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The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans:

Some present-day humans derive up to ∼5% …of their ancestry from archaic Denisovans, an even larger proportion than the ∼2% from Neanderthals…We developed methods that can disambiguate the locations of segments of Denisovan and Neanderthal ancestry in present-day humans and applied them to 257 high-coverage genomes from 120 diverse populations, among which were 20 individual Oceanians with high Denisovan ancestry…In Oceanians, the average size of Denisovan fragments is larger than Neanderthal fragments, implying a more recent average date of Denisovan admixture in the history of these populations (p = 0.00004). We document more Denisovan ancestry in South Asia than is expected based on existing models of history, reflecting a previously undocumented mixture related to archaic humans (p = 0.0013). Denisovan ancestry, just like Neanderthal ancestry, has been deleterious on a modern human genetic background, as reflected by its depletion near genes. Finally, the reduction of both archaic ancestries is especially pronounced on chromosome X and near genes more highly expressed in testes than other tissues (p = 1.2 × 10−7 to 3.2 × 10−7 for Denisovan and 2.2 × 10−3 to 2.9 × 10−3 for Neanderthal ancestry even after controlling for differences in level of selective constraint across gene classes). This suggests that reduced male fertility may be a general feature of mixtures of human populations diverged by >500,000 years.

Take a look at the supplements for the functional stuff. I am not going to address that. Much of those results have been circulation or in other papers over the years. Rather, I want to highlight the variation in patterns of Denisovan admixture in non-Oceanian groups. Here is an important section:

Taken together, the evidence of Denisovan admixture in modern humans could in theory be explained by a single Denisovan introgression into modern humans, followed by dilution to different extents in Oceanians, South Asians, and East Asians by people with less Denisovan ancestry. If dilution does not explain these patterns, however, a minimum of three distinct Denisovan introgressions into the ancestors of modern humans must have occurred.

You see it on the figure above. The South Asian groups consistently jump well above the trend line for inferred Denisovan as a function of shared ancestry with Australians non-West Eurasian ancestry. Also, if you look at the admixture patterns for Denisovan ancestry in South Asia you see they follow the ANI-ASI cline. That is, it seems to come into the South Asian populations through the “Ancestral South Indians.” Interestingly, the Onge sample of Andaman Islanders has less Denisovan than low caste South Asian groups, reminding us that though the Onge and their kin are the closest modern populations to the ASI, they are not descended from the ASI. The highest fraction of inferred Denisovan is in the Sherpa people of Nepal.

sherpa The figure to the right is from Admixture facilitates genetic adaptations to high altitude in Tibet, and the authors find that the Sherpa are at one extreme in an ancestry cline in comparison to other East Asians. The figure is hard to make out, so I will tell you that many of the Sherpa are fixed for the red component, while other Tibetans are in positions in the middle, and most East Asians have low fractions of the red, with the Dai having none. The Gujarati sample form the HapMap have low fractions of both East Asian components. This is almost certainly an artifact of the shared ancestry of all eastern Eurasians (and perhaps Oceanians), of which the ASI were one descendant group. The proportion of Denisovan in low caste South Asians indicates that the fraction in ASI was about at the same level as the Sherpa. I suspect that ASI and the Tibetan groups got their Denisovan via different paths, but it doesn’t seem like we know yet.

Overall I do marvel at what ancient DNA can tell us. Without it we wouldn’t be talking about any of these admixture events; they’d be signals too weak to have left an obvious mark in the genome.

• Category: Science • Tags: Denisovan, Neanderthal 
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250px-Caveman_1 By now you may have heard that mitochondrial DNA, passed down the female lineage, has been extracted from a ~400,000 year old human fossil from Spain. If you haven’t heard, I recommend Ewen Callaway and Carl Zimmer’s takes. The paper is at Nature, so gated, A mitochondrial genome sequence of a hominin from Sima de los Huesos. The big surprise is that these proto-Neandertals carry a mtDNA lineage which is closer to that of the Siberian Denisovans than that of later Neandertals. That’s the specific finding, and if you read the reaction it is rather clear that this is confusing researchers who work in this area. But take a step back, imagine what a world without ancient DNA would be like. Yes, the broad conjectures would be supported (e.g., Out of Africa), but many specific details would be off. So praise the data! Sometimes complexity is closer to the truth, and this is one of those cases. These are good problems to have.

