Abstract
We study the gene MUC19, for which modern humans carry a Denisovan-like haplotype. MUC19 is a mucin, a glycoprotein that forms gels with various biological functions. We find the diagnostic variants for the Denisovan-like MUC19 haplotype at high frequencies in admixed Latin American individuals among global populations, and at highest frequency in 23 ancient Indigenous American individuals, all predating population admixture with Europeans and Africans. We find that the Denisovan-like MUC19 haplotype carries a higher copy number of a 30 base-pair variable number tandem repeat, and that copy numbers of this repeat are exceedingly high in American populations and are under positive selection. This study provides the first example of positive selection acting on archaic alleles at coding sites and VNTRs. Finally, we find that some Neanderthals carry the Denisovan-like MUC19 haplotype, and that it was likely introgressed into human populations through Neanderthal introgression rather than Denisovan introgression.
One-Sentence Summary Modern humans and Neanderthals carry a Denisovan variant of the MUC19 gene, which is under positive selection in populations of Indigenous American ancestry.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
1) We carefully considered the robustness of our null expectation for the PBS analyses. In particular, we addressed concerns about how a strong population bottleneck during the emergence of the Mexican population would impact that null distribution, and came up with multiple sanity checks to eliminate this possibility. 2) We used iHS and U30 statistics to provide additional evidence that MUC19 exhibits signatures of positive selection. We also show that PBS has power to detect adaptive introgression. 3) We phased the Chagyriskaya and Vindija Neanderthals and show that they carry one copy of the Denisovan-like haplotype. We confirm that this haplotype is closest to the haplotype in MXL. 4) We clarify the quantification of VNTRs in the archaic individuals, we address the technical limitations of such analyses, and our logic for why the copy-number expansion we see in humans is not expected to also be found in the sequenced Denisovan individual. 5) We show that in MXL, there is a positive correlation between the number of copies of the archaic haplotype with the number of repeat copies in MUC19.