I have already posted about this paper paper published by Villanea et al., (2025) that looked into the MUC19 gene and suggested that it introgressed into Eurasians and Native Americans through Neanderthals, but that its ultimate origin was Denisovan. The interesting part of this research, is that it was also found in a Sub-Saharan individual of the San people. How did it get there? Furthermore the Migration Route into America is not clarified. I decided to give it another go.
The paper is this one: Villanea, F. A., Peede, D., Kaufman, E. J., Añorve-Garibay, V., Chevy, E. T., Villa-Islas, V., Witt, K. E., Zeloni, R., Marnetto, D., Moorjani, P., Jay, F., Valdmanis, P. N., Avila-Arcos, M. C., & Huerta-Sánchez, E. (2025). The MUC19 gene: An evolutionary history of recurrent introgression and natural selection. Science, 389(6762), eadl0882. https://doi.org/10.1126/science.adl0882
The MUC19 Gene
There is a gene called MUC19 in chromosome 12 that codes proteins called mucins, they are involved in mucus and mucus membranes, and therefore have a relationship with immunity (mucus, think snot, protects tissue as a barrier against pathogens in the gut and the lungs). Villanea et al., found that the gene originated in Denisovans, who passed it on to Neanderthals , who in turn passed it on to modern humans.
The Denisova variant is quite rare, but found in higher frequencies among people with Native American genes. This paper suggests that it has been positively selected among Amerindians due to its immune protecting effects. It probably had the same effect in Neanderthals. As these people entered new environments (America) this gene improved their odds of survival.
The gene is long, and it has what is known as a variable number tandem repeat (VNTR) polymorphism where a specific sequence that is 30 base pairs long is repeated many times (from 250 to 900 times). This increase in the number of repeats may make a difference in the immune-protecting effect of the gene. For instance some individuals living in America, with Native American roots, have over 800 repeats and an average of 417, far more than the Eurasian average of 250-350.
The authors, in a 2023 pre-print Biorxiv file state that "2e found that non-American populations range from an average of 345 to 355 repeats. In contrast, admixed individuals from the Americas have on average 417 copies."
The paper number of tandem repeats in the ancient samples are quite low: Altai Denisovan: 296 copies; Altai Neanderthal: 379; Vindija Neanderthal: 268, and Chagyrskaya Neanderthal: 293.
Proteins have two tips, one with a carboxilic acid group (‐COOH), the other with the amino group (—NH2) hence the name aminoacids for the building blocks of proteins. The MUC19 gene codes both tips, the tip related to the amino group is coded by the N-terminal part of the gene which contains three sectors known as von Willebrand factor type D domains, VWD for short. This study found that there is a chunk that is 72,000-base-pairs-long (72 kbp) that came from Denisovans, which overlaps two of the three VWD domains. Those carrying variant (haplotype) also shared "nine Denisovan-specific missense variants", single nucleotide polymorphisms, or SNPs in the MUC19 gene. This surely modifies how the gene works, but, we don't know the effect of this introgression or mutation. Below is a figure from the paper explainig how MUC19 evolved.
Two later Neanderthal genomes, one from Chagyrskaya and the other from Vindija, carry one copy of the same 72-kb Denisovan variant. And genetic data shows that it is found at high frequencies in modern samples from Mexicans living in Los Angeles (MXL), Peruvians from Lima (PEL), Colombians in Medellin (CLM) and People from Puerto Rico (PUR). It is also found, at lower frequencies in East Asia: in Beijing (3% frequency) and Chinese Dai in Xishuanagbanna, China (CDX) close to Myanmar and Vietnam in Southern China.
Interestingly, ancient Americans samples that were analyzed carried these variants at even higher frequencies than modern ones (Fig. 3 in the paper and Table S29). Roughly 36-40% frequencies vs. current levels of 30% in MXL, 21% in PEL, 7% in CLM, and 9% in PUR. As a reference, the Neanderthals had ~50% frequency. The CDX Chinese have ~12%, while samples of ITU (Indian Telugu in the UK) and STU (Sri Lankan Tamil in the UK) with South Asian ancestry both carry ~11% and BEB (Bengali in Bangladesh) has 15%, KHV (Kinh in Ho Chi Minh City, Vietnam) has 8.5%, and GIH (Gujarati Indian from Houston, Texas, USA), 10%. As you can see, some Asians carry this variant in higher frequencies than the Colombian or Puerto Ricans! In Western Asia and Europe it is found at very low frequencies.
But the origin does not seem to be among the Denisovans of Altai. The paper suggests it was another group of Denisovans that carried the mutation: "the introgressed haplotype in the 72-kb region is present at low frequencies in other non-African populations including Papuans, where the genome-wide Denisovan ancestry of Papuans has been estimated to originate from a population of Denisovans that was not closely related to the Altai Denisovan."
Its African Presence
The study also sampled 44 African subjects and found this variant at a very low frequency of 1.1%: "all nine Denisovan-specific missense variants at a frequency of ~0.011, in a single chromosome from a Khomani San individual (table S33)." This is a surprise because Denisovans are an Asian species, they did not live in Africa, and also because the San are often touted as the most basal, diverse, original, ancestral root of modern humans. So how did this variant get into the genes of a San person in Sub-Saharan Africa?
The authors explain this incongruence as follows:
"Finally, we find a single San individual who carries the nine Denisovan missense variants in heterozygous form, uniquely among all African individuals considered here. The sequence divergence between this San haplotype and the archaic MXL haplotype at the 72-kb region is high (0.001342), further supporting the origin of the archaic haplotype in non-Africans as introgressed. Khoe-San populations are estimated to have diverged from other African groups 120,000 years ago. Finding a divergent haplotype in the San is consistent with a previous study, as ~1% of their ancestry can be attributed to lineages that diverged from the main human lineage more than 1 million years ago. We note that this San individual does not harbor an elevated number of copies of the VNTR (301 copies), which further supports the importance of the VNTR expansion in the Americas. Furthermore, we cannot determine whether this variant found its way into the San through modern admixture of non-African ancestry into Sub-Saharan populations."