Neander In the primary figure of the paper you can see that these humans are closest on the mtDNA phylogenetic tree to the Denisovans. But, it is important to note that they’re also hundreds of thousands of years older than any other ancient human DNA. Because mtDNA is only passed down through females it tends to be more strongly subject to genetic drift, which might turn over lineages rather rapidly. It is not that unlikely that over hundreds of thousands of years some populations would lose ancestral mtDNA lines. This is what occurred with “mitochondrial Eve.” She wasn’t the only female alive in Africa at the time, but all the other direct maternal lineages went extinct. There are ‘ghost branches’ within the tree which terminated. All you see are the lines of descent back up to the single last common ancestor on the mitochondrial lineage. This doesn’t mean that the ancestry of these women who did not contribute mtDNA disappeared. It is just that their lines of descent may have passed through sons at a given point (my maternal grandmother’s specific mtDNA almost went extinct, she had six son and one daughter). And of course there are other explanations for this pattern, highlighted in the articles linked. Gene flow between lineages, or from a different lineage altogether. We have to remember that the mtDNA of the Denisovan human was more diverged from Neandertals than the whole genome was later found to be, perhaps indicating complex admixture scenarios. The mtDNA tree falsifies, but I do not think it allows us to draw any robust conclusions.

These results are going to get updated in the next year or so with autosomal DNA from the rest of the genome. Even if they can’t get the whole genome sequenced, even a few tens of thousands of markers should be sufficient to clarify issues. Though all of these findings need to be interpreted cautiously in light of the fact that this is a very old lineage, perhaps closer to the time period of diversification for many Eurasian ‘archaic’ H. sapiens than we may have thought.

• Category: Science • Tags: Denisovan, Neandertal, Paleoanthropology 
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Q Fu, M Meyer, XGao, U Stenzel, H A. Burbano, J Kelso, S Pääbo
DNA analysis of an early modern human from Tianyuan Cave, China
PNAS 2013 ; published ahead of print January 22, 2013, doi:10.1073/pnas.1221359110

The above is a graph which illustrates phylogenetic relationships using the TreeMix package. It is from the paper I alluded to yesterday. The paper, DNA analysis of an early modern human from Tianyuan Cave, China, is open access, so everyone should be able to read it. Its mtDNA analysis shows that the Tianyuan sample, from the region of Beijing and dating to ~40,000 years B.P., is a basal clade in haplogroup B, which is common in eastern Eurasia and the New World. This is a satisfying result insofar as the understanding in relation to this haplogroup is that it diversified ~50,000 years B.P. There is very strong support in these data for the proposition that Tianyuan forms a distinct clade with the populations you see above, as opposed to western Eurasians. This is important because this sample seems to date with relatively good precision to 40,000 years B.P., supporting the archaeological contention that modern humans were already diversifying into western and eastern lineages 40-50,000 years ago. In contrast statistical genomic inferences tend toward a lower date for divergence. We can be moderately confident at this point that some aspect of the west-east divergence predates subsequent later gene flow events, which might lead to confusing archaeology-blind methods.

More interesting to me is that these data do not resolve very well the relationship of Tianyuan with Melanesians vs. East Asians & Amerindians (that relationship are supported in 31% of bootstraps as opposed to 100% for all the others). This may be a function of poor data quality (one reason Tianyuan presumably is on a ‘long branch’). But, it may also be a function of the fact that at ~40,000 years B.P. the extant clades of humans as we understand them were in only their early stages of formation. And critically it seems likely that some of the modern populations which are included in this data set are the byproducts of complex demographic admixture events subsequent to ~40,000 B.P. Seeing as we are getting very strange results out of Oceanian populations, some well supported now, others more speculative, the fact that the tree is unclear at this particular point is not entirely out of our expectation. I assume that in the near future with more of the genomes of ancient individuals sequenced a picture of the past not so reliant on the variation of the present will emerge. As it is with only a few individuals it is necessary to filter the past through the lens of the present, and that is going to add distortions.

