Human skin, hair, and eyes come in a huge variety of colors, but until now, scientists have only known a fraction of the genetic diversity driving this variation. Now, new research finds many dozens of genes that may produce this broad diversity.
In a genome-wide screening, researchers pinpointed 169 genes that are likely involved in human pigmentation, including 135 previously not known to play a role. Because of the wide distribution of pigments within the human body, some of these genes might be involved in disorders such as the skin cancer melanoma and even Parkinson's disease, which affects pigmented cells in a region of the brain important for movement, the study authors reported.
"Pigmentation by itself is interesting both in the context of human variation and evolution, but also in the context of disease," study leader Joanna Wysocka, a developmental biologist at Stanford University and the Howard Hughes Medical Institute, told Live Science.
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The diversity of coloration
Humans get their skin, eye and hair colors from a pigment called melanin, which comes in a brown-and-black form, called eumelanin, and a yellow-and-red form, called pheomelanin. How much of each melanin type is expressed, and in what balance, determines whether someone will have, for example, jet-black hair or fiery-red locks, and the same goes for skin tone and eye color. (The more melanin in the eye, the darker it is. People with blue eyes lack melanin in the iris, while people with green eyes have it in only one layer.)
Cells called melanocytes make melanin, but the difference in a dark-featured person and a light-featured person isn't in the number of melanocytes but in how much melanin those melanocytes produce, Wysocka said.
Previous studies had revealed some genes behind melanocyte maturation and melanin production, but only enough to explain between 23% and 35% of the variation in human skin color, Wysocka and her team wrote Thursday (Aug. 10) in the journal Science. To find out which other genes might contribute to human pigmentation, the researchers conducted a whole-genome study.
First, they had to differentiate high- and low-melanin melanocytes. To do so, they sorted cells in lab dishes, using the light-scattering properties of melanin, which describe how light behaves when it strikes the pigment. This new method, which involves shining fluorescent light on cells flowing through a channel, efficiently sorted both human melanocyte cells and melanoma cells, a cancerous version of melanocytes, by their melanin levels.
Next, the researchers used CRISPR-Cas9 gene-editing technology to systematically go into cells and mutate every gene, one at a time. If the broken gene was associated with melanin production or melanocyte maturation, the team reasoned, pigment levels in the melanocyte would fall and then be detected by the sorting tool.
This method returned the list of 169 genes, whose activity levels the researchers then checked in real human tissue — in this case, samples of infant foreskin donated after circumcisions. They found that nearly 70% of the genes were more active in babies with darker skin tones than in those with lighter skin tones.
Protective pigments
Not every gene necessarily drives melanin production, Wysocka said. While some determine how melanocytes mature and how much pigment they make, others are likely involved in a more peripheral way.
The genes largely fell into two categories: One group helped regulate genes, while the other influenced endosome trafficking. Endosomes are tiny transport packets within cells that shuttle materials around. The researchers closely analyzed one gene from each group and discovered that one was involved in the maturation of melanosomes, the tiny cellular organs that make and store the pigment within melanocytes. The other regulates the pH of the melanosomes, ensuring that the enzymes that piece together the pigments can function properly, Wysocka said.
Melanin isn't just ornamental; it protects the skin and eyes from sun damage. It also shows up in the brain in a structure called the substantia nigra, whose name means "black substance." The structure's high melanin content protects cells from reactive molecules, but in Parkinson's disease, substantia nigra cells die off, and thus melanin declines.
"It's an interesting question whether some of these pathways we have identified in melanocytes will also be important for neuroprotection in the brain," Wysocka said.
