2025-08-21 ブラウン大学
<関連情報>
- https://www.brown.edu/news/2025-08-21/denisovan-genes
- https://www.science.org/doi/10.1126/science.adl0882
MUC19遺伝子:反復的な導入と自然選択の進化史 The MUC19 gene: An evolutionary history of recurrent introgression and natural selection
Fernando A. Villanea, David Peede, Eli J. Kaufman, Valeria Añorve-Garibay, […] , and Emilia Huerta-Sánchez
Science Published:21 Aug 2025
DOI:https://doi.org/10.1126/science.adl0882
Editor’s summary
Introgression from Neanderthals and Denisovans into modern humans has been widely documented. However, how selection has affected introgressed genomic regions has been inconsistently studied across populations. Villanea et al. characterized an introgressed region around the gene MUC19 in admixed American individuals that results in expanded copy number of a tandem repeat. This haplotype features multiple Denisovan variants, although it likely entered human populations through a Neanderthal intermediate. The patterns of positive selection indicate that this introgression occurred in Indigenous Americans during their migration to the Americas. How this change was adaptive for these populations has yet to be determined, but this work does disentangle a complex selection signal in these understudied groups. —Corinne Simonti
Structured Abstract
INTRODUCTION
Modern human genomes contain a small number of archaic variants, the legacy of past interbreeding events with Neanderthals and Denisovans. Most of these variants are putatively neutral, but some archaic variants found in modern humans have been targets of positive natural selection and may have been pivotal for adapting to new environments as humans populated the world. American populations encountered a myriad of novel environments, providing the opportunity for natural selection to favor archaic variants in these new environmental contexts. Indigenous and admixed American populations have been understudied in this regard but present great potential for studying the underlying evolutionary processes of local adaptation.
RATIONALE
Previous studies identified the gene MUC19—which codes for a mucin involved in immunity—as a candidate for introgression from Denisovans as well as a candidate for positive natural selection in present-day Indigenous and admixed American populations. Therefore, we sought to confirm and further characterize signatures of both archaic introgression and positive selection at MUC19, with particular interest in modern and ancient American populations.
RESULTS
We identify an archaic haplotype segregating at high frequency in most admixed American populations, and among ancient genomes from 23 ancient Indigenous American individuals who predate admixture with Europeans and Africans. We conclude that the archaic haplotype has undergone positive natural selection in these populations, which is tied to their Indigenous components of ancestry. We also find that modern admixed American individuals exhibit an elevated number of variable number tandem repeats (VNTRs) at MUC19, which codes for the functional domain of the MUC19 protein, where it binds to oligosaccharides to form a glycoprotein, a characteristic of the mucins. Remarkably, we find an association between the number of VNTRs and the number of introgressed haplotypes; individuals harboring introgressed haplotypes tend to have a higher number of VNTRs. In addition to the differences in VNTRs, we find that the archaic MUC19 haplotype contains nine Denisovan-specific, nonsynonymous variants found at high frequencies in American populations. Finally, we observed that the Denisovan-specific variants are contained in a 72-kb region of the MUC19 gene, but that region is embedded in a larger 742-kb region that contains Neanderthal-specific variants. When we studied MUC19 in three high-coverage Neanderthal individuals, we found that the Chagyrskaya and Vindija Neanderthals carry the Denisovan-like haplotype in its heterozygous form. These two Neanderthals also carry another haplotype that is shared with the Altai Neanderthals.
CONCLUSION
Our study identifies several aspects of the gene MUC19 that highlight its importance for studying adaptive introgression: One of the haplotypes that span this gene in modern humans is of archaic origin, and modern humans inherited this haplotype from Neanderthals who likely inherited it from Denisovans. Then, as modern human populations expanded into the Americas, our results suggest that they experienced a massive coding VNTR expansion, which occurred on an archaic haplotype background in MUC19. The functional impact of the variation at this gene may help explain how mainland Indigenous Americans adapted to their environments, which remains underexplored. Our results point to a complex pattern of multiple introgression events, from Denisovans to Neanderthals and Neanderthals to modern humans, which may have later played a distinct role in the evolutionary history of Indigenous American populations.
The proposed evolutionary history of MUC19.
The Denisovan-like haplotype (in orange) was first introgressed from Denisovans into Neanderthals and then introgressed into modern humans. The introgressed haplotype later experienced positive selection in populations from the Americas. The introgressed MUC19 haplotype is composed of a 742-kb region that contains Neanderthal-specific variants (blue). Embedded within this Neanderthal-like region is a 72-kb region containing a high density of Denisovan-specific variants (orange), and an exonic variable number tandem repeat (VNTR) region (gray). The box below the 742-kb region depicts zooming into the MUC19 VNTR region, in which admixed American individuals carry an elevated number of tandem repeat copies.
Abstract
We study the gene MUC19, for which some modern humans carry a Denisovan-like haplotype. MUC19 is a mucin, a glycoprotein that forms gels with various biological functions. We find diagnostic variants for the Denisovan-like MUC19 haplotype at high frequencies in admixed American individuals and at highest frequency in 23 ancient Indigenous American individuals, all pre-dating population admixture with Europeans and Africans. We find that the Denisovan-like MUC19 haplotype is under positive selection and 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 admixed American populations. Finally, we find that some Neanderthals carry the Denisovan-like MUC19 haplotype, and that it was likely introgressed into modern human populations through Neanderthal introgression rather than Denisovan introgression.
