How does environmental calcium affect the amount of melanin available in certain populations and what are the evolutionary implications?


Earyn McGee, Department of Biology, Howard University '16


Introduction


The Earth is currently inhabited by more than seven billion people. These 7 billion people share about 99.9% of their DNA however; that .1% difference can produce an unimaginable amount of diversity making each person and individual who is very different from the person standing next to them. Although the diversity in human DNA creates the individual, groups of people who live in close proximity to one another share many phenotypic features. One of the most distinctive phenotypic features that aids different groups of people identify with one another is skin color.


How and why different populations differ in their skin pigmentation has been a hot topic in the scientific community for years now. However it’s such a hot topic not only due to scientific curiosity, but because of racism. The age of exploration began in the 15th century. At this point in time, many of the great nations in Europe where sending fleets of ships to find “new lands.” Columbus “discovered” the “Americas” in a quest sent by the Spanish to find new trade routes.  The Spanish weren’t the only ones to come to the Americas, the English came as well. 
In the beginning, the English colonized the East Coast of the North America. In the early years of colonialization, the English realized that they could turn the coast into an agricultural power house. They also realized that they didn’t have the resources to or man power to farm the land. At first, they used indentured servants, white and black. However, they soon learned that they could make a lot more money if they did not have to pay their workers and if they could have a lot more workers. Of course, they could put their own country man man and woman into chattel slavery, because that would create too much of an uproar. They could not enslave the Native Americans, because they were extremely susceptible to the diseases of the Europeans. The Europeans then turned their eyes to Africa. They went to Africa and stole the Africans away from their homelands to be enslaved in the Americas. This birthed the trans-Atlantic slave trade. In order to justify their actions, the Europeans spread rumors that the people of Africa were feeble minded and needed the Europeans to take care of them and that African peoples were less than human. In 2015, although slavery has been abolished in many parts of the world for slightly more than a hundred years, persons of African decedent all around the world still face discrimination simply, because their skin is darker than others. So what is it that makes such a variation in skin color and does environmental availability of calcium play a major role? 

Part 1


Produced in the cells called melanocytes at the boundary of the dermis and the epidermis, melanin is the most important pigment that influences skin, hair, and eye color.  Melanin is stored in vesicles called melanosomes, which are transferred in keratinocytes. Melanocytes produce two different types of melanin that have different chemical structures. Eumelanin creates brown/black pigments while pheomelanin produces red/yellow pigmentation. Most individuals have the same amount of melanocytes. Differences in skin color are observed because individuals can have variable numbers melanosomes in the keratinocytes. Melanosomes also differ in size and distribution. Individuals who have a lighter complexion have smaller and less dense melanosomes than that of individuals with a darker complexion. 
It is believed that most hominins had white skin because most of their bodies were covered in thick hair. Most modern primates have white skin covered my dark hair while the exposed, hairless, skin has a darker pigmentation. So as hominins evolved and moved to bipedalism and experienced brain expansion, it was necessary for the adaption of a system to keep the body cool. The adaption included hair loss and an increased number of sweat glands. However, in the blistering heat, pale skin would easily burn so it makes sense that hominins would evolve to have darker skin pigmentation. 


There are many widely accepted reasons as to why different populations have more melanin than others. Than main reason being that darker pigmentation helps reduce the harmful UV radiation emitted by the sun. Melanin not only absorbs and scatters UV radiation, specifically UV-B, thus preventing the radiation from reaching the deeper layers of the epidermis, but it also filters out harmful chemical byproducts of the radiation. A more debated reason is that the availability of calcium plays a role in the amount of melanin present in certain populations.
A purpose of calcium in the body is to promote bone and tooth development and to promote nervous system and muscle action. Calcium is stored in the skeleton. When calcium is low in intracellular fluid, hormones are released which release calcium from the bone and into the blood stream. In order to maintain necessary calcium levels, the body needs Vitamin D. Its main function is to promote calcium absorption from across the wall of the small intestine to the blood stream. The body can obtain Vitamin D from either food or UV radiation. Foods such as milk, cheese, eggs, yogurt, leafy greens, and seafood are good sources of calcium. When UV-B comes into contact with skin it produces it reacts with a precursor molecule for Vitamin D called 7-dehydrocholestorol (7-DHC). 7-DHC is then photochemically converted into pre-vitamin D. Over the course of two to three days pre-vitamin D is converted to vitamin D and is then released into the blood vessels of the dermis. It may have been necessary for modern humans who migrated out of Africa and into cooler climates to adapt with lighting of skin in order to absorb more vitamin D.


