Genetics of Skin Color Defies Evolution

We used to believe skin color
was produced by 3 genes.
The number is now 135.

by Jerry Bergman, PhD

One observation I have made in my field of human anatomy and physiology is that as science progresses, the body is revealed to be more complex and evolution less probable. A seemingly simple example has been the conclusion that skin, hair, and eye color are the result of only three genes. Each of these three genes regulate the amount of the light-absorbing pigment called melanin. The genes have two forms, a dark-skin allele (A, B, and C) and a light-skin allele (a, b, and c).[1] Melanin gives hair and skin its color, specifically shades of brown, red, and black. Grey hairs contain very few melanin granules spread throughout the hair. White hairs contain no melanin and the whiteness is due to how the hair without pigment reflects light.[2] The pigments’ main function is to protect epidermis cells from damage due to cancer-causing ultraviolet (UV) radiation.

Melanin is produced within melanosomes which are located inside melanin-producing pigment cells called melanocytes. All humans have the same number of melanocytes. Only the amount of melanin they produce differs, causing a wide scope of human skin- and hair-color variations.[3]

It was for decades assumed that the production of melanin was a simple process of secretion of pigment by melanocyte enzymes that were involved in melanin synthesis. Melanin has long been known to be extremely important for health. It not only protects the skin and eyes from the harmful effects of UV irradiation, but also protects the neural cells in the skin from toxic insults, and is even required for sound conduction in the inner ear. Aberrant melanogenesis regulation causes skin disorders (such as melasma and vitiligo), ophthalmologic disorders (age-related macular degeneration) and neurologic and auditory disorders.[4] Furthermore, in vertebrates, melanocytes are important not only for skin pigmentation, hair and feather coloration, but also for their ability to produce and distribute melanin to the surrounding keratinocytes.[5]

The New Research

Up until now it was unknown how different amounts of melanin are produced. To find out, researchers in the Department of Chemical and Systems Biology at Stanford University School of Medicine used CRISPR-Cas9 to genetically engineer cells by systematically removing over 20,000 genes from hundreds of millions of melanocytes and then observing the impact of the removal of melanin production. Detecting and quantifying the melanin-producing activity of melanocytes was achieved by passing light through them. It was determined that the light was either absorbed or scattered by the melanin inside the cells.

These results were observed because melanin-producing melanosomes cause light to scatter to a greater degree in cells with large amounts of melanin.  Side-scatter of flow cytometry was then used to separate cells according to melanin levels. The cells were then analyzed to determine the identity of melanin-modifying genes. Both new and previously known genes that play important roles in regulating melanin production in humans were located. The researchers determined that there were 169 functionally diverse genes that impacted melanin production, including 135 not previously associated with pigmentation. One newly discovered gene produced a protein that regulated melanin synthesis by controlling the acidity of the melanosomes.

Darker pigmentation was required to protect against ultraviolet radiation in areas of the Earth’s surface closer to the equator and for people who spend hours in direct sunlight. For humans living in areas with less-direct sunlight, or fewer hours of daylight, less melanin was required. This condition would then allow them to absorb more sunlight. This is important because sunlight is required to produce critically important vitamin D. Vitamin D has an important role in helping your body absorb calcium and supporting the muscles required to avoid falls. Children require vitamin D to build strong bones, and adults to maintain strong and healthy bones. Clinical applications of the research include the use of melanin-modifying drugs which could treat vitiligo, (patches of melanin loss, which produce white skin). Other objectives of the research include to understand the many functions of melanin, including to protect the neural cells and its role in sound conduction in the inner ear.

Sun Tanning

Sun tanning produces the changes in melanin production shown in figure 1. All persons regardless of skin color respond to sunlight by tanning, but some persons, specifically those who have darker skin, have more genetic protection to sunlight. The darker the skin, the more the protection. Dark skinned persons can experience sunburn, they just have more protection and it takes longer for damage to occur. For persons born with darker skin, close to their entire body is close to what is shown on the left of figure 1. All of the genes located in the Bajpai et al., research function in all persons regardless of their skin color. The only exception is in cases where mutations damage the system, such as in cases of melasma or vitiligo. The difference is the size and number of melanosomes which is partly genetic:

For the same body region, light- and dark-skinned individuals have similar numbers of melanocytes (there is considerable variation between different body regions), but pigment-containing organelles, called melanosomes, are larger, more numerous, and more pigmented in dark compared to intermediate compared to light skin, corresponding to individuals whose recent ancestors were from Africa, Asia, or Europe, respectively.[6]

One gene, or at most two genes, control the specific hereditary differences between people but all of the genes are required in all persons to regulate the melanin system.[7]

For several reasons, melanin production in fungi and bacteria enables them to be more pathogenic to humans or crops. Researchers could develop effective interventions against these microbes and their diseases by discovering and destroying their melanin-producing genes.

Melanin production as a result of tanning, i.e., the effect of sunlight. The left side of the illustration shows the results of exposure to sunlight. Consequently, much larger amounts of the UV-protective pigment were produced by melanocytes than shown on the right side, which was not exposed to sunlight. The brown cells with the black center show the location of the melanocytes. From Wiki Commons.

Summary

A previously assumed “simple” system called sun-tanning, which produces various shades of brown skin, has turned out to be enormously complex. The specific functions for most of the newly identified 135 genes involved in melanin production have yet to be determined. Likely, if the past is any indicator, these genes will prove to have several functions, not only for melanin production, but also in other human-body operational processes. As a result, the evolution of this once “simple” system has become even less probable than before.

References

[1] Ganesan, Anand, et al. Genome-wide siRNA-based functional genomics of pigmentation identifies novel genes and pathways that impact melanogenesis in human cells. PLoS Genetics 4(12):e1000298, 2008.

[2] DeLozier, Josh. Researchers identify 135 new melanin genes responsible for pigmentation. Science Daily; https://www.sciencedaily.com/releases/2023/08/230811115439.htm, 11 August 2023.

[3] Bajpai, Vivek K., et al. A genome-wide genetic screen uncovers determinants of human pigmentation. Science 381(6658):DOI: 10.1126/science.ade6289, 11 August 2023.

[4] Ganesan, et al., 2008.

[5] Sulaimon, Shola S., and Barbara E. Kitchell. The biology of melanocytes. Veterinary Dermatology 14)2):57-65, April 2003.

[6] Barsh G. S. et al.  What Controls Variation in Human Skin Color? PLoS Biology. 1(1): e27. https://doi.org/10.1371/journal.pbio.0000027. 2003.

[7] Naik, Piyu Parth and Syed Nadir Farrukh. Influence of Ethnicities and Skin Color Variations in Different Populations: A Review. Skin Pharmacology and  Physiology,  35(2): 65–76. 2022.

Dr. Jerry Bergman has taught biology, genetics, chemistry, biochemistry, anthropology, geology, and microbiology for over 40 years at several colleges and universities including Bowling Green State University, Medical College of Ohio where he was a research associate in experimental pathology, and The University of Toledo. He is a graduate of the Medical College of Ohio, Wayne State University in Detroit, the University of Toledo, and Bowling Green State University. He has over 1,300 publications in 12 languages and 40 books and monographs. His books and textbooks that include chapters that he authored are in over 1,800 college libraries in 27 countries. So far over 80,000 copies of the 60 books and monographs that he has authored or co-authored are in print. For more articles by Dr Bergman, see his Author Profile.