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Genetic Architecture of Human Skin Pigmentation More Complex Than Previously Thought

NEW YORK (GenomeWeb) – The genetic architecture of human skin pigmentation is more complex than previously thought, according to a new study.

Previous studies of genes involved in skin pigmentation have relied on analyses of people of Eurasian or admixed African-American ancestry, and found pigmentation to be the work of about a dozen genes. But by studying an African population that exhibits a range of pigmentation levels, a State University of New York at Stony Brook-led team of researchers found the genetics of skin tone to be more complicated.

Stony Brook's Brenna Henn and her colleagues measured the skin pigmentation of more than 400 KhoeSan individuals and genotyped them. As they reported in Cell today, the researchers found that genes previously linked to pigmentation explain only a sliver of variance in skin color seen among the KhoeSan, and suggested that skin pigmentation is a complex, polygenic trait. 

"Light skin pigmentation in the KhoeSan appears to be due to a combination of many small-effect mutations as well as some large-effect variants," Henn said in a statement.

A study appearing in Science last month likewise found that other, unappreciated variants contribute to variation in skin pigmentation, particularly among African populations.

In this study, Henn and her colleagues assessed the skin pigmentation of 479 KhoeSan individuals using a device that measures light reflectance at inner arm sites that are less exposed to the sun. While the researchers found that skin pigmentation is highly heritable among the KhoeSan, they also noted that more genes are involved than the ones uncovered in people of Eurasian descent.

At the same time, the researchers noted that there was a strong correlation between latitude and average skin pigmentation, as previous studies have indicated. When they compared their cohort to global populations, they found that populations with lighter skin tones that live in northern regions have reduced genetic variation compared to those closer to the equator. This, they said, could explain why those studies of Eurasian populations uncovered a near-Mendelian inheritance pattern for pigmentation. They also argued that different selection forces are at play on pigmentation at different latitudes.

Henn and her colleagues tested the contribution of three different gene sets to the heritability of pigmentation among the KhoeSan: 14 genes linked to skin pigmentation in other human populations; 50 genes uncovered in association, positive selection, or model organisms studies;or 50 loci they uncovered in a genome-wide association study of pigmentation in the KhoeSan. Based on this analysis, the researchers found that variants in genes in the first two gene sets did not explain a significant portion of the heritability of pigmentation.

Instead, they found that the third set of genes — ones they uncovered in a GWAS of pigmentation in the KhoeSan — explained a small portion of the heritability of pigmentation. But, they noted, most pigmentation genes remain unknown.

In that GWAS of 216 KhoeSan individuals, the researchers traced association signals to near canonical pigmentation genes like TYRP1 and SLC24A5 as well as to other spots in the genome. Through a targeted sequencing analysis of 36 candidate pigmentation genes in 451 KhoeSan individuals, the researchers further found that the strongest signal emanated from SLC24A5, which has also been linked to pigmentation in Europeans.

They also noted a number of low-frequency SNPs near additional genes, including ones with no known roles in pigmentation.

Based on their findings, the researchers suggested that lighter skin pigmentation in the KhoeSan stems from a combination of small-effect and large-effect mutations, some of which cannot be found in Eurasian populations.