If the body is deficient of calcium, infants and children can develop rickets and adults can develop osteomalacia. Rickets is a disease where growing bones have a defect in calcification. This makes it hard for the skeleton to support the body because the bones are weak. Symptoms of rickets include deformities of the long bones such as bowed legs, rachitic rosary, and deformities to the pelvis. In adulthood, pelvic deformities can be very difficult for women as it would make childbirth difficult or even fatal. A narrowing of the birth canal makes its difficult for the child to move through. Osteomalacia is a softening of the bones. Excessive calcium in the body can be toxic causing hypocalcemia. Symptoms include poor appetite, frequent urination, nausea and vomiting, weakness, and kidney problems. 
Although over exposure to UV radiation can cause sun burn, it has not been shown to lead to a toxic level of synthesis of pre-vitamin D. Pre-vitamin D can isomerize into inactive forms. Most populations who lack vitamin D from UV radiation can make it up in their diets. For example populations in artic regions eat large amounts of oily fish.  That is why populations there can afford to keep their darker complexion. Eurasians drink farm milk from cows to supplement their calcium intake. There is not much evidence of rickets or osteomalacia in ancient populations. The need for adequate calcium uptake through UV radiation may play some minor role in the pigmentation differences of populations but it is most likely not the deciding factor. 

Part 2

    Comparative genomics was used in identifying genes that influence pigmentation. Over 370 genes have been identified in mice that affect coat color and over 170 have of these genes have been identified in human orthologs. Mutations in some genes can lead to albinism. Mutations in the TYR, OCA2, TYRP, and SLC45A2 genes cause various types of oculocutaneous albinism. This leads to lack of pigmentation in skin and eyes. Some mutations for example a mutation in the gene PAX3, can cause deafness because melanin is necessary in the cochlea for proper development of hearing.  Genes for skin color seem to go under natural selection. For example the gene SLC24A5 seems to have gone through positive selection, producing the light skin phenotype in Europeans. There is a high variation in the genes for pigmentation. The ancestral allele in East Asians is Ala111, however, they have paler skin than other populations with the same allele. 


The melanocortin 1 receptor (MC1R) gene is responsible for regulating the melanocortin 1 receptor. It is located on the q arm of chromosome 16. This receptor controls which type of melanin is made. If it is working properly and is activated it produces eumelanin, which gives the phenotype of brown or black skin. If the melanocortin 1 receptor is not working correctly, is blocked, or is not activated, then the melanocytes only make pheomelanin resulting in the lighter skin phenotype. Three alleles of the MC1R gene are thought to produce the phenotype of red hair, fair skin, and freckles. Another allele is thought to produce fair skin and blonde hair. Mutations in the MC1R gene can lead to melanoma. This is one of the most dangerous forms of skin cancer. It happens when intense UV radiation, from the skin or from tanning beds, come in contact with skin cells. These skin cells then multiply quickly multiply and produce malignant tumors. These tumors originate in the melanocytes. A mutation in this gene can also cause oculocutaneous albinism. Mutations in the MC1R gene and in the OCA2 genes can lead to albinism, however, these individuals are more likely to have red hair as opposed to yellow, blonde, or light brown hair.


There are many types of albinism in addition to OCA2 albinism for example OCA1, caused by a flaw in the tyrosine enzyme, which has two subtypes OCA1a and OCA1b.  OCA1 is more severe than OCA2. Individuals with an OCA1a defect lack any kind of pigmentation. They have white skin and white hair, and very pale eyes. These individuals do not produce any melanin throughout their lifetime. Exposure to sunlight will cause them to burn however they will not tan. In order to tan, melanocytes need to be actively working to produce melanin when it comes into contact with UV light. Individuals with an OCA1b defect are born with pale hair, eyes, and skin. They may produce some melanin later on in life.  If the skin is not fully protected throughout life, individuals may develop rough and thick skin. They can also develop premalignant lesions and skin cancer. If these individuals do develop cancer they are most likely to develop basal cell carcinoma and squamous cell carcinoma. They are unlikely to develop melanoma as these individuals do not produce melanin. In addition to the pale skin, hair, and eyes, these individuals tend to suffer from nystagmus throughout their lives. Nystagmus causes reduced vision and involuntary movement in the eyes.  


    When there is a defect in the TYRP1 gene, individuals can develop OAC3 albinism.  This type normally affects populations that would otherwise have a darker complexion. Principally black South Africans develop this kind of albinism. OCA3 is characterized by reddish/brown skin, reddish hair and hazel eyes. Like most other forms of albinism, it is inherited and autosomal recessive. Frequently found in individuals of East Asian descent, OCA4 albinism is caused by a defect in the SLC45A2 gene. It reduces the production of melanin. It is similar to OAC2.
    

