Lactose Tolerance

The origin of domestic livestock (Goat, sheep, pig, cattle) started in the Middle East at least 10,000 years ago and spread from there all over the world. In the scientific publication “Domestication and early agriculture in the Mediterranean Basin: Origins, diffusion, and impact,” by Zeder et al., 2008, a comprehensive map is shown highlighting the historical importance of this region for mankind and its current diet.

The change of the diet from hunter/gatherers to farmers impacted not only the genetics of crop and livestock but also the genetics of humans. The most known and best described change is the ability of digesting and thus tolerating of milk as a food product, not only as infant but also as adult. Lactose, the sugar of milk, is the critical ingredient in milk that defines if someone can digest and thus tolerate milk or not. The responsible enzyme for digestion of lactose is called lactase, an enzyme that is highly expressed at early age in the small intestine and down-regulated after weaning, that's why adult hunter/gatherers are intolerant towards milk (lactose intolerant), while farmer populations can tolerate milk (lactose tolerant).

Dairy products (milk, yogurt, cheese) play an important role in the diet of the Iranian and Kurdish people, probably for thousands of years. It should be noted that Kurdish dairy products mostly rely on sheep and goat milk, while in Arabia camels were the main source of milk. In Europe bovine milk is dominating. Due to the size of camels and cattle it is very likely that Bedouins and Europeans consumed more dairy products than e.g. Iranians.

However, for quiet a while I am surprised to see how many Kurds are genetically lactose intolerant but physically lactose tolerant, even at high age. The best known SNP that is responsible for lactose tolerance is rs4988235.
1. People with "CC" at rs4988235 (also called C/T-13910) are genetically lactose intolerant; at 23andme it is "GG" (because MCM6 gene is in minus orientation but 23andme does not address it).
2. People with "CT" or "TT" at rs4988235 (also called C/T-13910) are genetically lactose tolerant; at 23andme it is "AG" or "AA" (because MCM6 gene is in minus orientation but 23andme does not address it)


Note: The actual gene for the enzyme lactase is called LCT and it is close to the gene MCM6. The MCM6 gene region seems to be important for the gene regulation of the LCT gene.

Let's take a look at the worldwide frequencies of rs4988235 (also called C/T-13910) in the Alfred database. The yellow bar shows the frequency of people that are genetically lactose intolerant (based on this one SNP), the green bar shows the frequency of people that are lactose tolerant:

Only 2-6% of Arabs, Bedouins, Druze, and Palestinians are genetically lactose tolerant.
Unfortunately, Northern Middle Eastern populations are not included in the ALFRED database but just looking at available data frequency of several Middle Eastern populations for this SNP rs4988235 it becomes obvious that rs4988235 cannot be only SNP responsible for lactose tolerance, there must be other independent mutations in the Middle Eastern genepool resulting in lactose tolerance.

Yuval Itan presented a nice map in his dissertation regarding the worldwide frequency of  C-13910:

So, where can we find more data about other SNPs that are related to lactose tolerance in the Middle East?

Enattah et al., 2008, showed that other Middle Eastern populations are lactose tolerant without having the mutation at SNP rs4988235 (also called C/T-13910). Instead they found mutations very close to rs4988235 (all in intron13) and one on exon17 of the MCM6 gene. The latter one on exon17 (T/C-3712) seems to be Arab specific.

The allele frequency of these SNPs in the Middle East (from Enattah et al., 2008):

Based on these data it seems that the major SNPs for Saudi-Arabian lactose tolerance are found:
1. It is T/G-13915 + T/C-3712, both SNPs always occur in pairs, which shows the strong positive selection for lactose tolerance and the common origin of both SNPs.
2. Even though 23andme is just determining T/G-13915 but not T/C-3712, it's okay because the two SNPs always come as pairs.

So, if you are an Arab (especially Saudi-Arabian) and lactose tolerant you most likely have at least one C allele at T/C-3712 and one G at T/G-13915.
The latter one is covered by 23andme, look up rs41380347 (Note: Again, because MCM6 gene is in the minus orientation and 23andme does not address it, all nucleotides are switched in the following manner: "G=>C", "C=>G", "T=>A" and "A=>T"):
rs41380347: If you have "AA" then you don't have the "Arabian lactose tolerance".
rs41380347: If you have "AC" or even "CC", then you do have the "Arabian lactose tolerance".

