My previous, first post on MUC19 gene ended with a question: Where (and when) did the Denisovans admix with the Neanderthals (Denisovans closer to the Sunda group than to the Altai group) passing the MUC19 variant to them, and when did Neanderthals mix with the Humans that eventually carried MUC19 to America?
Denisovans, Neanderthals and Humans how we split and mated along the way
The current consensus is that the lineage of the common ancestors leading to Neanderthals and Denisovans split from the branch leading to the ancestors of Modern Humans around 630,000-744,000 years ago depending on the study and the criteria adopted by the authors. As usual, genetics and bones don't quite match so there is an uncertainty in the actual date.
The split took place in Africa, with the Neanderthal-Denisovan ancestors leaving Africa, and our ancestors, who became Homo sapiens, remained in Africa.
Prüfer et al., 2017 find the following dates: "The estimated population split time between the Vindija Neandertal and the Denisovan is 390 to 440 ka and that between the Vindija Neandertal and modern humans 520 to 630 ka, in agreement with previous estimates using the Altai Neandertal. The split time between the Vindija and the Altai Neandertals is estimated to be 130 to 145 ka." Vindija is in Croatia, Europe, Altai is 5,131 km (3,188 miles) further east, in Asia, where China, Russia, Monglia, and Kazakhstan meet. Both Neanderthals are at the opposite ends of the Neanderthal territory.
Rogers, Bohlender, & Huff, 2017 disagree with Prüfer et al., and propose an earlier date: "our own date estimates inherit the uncertainty of the molecular clock. Using the YRI.CEU data, our point estimate of the Neanderthal–Denisovan separation time is 744 kya. Many authors prefer a higher mutation rate... Under this clock, our estimate becomes 616 kya..."
In 2020, the same Rogers of the 2017 paper, teamed with Harris and Achenbach, reviewed this work and updated its conclusions: "Our point estimate, 737 ka ago, is remarkably old... We suggest that around 700 ka ago, neandersovans expanded from Africa into Eurasia, endured a bottleneck of population size, interbred with indigenous Eurasians, largely replaced them, and separated into eastern and western subpopulations—Denisovans and Neanderthals."
Split in Western Asia
The introgression with "indigenous" Eurasians mentioned by Rogers, Harris, and Achenbach is an interesting point, and it could involve Homo erectus or the Homo antecessor (probably descended from the erectus group). There is of course the Homo heidelbergensis question. Vincenzo and Manzi, 2023 place the H. heidelbergensis as the last common ancestor of Neanderthals, Denisovans, and Modern Humans. So it probably lived in Africa and Western Eurasia at that time. Due to the lack of consensus (see Buck and Stringer, 2014 for a good review of this hominin), I will not mention it in this post.
Roger et al. 2020 have the Neanderthals moving west, into Europe, and the Denisovans heading east into Asia. There were no humans in Eurasia at this time ~600 kya, and it would remain this way until the first Out of Africa event some 120 kya.
Was it was during this period that the Denisovans and Neanderthals admixed and the MUC19 of the Denisovans introgressed into the Neanderthals?
Before trying to find out where and when this admixing took place, let's look at how the Denisovans spread across Eastern, Central, and Southern Asia after parting ways with the Neanderhtals in the Middle East around 440 kya
The Denisovan Groups
The Denisovan dispersal according to Rikai Sawafuji et al., 2024 took place as follows (it begins where Rogers left them):
"The common ancestor of Denisovans and Neanderthals which occupied around the Middle East interbred with a super-archaic hominin, and afterwards the Denisovan ancestors diverged from the Neanderthal ancestral group and moved into Asia. Some of them spread towards Papua and settled in Island Southeast Asia (D1). Another group remained in South or Southeast Asia (D2), and from there, another group moved further north into East Asia (D0, D3). During the early phase of this migration, they encountered a super-archaic hominin population and interbred. The D0 group settled somewhere in East Asia. The D3 group reached the Altai in Siberia (D3), where they met and interbred with Neanderthals. It is important to note that this only reflects the history of the Denisovan population that interbred with modern humans. If there were other populations that went extinct without any admixture, analysis of modern human genomes would not provide any information about these."
This distribution can be seen in the map below, which includes an undated phylogenetic tree, and shows what we currently know about Denisovans. It comes from Ongaro and Huerta-Sánchez, 2024 (free access here).
By the way, there are very few bones that have been assigned to Denisovans, and most of our knowledge comes from genetics.