There are three very rare forms of albinism Hermansky-Pudlak syndrome (HPS) , Chediak-Higashi syndrome, and Griscelli syndrome (GS).  Like other forms of albinism, HPS causes pale skin, pale eyes, white hair, and nystagmus. However, individuals who suffer from HPS are more likely to develop skin damage and cancer when exposed to excessive sun exposure.  In addition, these individuals do not clot blood properly so they bruise easily and have prolonged bleeding. They may also develop pulmonary fibrosis in their thirty’s. Normally, once individuals develop pulmonary fibrosis, because the condition gets worse swiftly, they do not live past ten years. There are 9 types of HPS, with types 1 and 4 being the most severe, types 1, 2, and 4 tend to be the only ones where people with HPS develop pulmonary fibrosis. Types 3, 5, and 6 seem to be the mildest. More research needs to be conducted to understand the symptoms and severity of types 7,8, and 9. Individuals may also develop granulomatous colitis, inflammation of the large intestine, and kidney failure, however, this is uncommon. There are at least 9 genes that affect the proteins that make 4 different protein complexes that form lysosome-related organelles (LROs). These organelles are highly specialized, they are found in melanocytes, blood clotting cells, and lung cells. Mutations in these genes prevent LROs from producing and distributing melanin. The gene also prevents platelets from sticking together and prevents LROs from working properly in lung cells. In 75 percent of the cases of HPS from Puerto Rico, HPS is caused by a mutation in the HPS1 gene. It also causes HPS in 45 percent in other populations. In 25 percent of known cases of HPS in Puerto Rico, a mutation in the HPS3 gene causes the syndrome. A HPS3 gene mutation affects only about 20 percent of individuals from other populations. 


    In addition to the symptoms caused by OCA, Chediak-Higashi syndrome affects many other parts of the body. It is a very rare disorder with only 200 cases reported worldwide. Like HPS, it can prevent proper coagulation. It also prevents the immune system from working properly. Persons with Chediak-Higashi syndrome are sickly and have to fight potentially life threatening infections throughout their lives. Chediak-Higashi syndrome can also affect the nervous system, which leads to weakness, difficulty walking, and seizures. Individuals suffering with Chediak-Higashi syndrome need immediate, proper, and successful healthcare. If they do not receive it, in childhood, they can reach a stage of Chediak-Higashi syndrome, called the accelerated stage. This stage, thought to be caused by a viral infection, causes the white blood cells to swiftly reproduce and attack the person’s internal organs. This leads to fever, abnormal bleeding, and organ failure. It can be fatal in children. Most people with Chediak-Higashi syndrome are born with it, however, there are a few people who develop a milder form of the syndrome later in life. These individuals will start to see changes in pigmentation. They are also at risk of developing severe and progressive neurological disorders, for example, they will begin to experience difficulty moving, difficulty with balance, tremors, reduced feeling and strength in the extremities, and a decrease in brain function. 


    A mutation in the LYST gene prevents normal function of LROs. It also prevents related other structures in cells throughout the body from having the proper size, shape, and function. This is what causes Chediak-Higashi syndrome. This mutation can cause lysosomes in certain immune cells to become enlarged, thus preventing the immune cells from properly protecting the body from invasive viruses and bacteria. The mutation causes melanosomes to become enlarged which prevents melanin from being able to give skin, hair, and eyes the proper pigmentation. 


    Out of the three more rare albinism disorders, Griscelli syndrome (GS) probably the most rare with only 60 cases being reported in the world since 1978. It is caused by a mutation in one of three genes and it can also affect the nervous system. This disorder is normally fatal and people who suffer from it, normally, do not see their teenage years. There are three different types of GS, type 1, type 2, and type 3. It is thought by some researchers that type 1 GS and another disease, Elejade disease, are in fact the same disorder. They have the same symptoms which are delayed development, intellectual disabilities, seizures, and weak muscle tone. Individuals with type 2 do not have the same neurological disorders as those with type 1, however, they may have issues with their immune systems. In addition to having reoccurring infections, they may develop hemophagocytic lymphohistiocytosis, which can cause too many active T-lymphocytes and macrophages to be produced. The activity of too many of these cells can cause damage to organs and tissue throughout the body. This can cause life threatening problems. Individuals with type 3 of this disorder have the mildest type as they do not experience the neurological problems or immune system problems.


