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Identifying Genetic Variants Associated With Skin Pigmentation May Offer Disease Insight

Published on November 11, 2020 in Cornerstone Blog · Last updated 3 years 2 months ago


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Cell biologist Michael Marks, PhD, working with a cohort of ethnically diverse Africans, is in search of the genetic variants associated with the many different shades of skin tone. By studying these genes and how they affect skin pigmentation, new insights into cancer and other diseases may be gained.

mccannn [at] (By Nancy McCann)

One of the most distinguishing traits of the human race is skin color. From pale to dark and all shades in between, this pigmentation is critical for protection against the sun’s harmful ultraviolet rays and is altered in melanoma skin cancers, as well as genetic diseases. For something that affects the largest organ of our bodies, little is known about the genetic basis of normal human skin pigment variation.

In search of molecular and cellular answers to this knowledge deficit is Children’s Hospital of Philadelphia cell biologist Michael Marks, PhD, who studies the formation of melanosomes — organelles within melanocyte skin cells where the pigment melanin is made — and the diseases that develop when melanosomes don’t form properly, like albinism.

“We think that by trying to study these genes and how they affect pigmentation, we might also gain a lot of new insights into other diseases that we might not even have any clue about,” said Dr. Marks, who is also on faculty at the Perelman School of Medicine in the University of Pennsylvania. “It’s quite possible that if we understand how the products of these genes work, and they are involved in a disease like cancer, we might be able to develop drugs that can actually attack them.”


A woman of Nilo-Saharan-associated ancestry is part of the study’s unique cohort of ethnically diverse Africans with varied skin tones. Photo courtesy of Alessia Ranciaro.

With a million dollar grant from the National Institutes of Health, Dr. Marks and his co-primary investigators Elena Oancea, PhD, from Brown University, and geneticist Sarah Tishkoff, PhD, of the Perelman School of Medicine at Penn, seek to identify the genetic variants associated with skin pigmentation in a unique cohort of ethnically diverse Africans with varied skin tones. To date, most of the genome-wide studies for pigmentation have included Caucasian populations, even though there is little variation in skin tone among these populations.

“Take someone in Scandinavia versus somebody in southern Spain,” Dr. Marks said. “On a scale from low to high pigmentation, Caucasians are essentially at the bottom 10 percent. Whereas, African populations are particularly informative for discovering genes that regulate pigmentation because of their high genetic diversity and wide spectrum of skin tone.”

Building Blocks


Co-primary investigator Sarah Tishkoff, PhD, of the Perelman School of Medicine at Penn, works with study participants in Africa.

In an earlier study published in Science, Dr. Tishkoff worked with samples from a cohort of ethnically diverse Africans and screened for genes that differed among the populations, focusing primarily on what varied between the darkest skinned and the lightest skinned study participants. The identification of genes with previously unknown functions in pigmentation, such as MFSD12, was of most interest to Dr. Marks. Working with this new information, researchers in the Marks Lab discovered that the protein encoded by the MFSD12 gene does not live on melanosomes. It lives on another organelle, the lysosome, which is basically the digestive system of a cell.

“That was odd,” Dr. Marks said, “because most of the genes that affect pigmentation encode proteins that live on the melanosome. That means those two organelles inside of the melanocytes have to be talking to each other. This interaction between these two different organelles revealed something completely new about the inner workings of melanocytes: Crosstalk with lysosomes is influencing how well the melanosome is able to make melanin.”

Lysosome function is known to be off-kilter in cancers, Dr. Marks said, and MFSD12 is unusually highly expressed in a number of cancers, including melanoma, which means it might affect the ability of cancer cells to survive.

With the new grant and a larger cohort of samples, the researchers will study this phenomenon further to try to comprehend how lysosomes’ functions affect melanosomes’ functions. They will also dig deeper into the genetic analyses of 3,000 samples that have been whole genome sequenced. This represents a novel approach to try to understand pigmentation at a level that hasn’t been understood previously.

“What we’re really getting at here are genes that might influence pigmentation in subtle ways,” Dr. Marks said. “These genes that have been identified — although they have some role in pigmentation — it seems they might have more important roles in other systems.”