In other words, there are two options: (1) the San admixed with an archaic hominin (this is a great way to explain their diversity, they added divergent genes by mating with ancient hominins that co-existed with them in Africa!), the archaic then carried into Eurasia in Denisovans (They split from our lineage 700 kya) and in Asia it introgressed in Humans via Neanderthals. (2) Back migration. Modern humans carried the Denisovan introgression back into South Africa in more recent times and mating with San, passed it on to them.
The authors mention its presence in Papuans, but do not give a frequency value or indicate if it increased its frequency among them in the final version published in Science, however, in a previous 2023 preprint they indicate a 10% frequency: "We additionally confirmed the presence of the Denisovan-like MUC19 haplotype amongst the 15 Papuan individuals (Denisovan-like haplotype frequency: 0.1)"
It would be interesting to have data from the Australian Aboriginal people who landed in Australia 50 kya? Didn't they have to face a new, hostile environment?.
The Complex Introgression Route
The Denisovan introgression into Neanderthals involves a later population like the Vindija Cave (Croatia) individual ~40 kya, and the Chagyrskaya Cave in the Altai Mountains ~55 kya. But, it did not include the Altai Denisovan, only the ones of Southeast Asia and Indonesia-Sunda region.
Did the Neanderthals and the Denisovans heading for SE Asia admix in Western Eurasia after the Denisovans heading north towards Altai split? Did the Neanderthals of Croatia split and head west into Europe? Then, did these Neanderthal mate with humans heading into East Asia and South Asia? Or did the Neanderthals reach East and South Asia and mate there with humans in each region?
Surprisingly the Neanderthal samples are from Europe and Altai, nowhere near Sunda or India-South Asia!
The authors note that their analysis indicates "that the introgressed haplotype at the 742-kb MUC19 region has a high affinity for the Altai Denisovan and the two late Neanderthals, but not the Altai Neanderthal." The latter is about 110-120 kya. So the introgression into Neanderthals from Denisovans probably took place later.
In my first post on MUC19, I wondered if "Could it be possible that a band of Neanderthals reached America long ago, after trysting with Denisovans, and the later waves of Homo sapiens mingled with them, picked up their mutations?" But, this hypothesis does not explain how the MUC19 spread across Eurasia and at higher frequencies in East and Southeast Asia. Back migration, or a population that remained there in Asia could account for this dispersal, but it does not require Neanderthals entering America before modern humans. The presence in America can be explained by admixture of H. sapiens and Neanderthals in East Asia and then the humans moving on, into America.
The map above shows spots where MUC19 has been mentioned in this text, and the possible (unconfirmed) migration routes of Neanderthals (red arrows), their homeland (Yellow), and Denisovans (blue arrows), the red stars mark the location of the Neanderthal samples from Chagyrskaya (close to Altai) and Vindija, and Denisovan (Altai). The green arrows mark part of the Homo sapiens journey out of Africa, and into America.
Where did the Denisovans mix with Neanderthals? And Neanderthals with humans? For now, we don't know. But, the introgression is a fact, and was mentioned by previous papers, as we will see below.
There are two other papers that noticed an enrichment of MUC19 in Native Americans and the influence of natural selection enhancing its frequency. Both were published before Villanea et al. One noted it was shared by MXL people and Denisovans.
Reynolds et al., 2019, studied Native American populations and reported that "One gene related to immune response (MUC19) also shows a strong signal of selection in the central Mexico population... We also found that the southeastern US and central Mexico populations share signals of selection at two SNPs each in the genes MUC19 and CNTN1..." The authors attribute the selective forces in Central Mexico as caused by disease introduced by the Europeans after Cortés expedition in 1519 that caused a smallpox epidemic and pathogens introduced by African slave trade. The paper adds that "This history likely contributed to genomic signatures of selection seen in the central Mexico population in this study. We see the strongest signal of selection on the mucin gene MUC19 in the central Mexico population. Mucin genes are primarily involved in the immune response to parasitic infection. Past work has shown that parasite load is strongly correlated with latitude, with populations closer to the tropics having higher levels of parasitic infection." The paper links smallpox resistance to MUC19, suggesting that this European disease promoted selective pressure that increased the prevalence of MUC19: "Interestingly, the GenomeRNAi database shows that MUC19 is associated with decreased vaccinia virus (VACV) infection. VACV is a close relative of the variola virus, the causal agent of smallpox, and recombinant versions of the VACV were used as a vaccine against smallpox until it was eradicated in the late 1970s. ... Future work may help us identify the major pathogens afflicting the people of central Mexico during colonial times."
The second paper by Racimo, Marnetto and Huerto-Sánchez (2018) studied adaptive introgression from archaic hominins, admixture that conferred benefits that enhanced survival. The authors point out MUC19 as outstanding: "MUC19. This region is rather impressive in containing 115 sites where the archaic alleles are shared between the Mexican panel (MXL) and the Denisovan genome at more than 20% frequency, when using all populations that are not MXL as the outgroup. However, the actual proportion of individuals that contain a Denisova-like haplotype (though highly differentiated from the rest of present-day human haplotypes) is very small. Only 11.86% of haplotypes in the combined YRI + AMR panel show 69 differences or less to the closest archaic genome (Denisova), and the next closest haplotype has 134 differences (supplementary fig. S51D, Supplementary Material online)."
Patagonian Monsters - Cryptozoology, Myths & legends in Patagonia Copyright 2009-2026 by Austin Whittall ©
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