(Republished from Discover/GNXP by permission of author or representative)
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By now you have probably seen the new Denisovan paper in the media. John Hawks has an excellent overview, as you’d expect. The only thing I will add is to reiterate that I think population movements in near and far prehistory significantly obscure our comprehension of the patterns of past genetic variation. One reason that the Denisova hominin presents conundrums (e.g., how did Australians and Melanesians admix with a population whose only remains are found in Siberia) is that we’re viewing it through the lens of the present. What other lens can we view it through? We’re not time travelers. But we should be perhaps more conscious of the filter which that imposes upon our perception and model of the world. This is probably a time when it is best to have only a modest confidence in any given proposition about the prehistoric past.

Also, I don’t know why, but I much like this tree:

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Denisovan, Genomics, Human Genetics, Human Genomics 
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In The New York Times, DNA Turning Human Story Into a Tell-All:

The tip of a girl’s 40,000-year-old pinky finger found in a cold Siberian cave, paired with faster and cheaper genetic sequencing technology, is helping scientists draw a surprisingly complex new picture of human origins.

The new view is fast supplanting the traditional idea that modern humans triumphantly marched out of Africa about 50,000 years ago, replacing all other types that had gone before.

Instead, the genetic analysis shows, modern humans encountered and bred with at least two groups of ancient humans in relatively recent times: the Neanderthals, who lived in Europe and Asia, dying out roughly 30,000 years ago, and a mysterious group known as the Denisovans, who lived in Asia and most likely vanished around the same time.

Their DNA lives on in us even though they are extinct. “In a sense, we are a hybrid species,” Chris Stringer, a paleoanthropologist who is the research leader in human origins at the Natural History Museum in London, said in an interview.

First, for reasons of novelty we are emphasizing the exotic tendrils of the human family tree. Even Chris Stringer, the modern paleontological father of “Out of Africa,” is claiming we’re hybrids! But let’s not forget that non-Africans are the product of a very rapid radiation out of the margins of the Afrotropic ecozone within the last ~50-100,000 years. I am not entirely sure that this is as true of Africans (recall how extremely basal Bushmen are to the rest of humanity; they seem to have diverge well before the “Out of Africa” pulse).

Second, the old model was way easier to write about, even if there were confusions like the idea that mtDNA Eve was our only female ancestor from 200,000 years ago in the past. The new paradigm leaves one with awkward and unhelpful turns of phrase. For example:

But Dr. Reich and his team have determined through the patterns of archaic DNA replications that a small number of half-Neanderthal, half-modern human hybrids walked the earth between 46,000 and 67,000 years ago, he said in an interview. The half-Denisovan, half-modern humans that contributed to our DNA were more recent.

How to make sense of this gibberish? I suspect that the author didn’t have a good idea how to translate a particular population genetic statistic, and its importance to assessing time since admixture, into plainer prose. I have no idea either!

In other news, i09 has an interesting interview up with Rebecca Cann and Mark Stoneking. These two were heavily involved in the mtDNA Eve controversies of the 1980s. Nice capstone to an era. Like Stringer, even they admit the likelihood of a necessity to modify the simple “Out of Africa” with replacement model.

(Republished from Discover/GNXP by permission of author or representative)
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The Pith: More caveman admixture in modern humans, especially Melanesians!

A new paper on archaic adaptive introgression among Melanesians has been discussed elsewhere. But I think it is worth reviewing, because it’s probably a foretaste of what’s to come. Researchers are combing through the human genome, as more and more genomes come on line, in the search of weird and unexpected variation. The paper is in Molecular Biology and Evolution, and is titled Global genetic variation at OAS1 provides evidence of archaic admixture in Melanesian populations (why is it that this journal doesn’t even allow supplemental information to be free to the public?). The two primary figures from this paper do a good job of illustrating the main result.

