simply give a subject a large amount of lactose and see the reaction that occurs in the subject. If the subject is lactase persistent, then there will be a marked increase in their blood sugar levels while subjects without the allele for lactase persistence will become sick. The lactose will pass all the way to their colon where it will be fermented by gut bacteria into fatty acids, hydrogen, and a variety of other gases. Hydrogen here can pass easily into the blood stream and can be conveniently detected with a hydrogen analyzer, a simple device not unlike a breathalyzer that measures the amount of alcohol in a person's blood. (Itan, 2010) However this and other ways of testing for lactase persistence are prone to error, so any study to find the percentage of a population with lactase persistence from a sample is somewhat inaccurate.
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Yuval Itan and fellow researchers tried to overcome the lack of data surrounding the complete mapping of all alleles associated with LP by applying a surface interpolation, a statistical method of creating new data points within the scope of pre-existing data points, with the data categories available to them. Categories like genetic data, phenotypic data, etcâ€¦, were used to create data points of new information concerning the many forms and types of LP that may or may not exist, but are outside the reach of research to find them or that we simply have not yet found them. Then they put the aforementioned statistical information over a grid covering the worlds land mass to map out the locations the new data points landed on. In this way regions of relatively dense or particularly sparse LP in the populations there were singled out for future study and previously unknown people carrying the trait and where they would possibly reside could be predicted. The results of their cartographic study gave them an understanding of the limited nature of the so far completed studies of lactase persistence in human populations around the world. The lack of data only means that we cannot yet sufficiently explain the lactase persistence phenotype frequency in Eastern Africa and other regions of the world and that we cannot say with 100% certainty that we know all of the variants of the trait associated to LP. (Itan, 2010)
World Populations who are Lactase Persistent
There are two major hypotheses as to why lactase persistence persists in human populations of Northern Europe and part of Africa and the Middle East. One is the Gene-Culture Coevolution hypothesis which states that there is a nutritional advantage for pastoral populations to be able to digest lactose and the other is the Calcium Assimilation hypothesis which posits that people who carry the LCT*P (lactase production gene) allele(s), the primary gene in the production of lactase, are favored in high-altitude regions of the world where the sufficient amount of vitamin D synthesis in the skin does not occur properly. (Gerbault, 2009) In a study to see which hypothesis was more efficacious, Gerbault and others analyzed data on LP and attempted to find "a correlation between LCT*P variations, geography, and the variation of other independent polymorphisms" (Gerbault, 2009) at a variety of geographic locations in the world to try and see if whether LCT*P patterns were an oddity of genetic drift or whether they were formed by population demographics and histories of an area. Gerbault found in his study that there was a high and significant correlation between the LCT*P frequencies in the African populations and whether they were a pastoral society. For the European populations, the gradient LCT*P frequencies could be explained by positive selection on the allele, by population history, or both. This finding fits into the Gene-Culture Coevolution hypothesis and is also in agreement to another finding that the frequencies of LCT*P in the northwestern part of Europe is too prevalent for genetic drift to have caused such high rates of LP. Thus, a novel environment combined with a culture centered around surviving in a pastoral setting makes lactase persistence a useful allele to have as dominant in that population. (Gerbault, 2009)
The Genetic-Culture Coevolution hypothesis works best with explaining the frequencies of lactase persistence in Africa due to the fact that for the Calcium Assimilation hypothesis to work for the African populations they would have to be living in areas of very high altitude or of low light level conditions. Both of those conditions, elevation and diminshed light levels, were missing from the lives of the African populations and consequently dismissed as reasons to warrant the African populations selection for LP based upon a need for vitamin D creation and subsequent calcium absorption. Northern Europe is best explained through a combination of the Calcium Assimilation hypothesis and demographic effects, wherein the location of the populations in high altitude areas in northern parts of the globe preclude the populations to be exposed to lessened levels of sunlight that would interfere with the synthesis for vitamin D in the body. The study points out that in Northern Europe, that selective pressure for LP was higher than it was in the southern populations, but the full reason as to why that has yet to surface in its entirety. (Gerbault, 2009) Essentially here, both the coevolution of the allele frequency and the cultural growth of pastoral origins reinforced one another and selected for individuals who had lactase persistence and the in the North, people evolved a way to make up for the interrupted vitamin D synthesis in their skin and an as of yet unexplained reason that the demographics of the population selected for a higher allele frequency of LP.
