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Skin color more complex than expected
Skin pigmentation is far more genetically complex than previously thought. Many studies have suggested that the genetics of skin pigmentation are simple. A small number of known genes, it was thought, account for nearly 50 percent of pigment variation. However, these studies rely on datasets consisting almost entirely of information from northern Eurasian populations - people residing mostly in higher latitudes.
Reporting in the November 30 issue of Cell, researchers from the Broad Institute of MIT and Harvard, Stanford University, and Stony Brook University report that while skin pigmentation is nearly 100 percent heritable, it is hardly a straightforward, Mendelian trait. By working closely with the KhoeSan, a group of populations indigenous to southern Africa, researchers found the genetics of skin pigmentation becomes progressively complex as populations live closer to the equator.
"Africa has the greatest amount of phenotypic [observable] variability in skin color, and yet it's been underrepresented in large scale endeavors," said Alicia Martin, a postdoctoral scientist in the lab of Broad Institute member Mark Daly. "There are some genes that are known to contribute to skin pigmentation, but by and large there are many more new genes that have not been discovered."
"We need to spend more time focusing on these understudied populations in order to gain deeper genetic insights," says Brenna Henn, assistant professor in the Department of Ecology and Evolution at Stony Brook University who, along with Martin, is a co-corresponding author.
The paper is a culmination of seven years of research that spanned several institutions, starting with a collaboration between Stellenbosch University in South Africa and Stanford University in Carlos Bustamante's lab, where Martin and Henn trained. Martin, Henn, and their colleagues spent a great deal of time with the KhoeSan, interviewing individuals, and taking anthropometric measurements (height, age, gender), and using a reflectometer to quantitatively measure skin color. In total, they accumulated data for approximately 400 individuals.
The researchers genotyped each sample - looking at hundreds of thousands of sites across the genome to identify genetic markers linked with pigmentation measures - to sequence areas of particular interest. They compared this information to data from nearly 5,000 individuals representing globally diverse populations throughout Africa, Asia, and Europe.
What they found is a counter-narrative to our common view on pigmentation.
The prevailing theory is that "directional selection" pushes pigmentation from dark to light in high latitudes and from light to dark in low latitudes. But Martin and Henn's data revealed the trajectory is more complex. Directional selection, as a guiding principle, seems to hold in latitudes far north moving in a single direction.
As populations move closer to the equator, a dynamic called "stabilizing selection" takes effect. An increasing number of genes begin to influence variability. Only about 10 percent of variation attributed to genes affects pigmentation.
In addition, researchers found some unexpected insight into genes associated with pigmentation. A mutation in one gene, SLC24A5, is thought to have arisen in Europe roughly 10,000 to 20,000 years ago. However, in the KhoeSan populations of the Kalahari Desert, it appears in a much higher frequency than recent European admixture. This indicates that SLC24A5 either actually arose in the KhoeSan, or entered the European population gene flow thousands of years earlier. "We're still teasing this apart," says Martin.
They also found that a gene called SMARCA2/VLDLR, not previously associated with pigmentation in humans, seems to play that role among the KhoeSan. Several different variantsof SMARCA2/VLDLR are all uniquely associated with pigmentation near these genes. Additionally, variants in these genes have been associated with pigmentation in animals as well.
"Southern African KhoeSan ancestry appears to neither lighten or darken skin," explains Martin, a member of both the Program in Medical and Population Genetics and the Stanley Center for Psychiatric Research at the Broad Institute. "Rather, it just increases variation. In fact, the KhoeSan are approximately fifty percent lighter than equatorial Africans. Ultimately, in northern latitudes pigmentation is more homogenous, while in lower latitudes, it's more diverse - both genetically and phenotypically."
"The full picture of the genetic architecture of skin pigmentation will not be complete unless we can represent diverse populations worldwide," said Henn.
•Skin pigmentation in Africans is far more polygenic than light skin in Eurasians
•Southern African KhoeSan populations have lighter skin compared to equatorial Africans
•Highly heritable KhoeSan skin color variation is poorly explained by known genes
•The study of African skin color identifies novel and canonical pigmentation genes.
Approximately 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed, with genetic architecture varying by latitude. We investigate polygenicity in the KhoeSan populations indigenous to southern Africa who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13, using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.
Keywords: pigmentation, human evolution, Africa, heritability, population genetics
Authors: Alicia R. Martin, Meng Lin, Julie M. Granka1, Justin W. Myrick, Xiaomin Liu, Alexandra Sockell, Elizabeth G. Atkinson, Cedric J. Werely, Marlo Möller, Manjinder S. Sandhu, David M. Kingsley, Eileen G. Hoal, Xiao Liu, Mark J. Daly, Marcus W. Feldman, Christopher R. Gignoux11, Carlos D. Bustamante, Brenna M. Henn13,'Correspondence information about the author Brenna M. Henn.
This work is part of the Stanley Center's global initiative to ensure that datasets increasingly represent individuals from developing countries.
This research was funded by the Stanford Center for Computational, Evolutionary, and Human Genomics.
About the Broad Institute of MIT and Harvard
Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods, and data openly to the entire scientific community.
Founded by MIT, Harvard, Harvard-affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff, and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.
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Approximately 15 genes are directly associated with skin color variation in humans. But, a global survey of skin pigmentation demonstrates pigmentation is more complex than previously assumed.