The first figure is a phylogenetic tree of haplotypes at the OAS1 locus, with pie charts showing the proportion of individuals from a set of populations which contribute to the total number for that haplotye. So you see above that the “deep lineage” is relatively distant from a cluster of other haplotypes (as measured by mutational differences which are proportional to depth of common ancestry), and, that deep linage is exclusively found in Papuans in this set. The second figure shows the frequency of the deep lineage haplotype over a larger set of populations. I cut off the section which shows that Africans are at zero percent. The haplotype is found almost exclusively in Melanesian populations, except for the fact out of over 200 South Asians they sampled, 3 of them carried it (2 Pakistanis, 1 Sri Lankan). There is aspect though not evident in the figures above, but which is clear in the abstract that you need to know:

Recent analysis of DNA extracted from two Eurasian forms of archaic human show that more genetic variants are shared with humans currently living in Eurasia than with anatomically modern humans in sub-Saharan Africa. While these genome-wide average measures of genetic similarity are consistent with the hypothesis of archaic admixture in Eurasia, analyses of individual loci exhibiting the signal of archaic introgression are needed to test alternative hypotheses and investigate the admixture process. Here, we provide a detailed sequence analysis of the innate immune gene, OAS1, a locus with a divergent Melanesian haplotype that is very similar to the Denisova sequence from the Altai region of Siberia. We re-sequenced a 7 kb region encompassing the OAS1gene in 88 individuals from 6 Old World populations (San, Biaka, Mandenka, French Basque, Han Chinese, and Papua New Guineans) and discovered previously unknown and ancient genetic variation. The 5′ region of this gene has unusual patterns of diversity, including 1) higher levels of nucleotide diversity in Papuans than in sub-Saharan Africans, 2) very deep ancestry with an estimated time to the most recent common ancestor of >3 million years, and 3) a basal branching pattern with Papuan individuals on either side of the rooted network. A global geographic survey of >1500 individuals showed that the divergent Papuan haplotype is nearly restricted to populations from eastern Indonesia and Melanesia. Polymorphic sites within this haplotype are shared with the draft Denisova genome over a span of ∼90 kb and are associated with an extended block of linkage disequilibrium, supporting the hypothesis that this haplotype introgressed from an archaic source that likely lived in Eurasia.

There there is “more genetic diversity within Africa” is a cliche rooted in reality. But, this is not true at all genes. For example, at MC1R Africans have less genetic diversity than Europeans. Why? MC1R is implicated in pigmentation, and this locus is subject to strong functional constraint at low latitudes. In other words, there is more at work than just demographic history. When you see more diversity at a locus outside of Africa than within there is a strong suspicion that natural selection or admixture may be at play, because your null expectation is that the dominant “Out of Africa” event will imply more Africa diversity or modern humans. So at OSA1 you have a genetic variation which is very diverse, and very divergent, from the modal human variant. When you take away the deep lineage you also see a pattern which is constant with genome wide expectations. Africans are distributed across the unrooted tree, while non-Africans seem to be nested within a subset of nodes.

But if this was published in 2008 it might not be as notable, because the human genome is big, and there are going to be random patterns here and there. This might have been dismissed. The key is that the authors matched this divergent haplotype to the variant found in the draft Denisovan genome. Naturally it’s going to be harder to dismiss as a statistical fluke when you actually have concrete evidence in this form that the ancient lineage was shared with an archaic hominin group.

There are two scientific points that jump out at me. First, the authors don’t discuss adaptation or selection in very much detail (except to dismiss balancing selection). But if this is due to archaic admixture its fraction in Melanesians is far higher than the genome wide average. Again, some loci will naturally deviate from expected values, but those that do are excellent candidates for being targets of adaptation. And, this gene has a clear functional role related to immune response. Second, the presence of this haplotype in South Asians is strongly suggestive of the location of the admixture event between archaic humans and the ancestors of modern Melanesians. This sort of information needs to be synthesized with the two papers last fall that came out on Australian evolutionary genomics. One of the interesting aspects of the Denisovan admixture analyses is that it doesn’t seem that any South Asian group, including Andaman Islanders, exhibit it. And yet a few South Asians here carry a haplotype similar to the Denisovan variant. Interestingly, the authors present a rather unbelievable large value for the common ancestor between the deep lineage and other modern haplotypes, ~3 million years, which is an order of magnitude more than the divergence of Denisovans from modern humans.