Ongaro and Huerta-Sánchez, 2024, Fig. 3
There is an additional clade not shown in this map, reported by Larena et al, 2021, the Denisovans of the Philippines: "Philippine Ayta... possess the highest level of Denisovan ancestry in the world —∼30%–40% greater than that of Australopapuans— consistent with an independent admixture event into Negritos from Denisovans. The Philippine archipelago is thus likely inhabited by multiple archaic groups prior to the arrival of modern humans."
Timeline
Using the information provided by Rikai Sawafuji et al., 2024, the D1 and D2 data from C. Jacobs et al., 2019m and D3 from Ongaro and Huerta-Sánchez, 2024, we can define a chronology.
I also included the cates proposed by Choin et al., 2021, which differ from the others and highlighted them in bold font.
- D0 : split from Altai Denisovans more recently. Territory: East Asia, China, Mongolia (100-150 kya) Here I have included the fossil from Harbin (with close affinities to Denisova 3), Baishiya Karst Cave (BKC), and Tibet, Penghu, Taiwan.
- D1 : split from the line leading to Altai Denisovans 283 kya (261–297 kya) - 222 kya. Territory: New Guinea and nearby islands (Island South East Asia).
- D2 : split from the line leading to Altai Denisovans 363 kya (334-377 kya) - 409 kya. Territory: Oceania and Southern, and Southeast Asia, India, Myanmar, Vietnam, Laos, Cambodia, Thailand, Malaysia.
- D3 : Altai Denisovans, Siberia (200-30 kya. More details below).
- D4? : ~300 kya?. Territory: Philippines.
The Altai cave in Denisova, Russia, the site of the original Denisovan find includes the the D3 group, has produced several fossils, and they are grouped into two separate periods: the remains of Denisova 2, 8, 19, 20, and 21, and the Harbin, China, specimen, are Early Pleistocene, with ages ranging from 123 to 217 kya. The Late Pleistocene Denisova 3 and 4 are much more recent: 52 to 84 kya (Fu et al., 2025 and Z. Jacobs, 2025). I suspect the more recent Denisovans are associated to the D0 group.
The MUC19 introgression from Denisovans to Neanderthals
Neanderthals and Denisovans mixed many times, we know that they overlapped and shared the Denisova cave in Altai, over tens of thousands of years (Z. Jacobs, 2025), the remains of Denny a Denisovan-Neanderthal hybrid, was reported by Slon et al., 2018 (Denisova 11), who lived 90 kya. Her Neanderthal genes were a combination of alleles that were also found in a pure Altai Neanderthal genome and in the Vindija 33.19 Neanderthal genome (from Croatia). The genetic analysis suggests two possible hypothesis that are not mutually exclusive: " eastern Neanderthals spread into Western Europe sometime after 90 ka or that western Neanderthals spread to Siberia before that time and partially replaced the local population." Her Denisovan father also "had some Neanderthal ancestry... it is likely that there was more than one Neanderthal ancestor in his genealogy, possibly as far back as 300–600 generations before his lifetime [9000 - 18,000 years]... the Neanderthals that contributed to the ancestry of Denisova 11’s father were from a different population than her mother."
Furthermore, the first Denisovan to be identified, Denisova 3. (52-76 kya) also carries a small percentage of Neanderthal ancestry (between 1.8-2.5%, related to an old 120 ky Neanderthal group to which the Altai Neanderthal —Denisova 5— belonged).
So here we have evidence of Denisovans with Neanderthal genes (indicting admixture) from 52 to 108 kya. That Eastern and/ Western Neanderthals moved across Eurasia to and from Siberia.
Peyrégne et al., 2020 studied a specimen known as Denisova 25, 219,000 years old, who carried alleles of Neanderthal origin (3.6-5.2%). They found that the Altai Neanderthal specimen known as Denisova 5, had received gene flow from Denisovans and that Denisova 25 received his "Neandertal ancestry comes from a yet undescribed Neandertal population that split over 200,000 years ago from the Neandertal populations for which we have genomes" The team stresses that "both Denisovans inherited their Neandertal ancestry from multiple gene flow events... This indicates repeated contacts between Neandertals and Denisovans throughout their history."
But, we also have to consider which group interacted, because the MUC19 paper by Villanea et al. used Denisova 3 as the "Altai Denisova" in their analysis but specified that it was not the source of this allele.