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Historically Northern to Central Europeans started to have increased lactase persistence within approximately the last 20,000 years, but only had marked increases within the last 10,000 years in concordance with the domestication of cattle and the increased diet of dairy. The trait is thought to have given an advantage to those individuals who had consumed unfermented dairy on a regular basis. Though this theory opens up discussion for two new theories the first of which is the Cultural-Historical hypothesis, wherein some believe that lactase persistence alleles were rare until pastoralism was invented and people started keeping sheep, cattle, and other milk producing livestock that added to their diets and natural selection for individuals with the correct alleles took over from there. The other hypothesis is the Reverse Cause hypothesis, where subscribers to this train of thought stipulate that it was pastoralism and dairy collection that was adapted to a population that was already pre-adapted to having the lactase persistence allele. (Burger, 2007)
In the Burger article, DNA was obtained from ancient skeletons of individuals from the Mesolithic, approximately 2267 Â± 116 years old, and the Neolithic, approximately 5800 to 5000 years old. From there they sequenced the mitochondrial DNA and found through short tandem repeat genotypes across the eight Neolithic remains and the one Mesolithic remains, that the most common lactase persistence allele was absent. This means that the Cultural-Historical hypothesis is correct and it was only at a later date that a relatively strong and recent selection process amongst that population brought forth the dominance of the lactase persistence allele. (Burger, 2007) This new information along with evidence based off of the decay of long-range haplotypes and the variations in the microsatellites, the rough age of the âˆ’13.910*T allele in Europe is approximately 2,188 and 20,650 years ago and 7,450 and 12,300 years ago respectively. These dates for the age of the allele fit the theory that the population of northern Europeans had the allele in their genes before the domestication of cattle and other milk producing animals, but only came to prevalence during the period of domestication which marked the increase in dairy in the diets of the population.
Europeans have been shown through studies to have seven polymorphisms in the lactase gene that are highly associated to only 3 common haplotypes. The frequencies of these three haplotypes in the Harvey article were shown to exist in Caucasians from Northern and Southern Europe as well as the Indian sub-continent. In the southern regions, the latter two types of haplotypes, labeled simply B and C, were far more common than the former haplotype A. Which is to say that the haplotype most associated to LP was absent or rare amongst the populations of southern Europe and the Indian sub-continent. In the study, eleven unassociated individuals were tested for their RNA transcripts to determine their haplotype and it was found that haplotype A was almost always associated to the highly expressed allele of LP. (Harvey, 1998) This evidence points out the high prevalence of haplotype A amongst Northern populations along with their predominant lactase persistence allele was mainly responsible for the high rates of LP in northern populations. However, the two, haplotype A and the lactase persistence allele, most often occur together, this is not a guarantee that the two will show up together. Haplotype B can also result in lactase persistence in a few small instances and even a case of homozygosity with the C haplotype has resulted in lactase persistence. These cases are rare but show that haplotype A and the LP allele are not the only precursors for LP. Overall though, haplotype A is the best predictor of lactase persistence in a population and should be regarded as the haplotype to be searched for in a population if LP is to be ascertained. (Harvey, 1998)
With Europeans being explained for the LP through a novel environment that made the LP allele dominant in the populations there, African populations too can be lactase persistent, but they offer a different source of their persistence than their European counterparts. The -13910*T allele, the primary allele of northern populations for LP, which is extremely prevalent in the European populations, is sparse amongst the African dairy consuming populations. Ingram and her team conducted a series of gene resequences on the African populations which revealed three new SNPs (single nucleotide polymorphism) close to the original -13910*T allele of which two were within the Oct-1 binding site. The most common of the three, -13915*G, is curiously associated with lactose tolerance rather than lactase persistence. -13915*G breaks down Oct-1 binding instead of becoming involved with lactase persistence. It in essence instead of promoting the production of lactase, -13915*G causes the body to better tolerate the lactose from the dairy that is consumed. This opposite approach from the northern European method garners the same ends as the original allele but does it without the allele. This opposite approach to a similar problem in a different environment shows the complexity of the African polymorphism and of how it has differed from the European equivalents over time. (Ingram, 2006)
