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GWAS of Latin Americans Suggests Lip Shape Influenced by Locus of Denisovan Origin

NEW YORK — A new genome-wide association study has uncovered nearly three dozen gene regions that influence facial features, including a stretch of the human genome acquired from Denisovans that may influence lip shape.

An international team of researchers analyzed genetic and facial feature data from more than 6,000 volunteers from the Consortium for the Analysis of the Diversity and Evolution of Latin America (CANDELA) cohort. As they reported on Friday in Science Advances, the researchers' analysis nearly doubled the number of known genetic loci affecting face morphology.

Knowing which genes are involved in developing facial characteristics can also inform genetic studies of facial abnormalities, co-corresponding author Kaustubh Adhikari from University College London and the Open University said in an email. "If scientists know which genes those are, it can help them screen for such mutations when they get a new patient with abnormalities or when screening children, for example," he said.

Some of the loci, such as areas near the TBX15 and VPS13B genes, further hinted at how human and even mammalian facial features have evolved more broadly, and can inform genetic studies of facial abnormalities.

For their study, Adhikari and his colleagues generated facial profiles for 6,169 individuals from the CANDELA cohort, the overall average admixture of which was 51 percent European, 45 percent Native American, and 4 percent sub-Saharan African. In particular, they determined 59 facial measurements such as ear size, eye position, and nose height. 

In their analysis, 32 genomic regions exhibited genome-wide significance with at least one of the 59 facial traits and, conversely, 32 of the 59 traits were associated with at least one genomic region.

About two dozen of those regions have previously been tied to craniofacial morphology. For instance, the researchers noted a link between the PAX3 region and the position of the nasion — just above the bridge of the nose — similar to work they reported in 2016 that linked SNPs in the region to nasion position, bolstering its ties to facial morphology.

The researchers also uncovered SNPs in the WARS2/TBX15 gene region that were linked to two measures of lip shape. This region has previously been linked to outer ear traits as well as to other body characteristics and fat distribution. Additionally, among Greenland Inuits, this region has a strong signal of selection and overlaps with a region of introgression from archaic humans, likely Denisovans.

The CANDELA cohort, the researchers reported, also exhibited evidence of introgression that largely matched the one reported in Greenland Inuits as well as in Asian and Native American populations, indicating this genetic region affecting lip shape was inherited from Denisovans.

Adhikari noted that as early modern humans and archaic humans like Neanderthals and Denisovans moved into different regions, they evolved to adapt to their surroundings, such as the cold of Central Asia, and that this facial feature might represent such an adaptation. "We also know that some of the genes that helped us adapt were inherited from those ancient humans, Neanderthals and Denisovans, since these groups were already well adapted to those environments," he said. "So findings like these help us understand that story of evolution better."

Meanwhile, the researchers noted that a number of SNPs overlapping with the VPS13B gene were linked to the size of the columella — the tissue that divides the nostrils. In a follow-up mouse study, they found that this genomic region also affects mouse nose pointiness, indicating that its effect may be broadly shared among mammals.

Adhikari said that he and his colleagues are now applying other methods of assessing facial shape to their dataset and are including additional people into their cohort. He added that they are also using participants to examine other human traits.