Penn Study Finds Genes Affecting Human Skin Color

Until now, most studies of genes impacting human skin color have focused on European populations, but a study from University of Pennsylvania geneticists has identified genetic variants associated with skin pigmentation in a range of diverse groups in Africa. Their findings can help explain the genetics associated with conditions like skin cancer and vitiligo, as well as the history of human evolution.

“We have identified new genetic variants that contribute to the genetic basis of one of the most strikingly variable traits in modern humans,” said Sarah Tishkoff, senior author of the study and a PIK Professor and the David and Lyn Silfen University Professor in Genetics and Biology with appointments in the Perelman School of Medicine and SAS. “When people think of skin color in Africa most would think of darker skin, but we show that within Africa there is a huge amount of variation, ranging from skin as light as some Asians to the darkest skin on a global level and everything in between. We identify genetic variants affecting these traits and show that mutations influencing light and dark skin have been around for a long time, since before the origin of modern humans.”

Dr. Tishkoff and her colleagues used a color meter to measure the light reflectance of the skin from the inside of the arms of more than 2,000 Africans. The measurements produced can be use to infer levels of the skin pigment melanin. Researchers took measurements from ethnically and genetically diverse populations, obtaining a range of different measurements: the lightest skin was observed in San populations in southern Africa and the darkest skin in Nilo-Saharan populations in eastern Africa.

 The researchers also obtained genetic information, examining over four million single nucleotide polymorphisms across the genome from nearly 1,600 people. Using this dataset, researchers did a genome-wide association study, finding four key areas of the genome where variation was closely correlated with skin color differences. 

The strongest associations were found in the region in and around the SLC24A5 gene, one variant of which is believed to have arisen more than 30,000 years ago and plays a role in the light skin colors found in European and some southern Asian populations. This variant was common in Ethiopian and Tanzanian populations which are known to have southeast Asian and Middle Eastern ancestry, suggesting that the variant may have been carried into Africa through those populations. 

The second strongest association was found with the region containing the MFSD12 gene, which is expressed at low levels in depigmented areas of the skin in individuals with vitiligo, a condition where skin loses pigment in some areas.

Researchers found that mutations in and around this gene that were associated with dark pigmentation were present at high frequencies in Nilo-Saharan populations, and across sub-Saharan populations who tend to have darker skin. They also found thee variants in South Asian Indian and Australo-Melanesian populations, who tend to have the darkest skin coloration outside of Africa. 

“Our data are consistent with a proposed early migration event of modern humans out of Africa along the southern coast of Asia and into Australo-Melanesia and a secondary migration event into other regions,” said Dr. Tishkoff. “However, it is also possible that there was a single African source population that contained genetic variants associated with both light and dark skin and that the variants associated with dark pigmentation were maintained only in South Asians and Australo-Melanesians and lost in other Eurasians due to natural selection.”

The MFSD12 gene is highly expressed in the cells that produce melanin. To verify the gene’s role in contributing to skin pigmentation, the researchers blocked expression of MFSD12 in cells in culture and found an increase in production of the pigment type responsible for brown and black hair, skin and eye color. Knocking out the gene in zebrafish caused a loss of cells that produce yellow pigment, and knocking out the gene in mice changed the color of their coat from agouti, caused by hairs with a red and yellow pigment, to a uniform gray by eliminating production of pheomelanin, a pigment also found in humans.

Michael Marks, a professor in pathology & laboratory medicine and physiology at CHOP and at Penn Medicine, collaborated in the study. He demonstrated that unlike other pigmentation genes, which are expressed mainly in melanosomes, the organelles where melanin is produced, the MFSD12 gene is expressed in lysosomes, the organelles that produce eumelanin. 

Finally, researchers found that genes in a region associated with skin pigmentation also play a role in melanoma risk and ultraviolet response. DDB1, a gene involved in repairing DNA after UV exposure, is thought to be involved. 

“Africans don’t get melanoma very often,” Dr. Tishkoff said. “The variants near these genes are highest in populations who live in areas of the highest ultraviolet light intensity, so it makes sense that they may be playing a role in UV protection.”