    The three types of GS are caused by a mutation in three different genes. Type 1 is caused by mutations in the MYO5A gene, type 2 by mutations in the RAB27A gene, and type 3 by mutations in the MLPH gene. Mutations in these genes prevent the melanosomes from being transported from close to the center of the melanocytes to the edge of the cell. This movement is what gives the skin, hair, and eyes pigmentation. When working properly, the MYO5A transport materials in neurons and the RAB27A gene is supposed to produce a protein in immune cells that release compounds that assist in killing foreign cells. 


    Vitiligo is a skin condition that is not characterized as oculocutaneous. Individuals who suffer from this disease experience loss in pigmentation in patches on their bodies. It usually manifests during a persons’ 20’s to 30’s. This happens because melanocytes stop producing melanin or these cells die. Like albinism, this can affect people of all skin tones. It is, however, more noticeable on people who have darker skin. It is not clear what cause vitiligo. Research suggests it may be caused by autoimmune abnormalities, genetic abnormalities, oxidative stress, neural abnormalities, or viral causes. Regardless of the cause vitiligo can be either segmental vitiligo or non-segmental vitiligo. Non-segmental vitiligo is characterized by spots of depigmentation that seem to show some symmetry. Some subclasses of vitiligo include generalized vitiligo, which is most commonly and is characterized by randomly distributed patches of depigmentation, universal vitiligo which causes depigmentation over most of the body, focal vitiligo which is most common in children, Acrofacial vitiligo which occurs on the fingers and periorficial areas, and finally mucosal vitiligo which only causes depigmentation in mucous membranes. Segmental vitiligo is more severe than non-segmental and is often connected to diseases. 

Conclusion and Discussion

Proper calcium intake is an important part in being healthy. Calcium can be obtained from melanocyte cells processing UV radiation to turn it into vitamin D or from consuming enough vitamin D rich foods. It is important for proper calcium intake to prevent diseases, such as rickets. Rickets cause weak bones and deformities in the bones. Deformities in the pelvis can make childbirth fatal for mother and child. Populations that live in geographical regions where they receive prolonged and intense exposure from the sun need more vitamin D from their diet as they typically have darker skin pigmentation that reduces the amount of UV radiation absorbed to be used to produce vitamin D.  Populations that live in areas with less extreme UV radiation tend to have lighter skin and thus can absorb more UV radiation to be used to produce vitamin D. However, populations, such as the Inuit, have darker skin but live in colder climates. These populations supplement their calcium intake with oily fish. Leading many scientists to believe that the amount of environmental calcium affecting skin pigmentation is a “So, So” story.  


There are many genes that affect pigmentation, however, when some of these genes experience mutations, it can cause mild disorders, such as vitiligo or extreme disorders such as Hermansky-Pudlak syndrome. Mutations in genes that cause albinism can be very harmful, not only to individuals in climates that receive prolonged and intense sun light, but also whole populations. It can cause a complete lack of melanin, which, if the sufferer was not properly clothe or properly applying sun screen, can cause sun burn and eventually cancer. It also reduces the sufferers’ ability to see. Albinism in ancient populations could prove fatal because not only was there no sunscreen, there is a good chance these people we not properly clothe so the intense sun burn could possibly maim where they could not keep up with their group or out run predators. It could also prevent them from seeing predators. Both situations would end result in the death of the person. Today, albinism is rare in most parts of the world were only 1 in 17,000 people have albinism. However, in Africa those rates are much higher. In Tanzania 1 in 1,429 people have some form of albinism. 


It is thought that hominins, like most modern primates, had white skin under their thick dark hair. However, as they evolve towards bipedalism and experienced brain expansion, they lost that hair, in order to prevent overheating.  This would make it necessary for them also to evolve a trait that would protect their skin from burning under the sun, darker skin. Could it be possible that not all modern humans evolved to have darker skin, when others did and these populations migrated out of Africa before having white skin was too detrimental to their survival? Could it also be possible that all modern humans evolved to have dark skin yet some genes that coded for lighter skin existed in the genome, that work similar to the recessive genes that cause albinism, cause individuals in dark skinned populations to be born with lighter skinned and these individuals also migrated out of Africa before the pigmentation could become fatal for them? These are all questions that there are currently not answered and would need much more research done to be answered. 


What scientists do know is that skin pigmentation like any adaptation has its benefits in certain geographical locations and its draw backs in others. Scientists have done enough research to know that there is no such thing as races of people. No one group of people should be persecuted, because of their skin pigmentation. Instead, that energy should be directed at helping individuals with life threatening illnesses due to mutations in their genes. Although people come in all shades we still share 99.9% of our DNA. ***

References

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Jobling, Mark A., Matthew Hurles, and Chris Tyler-Smith. Human Evolutionary Genetics: Origins, Peoples & Disease. New York: Garland Science, 2004. Print.
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Earyn McGee

Cobb Lab