In the Sudan study conducted by Bayoumi in 2008, it was found that there was an interesting misnomer in the dairying peoples of Africa. In the Sudan where there is a long history of nomadic pastoralism, the rate of individuals who were not lactase persistent or lactose tolerant was high. It was found that in all subgroups, excluding a group called the Bedja, an allele for hypolactasia was showing up more than the allele for lactase persistence. Among the groups, one common thread connected them together as a reason for their falling lactase persistence frequencies and rising hypolactasia, settlement. The once nomadic peoples were beginning to settle into permanent locations and to start agricultural endeavors. Proof of this lied with already-settled peoples like the residential agriculturalists of the Nile valley, who had been settled for a long time and not surprisingly had some of the highest hypolactasia rates and lowest lactase persistence rates. This cultural gradient of allele frequencies mixed with the racial gradient of allele frequencies to create a highly complex frequency distribution over the population of Sudan whose details are nearly impossible to ascertain due to the size of the initial sample. However, this large coverage of a number of different frequencies presents a prime research spot in the future to observe the evolution of lactase phenotypes over time. (Bayoumi, 2008)
At a proximate level, LP is due, as far as we can tell from the data that we have collected, to the dominance of haplotype A with regards to where the allele for lactase production is located along with geographic and cultural specificities that have allowed for the dominance of lactase persistence to continue. At an ultimate level, the causes for LP differ between the African and the European populations. In Northern Europe, the Calcium Assimilation hypothesis and the Reverse Cause hypothesis best describe the proximate causes for LP in those populations. The environment in Northern Europe is not suited to the adequate synthesizing of vitamin D and the populations residing there were already predisposed to having the correct allele in in a relatively large portion of the population, which it then came to prevalence with the introduction of dairy into the diet of those peoples. In Africa the Genetic-Culture Coevolution hypothesis in conjunction with the Cultural-Historical hypothesis best describes the way in which African populations came to be able to tolerate lactose as a major part of their diets. The Cultural-Historical hypothesis explains that the African populations weren't necessarily predisposed to be LP, but the addition of pastoralism and the introduction of dairy forced what little genetics they had to deal with lactose to come the forefront. The Genetic-Culture Coevolution hypothesis explains how there was an advantage to those who could eat the dairy gotten from the newly tamed animals and how it was those individuals who were the most likely to survive in their new pastoral societies.
The difference of approaches between European and African populations in how LP is achieved in a population has far reaching effects that have precedence in today's world. The discrepancy in explaining lactase persistence between African and Middle Eastern populations and those of Northern Europe seems to stem from a difference of regional history despite the nutritional similarities, i.e. - dairy. The dietary needs of different races might leave open a possibility of a bias in nutritional needs as set forth by the federal government. Dietary guidelines as set by the government, best represented with the well-known "Food Pyramid," it is recommended for the average person to consume 2-3 servings of dairy a day. However, lactase nonpersistence tends to occur in disproportionately high rates amongst African-, Asian-, Hispanic-, and Native Americans than it does in Caucasians which makes them less likely to properly digest the lactose in the food that has been suggested to them. Instead, calcium can be obtained from other sources that do not contain lactose and minorities here actually suffered less from osteoporosis than Caucasians do. So, minorities have even less incentive to consume dairy when it has little to no positive effect on their health, and as such an alteration of the Food Pyramid to make the dairy products optional in view of other calcium sources might be helpful to the public health. (Bertron, 1999) And while this does not tell of a specific ultimate or proximate cause, it does shed light on the modern uses of understanding the differences in nutritional need and bodily capability to withstand a specific diet as is dictated by public policy.
Though in all of this, it is important to note that the amount of research and field work that has been completed in this area of study so far, cannot warrant any definite answers to the exacting proximate or ultimate causes of lactase persistence. The above articles are based off of limited data that has been collected so far, but as of yet we still don't know if we have found all of the haplotypes associated with lactase persistence in the world. There may still be some population in the world that has a completely different genetic approach to lactase persistence than neither the Northern Europeans nor the Africans possess and yet they are lactose tolerant.