The Supplementary Data Section S5 in Villanea's work says the following (my comments in bracketes, in regular font): "we believe that the sequenced Altai Denisovan [Denisova 3, with Neanderthal alleles belonging to Clade D0 or D3] belongs to a population that is divergent from the donor Denisovan population that interbred with modern humans [so the Denisovan was D1, or D2, the D4 were in the Philippines]...by analyzing the sequence divergence distribution of Denisovan introgressed tracts in Papuans, we confirm that the sequence divergence observed between the introgressed haplotypes and the Altai Denisovan at the focal 72kb region is consistent with a scenario of Denisovan introgression. However, the source of this introgressed segment likely did not originate directly from the population represented by the Altai Denisovan [ratifying D1 or D3 clades as the source]... This result suggests that the Denisovan-like segment observed at the focal 72kb region, while of Denisovan origin, was inherited by modern humans through introgression with a population closely related to the Chagyrskaya and Vindija Neanderthal"
The Neanderthal from Chagyrskaya Cave (Siberia) lived 100 km (62 mi.) from the Denisova Cave, while the Neanderthal from Vindija Cave lived in Europe, in Croatia. They both belong to recent Neanderthals who lived 50 to 60 kya. They are more similar to each other than to the Altai Neanderthal discovered at the Denisova cave (Denisova 5 specimen), who lived around 120,000 years ago.
The image below clarifies the situation, as it shows the convoluted interactions between all groups, it also includes some of the named specimens.
Nuclear, mtDNA and Y-chromosome information, Fig. 2 in Peyrégne et al., 2020
Where and When did these introgressions take place
The D1 or D2 clades of Denisovans, in Southern, Southeastern, and Island South Asia, New Guinea and Australia are the ones that introgressed the MUC19 variant into Neanderthals. Though we have no evidence of Neanderthals in this vast region. Then the Neanderthals, close to the late Croatian and Altai individuals carrying that allele passed it on to modern humans who carried it into America, and some in East Asia and South Asia have an extremely low frequency of these MUC19 alleles, stray members of the group heading to America perhaps?
The most simple explanation is that the branch of Denisovans that led to D1 and D2 clades which must have moved along the south coastal route of Asia, carried the MUC19 variant. This was before these clades originated the D3 and D0 clades (200-100 kya). During this period they passed it on to a group of Neanderthals: "the introgressed haplotype at the 742-kb MUC19 region has a high affinity for the... two late Neanderthals, but not the Altai Neanderthal." So these Neanderthals were ancestral to the Chagyrskaya and Vindija individuals but not to Denisova 5, the Altai Neanderthal. As mentioned further up (Prüfer et al.) these two groups split around 130-145 kya
This would imply an admixture between D1 or D2 Denisovans and pre-split Neanderthals around 130 kya, and Neanderthal- Human mixing after the Out of Africa event (First? or Second?) which could have taken place around 120 kya or later (1st OOA), some 60 kya (Final OOA).
I came across an interesting analysis of archaic introgressions with modern humans and how the first Out of Africa event 120-60 kya and the second one >60 kya interacted with Neanderthals and Denisovans. The paper is this one: Yuan K, Ni X, Liu C, Pan Y, Deng L, Zhang R, Gao Y, Ge X, Liu J, Ma X, Lou H, Wu T, Xu S. Refining models of archaic admixture in Eurasia with ArchaicSeeker 2.0. Nat Commun. 2021 Oct 29;12(1):6232. doi: 10.1038/s41467-021-26503-5. PMID: 34716342; PMCID: PMC8556419. It mentions the Ust'Ishim Siberian man who died 45,000 years ago. He was a human being and carried Denisovan introgression, and Neanderthal alleles, from two events: "we also detected two waves of Neanderthal-like introgression in the Ust’-Ishim genome: a recent one (1.41–1.57%) that occurred 61.4–57.8 kya and a weaker and more ancient one (0.04–0.20%) that occurred 204.1–95.6 kya."" This seems, in my opinion to point at an admixture during the first out of Africa event around 100 kya. In the Southern border between both groups, and one that allowed a route across Central Siberia. Possibly in the Caucasus region.
The telling inconsistency...
I am always on the look out for conflicting, incompatible, contradictory, or discrepant data involving Native American genetics and ancestry, ant this paper by Peyrégne et al., 2020 contains incongruous information. It adds one juicy piece of evidence about the introgression dates, of Neanderthals and Denisovans into Amerindians, one that the authors find inconsistent and try to explain away with vague, unfounded interpretations. The incongruity is that the admixture date for American data: it is far too old! Older than any Eurasian admixture events!. But this will be the subject of my third and final post on MUC19.
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