Finally, let's take a look at the worldwide frequencies of rs41380347 (also called T/G-13915) in the Alfred database. The yellow bar shows the frequency of people that are genetically lactose intolerant (based on this "Arabian" SNP), the green bar shows the frequency of people that are lactose tolerant: 

Yuval Itan presented a nice map in his dissertation regarding the worldwide frequency of T/G-13915 and two more African SNPs known to cause lactose persistence:

Here is another map summarizing all known lactose persistence SNPs and their worldwide frequencies:

Contrary, here is a map showing lactose persistence phenotype frequencies:

Summary:
Not all lactose tolerance SNPs are known, several SNPs resulting in lactose tolerance still need to be discovered. 


One way to discover the relevant regions in the human genome for such SNPs in the Middle Eastern genepool is by family studies:
If some of your family members are lactose tolerant while other family members are lactose intolerant and if you have enough 23andme results of both groups within your family, you might be able to pinpoint the genomic region by exclusion of not relevant genomic regions.

Prominent nose!

Today, I want to share some thoughts, actually a chain of thoughts about how very few hormonal changes may effect various aspects of the phenotype.

One of the most visible phenotypical differences between East- and West Eurasians are the eyes (epicanthic fold of many East Eurasians) and the nose ('Bigger' nose of West Eurasians compared to East Eurasians). The latter one is the topic of my post.

So what makes the nose grow big? Besides embryonic development, most guys with a big nose know the answer: puberty.

Puberty is characterized by a hormonal change maturing a child body to an adult body. For men, this means change of the voice, beard growth, body hair, and nose growth. All these mayor phenotypical changes are mainly caused by one molecule, Testosterone (and its derivative Dihydrotestosterone or short DHT) .

Testosterone and DHT are hormones produced in the testes (in the Leydig cells), so both are messengers, transmitted as a little molecule from one part of the body (testis) to another part of the body (e.g. nose, hair follicle, etc.) via the blood vessels (to be precise, the skin can produce DHT by converting Testosterone to DHT). To receive and 'read' this transmitted molecular information, these tissues express a specific receptor called Androgen receptor. The timing, time duration and the strength of the information (testosterone concentration in blood) as well as the sensitivity/number of the Androgen receptors contributes to final outcome of the phenotype.
For example, baldness is associated with a mutation in the Androgen receptor causing hypersensitivity, which makes body hair darker and longer, and hair on the scalp progressively thinner after adolescence. The Androgen receptor is located on the X-chromosome, so this baldness-causing mutation is inherited from the mother (recently, mutations on other chromosomes has been associated with baldness, too). More severe mutations in the gene of the Androgen receptor can cause a loss of function (Complete androgen insensitivity syndrome or CAIS). Male individuals with such a non-functional Androgen receptor have a female appearance and different from both men and women, they mostly lack secondary terminal hair (e.g. underarm hair).

To get an better idea where the Androgen receptor is present and most likely crucial for phenotypical outcome, I can recommend this website: http://biogps.org/#goto=genereport&id=367
Higher expression (and most likely more presence) of the Androgen receptor can be found in various tissues, most of them are important for sexual differentiation of men and women: skin, Deltoid muscle,  heart atrium, Skeletal muscles, in the epithelium of the Fallopian tube, Adipose tissue, breast (Breast ductal cells, breast lobular cells, mammary glands, nipple cross section), Penis, Prostate glands, Vulva, Vagina, Urethra, Cervix, Ovary, etc.

So, do men with more body hair have a more prominent nose? Viewed from a global perspective, I would say yes but I don't have any data for that.

Does the sexual dimorphism differ between the ethnic groups? Viewed from a global perspective, I would say yes but I don't have any data for that, either. I believe that sexual dimorphism is more pronounced in West Eurasians than in East Eurasians.

I believe that men with a more prominent nose are perceived as more dominant, similar to men with more facial hair. You might heard of the term 'Aristocratic nose', which is basically describing a bigger nose. And maybe big-nosed men are more dominant because Testosterone and the Androgen receptor are also present in the brain tissue where both together play an important role in behavioral outcome (e.g. aggression).

So, maybe there is a correlation between hormonal regulation, behavior, and 'nose' phenotype.  

So where did the 'prominent nose people' first emerge? Evolutionary speaking, it is believed that narrow noses are an adaption to colder climate, and bigger noses are an adaption to warmer climate, so the first people with a more prominent nose must have been living in a warmer climate. Interestingly, ethnic groups speaking Indo-European and Semitic languages tend to have more people with prominent noses.