How to resolve this confused situation? In the conclusion they point to the possibility that this haplotype may have introgressed into both the Denisovans and modern humans from H. erectus! The most recent genomics on Melanesians implies that their own history is relatively complex. On the one hand they may be some of the earliest distinct migrants out of Africa, and secondarily, they themselves may be successive compounds between those early migrants, archaic humans, and a second wave of Eurasians. All that being said, I think there is some hope in the combination of full genome sequencing of modern populations as well as the same of ancient populations via DNA from subfossils. The main qualification is that I doubt we’ll ever get good samples of ancient DNA from the tropics.

Citation: Fernando L. Mendez, Joseph C. Watkins, and Michael F. Hammer,
Global genetic variation at OAS1 provides evidence of archaic admixture in Melanesian populations, Mol Biol, doi:10.1093/molbev/msr301

Image credit: Wikipedia

(Republished from Discover/GNXP by permission of author or representative)
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A new paper in PNAS, Archaic human ancestry in East Asia: “These results suggest admixture between Denisovans or a Denisova-related population and the ancestors of East Asians, and that the history of anatomically modern and archaic humans might be more complex than previously proposed.” It’s open access, so do go read it. John Hawks has a long rumination. My main thought is that I’m starting to think that people are squeezing this orange too much. I wouldn’t be surprised if the broad conclusions here are correct, and in fact I’d lean in that direction. But is the discovery of relatively trace ancestry all that earthshaking? The reality is that a little over a year ago the interpretative framework of science in this area shifted. That was because of the concreteness of ancient DNA, which allowed for a direct comparison, instead of statistical sifting through the genomes of extant populations. Remember, before 2010 there were plenty of papers utilizing subtle statistics and computational muscle which “proved” and “confirmed” an Out-of-Africa with replacement model. The power and precision of these techniques tended to overshadow the reality of a margin of error, and uncertainty in their conclusions. We need to be cautious when the machinery turns itself in the opposite direction, gleaning glimpses of what we now know is likely there….

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Anthropology, Denisovan, Human Evolution 
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The class human or H. sapiens refers to a set of individuals. On the grand scale it’s really not all that clear and distinct. When do “archaic” humans become “modern” humans? Taking into account human variation, what is a “human universal”? A set of organisms are given a name which denotes the reality that they may share common ancestry, and interact behaviorally, and are potential mates. But many of these phenomenon are fuzzy on the margins. Many of the same issues which emerge in the “species concept” debates are rather general up and down the scales of natural complexity. A similar problem crops up when we conflate the history of genes with the history of populations. Such a conflation has value and utility to a first approximation. The story of mitochondrial Eve was actually the history of one particular locus, the mitochondrial genome. But it did tell us quite a bit about the history of the human species, even if in hindsight it looks as if some scientists overinterpreted those findings. One of the major issues I’ve noticed over the past year, with the heightened likelihood of archaic admixture in the modern human genome, is that people regularly get confused by the difference between total genome ancestry, and the evolutionary history of one particular gene.

Consider the possibility that a substantial proportion of the genetic variants at the dystrophin locus amongst Eurasicans (non-Africans) derive from Neanderthals. As I have observed one of my siblings carries only the Neanderthal variant (males have only one copy as this gene is on the X chromosome). Does this mean he is 100% Neanderthal? Obviously not. The patterns at one gene tell you the history of that one gene. Since the patterns across genes are correlated because of shared evolutionary history (ergo, the existence of geographical racial clusters) one gene can tell you more than just its own history because you are aware of the correlations. But you can’t take this too far. My sibling is less than 5% Neanderthal across his whole genome. He just happens to be “100% Neanderthal” at that gene. There isn’t a great contradiction here. His genome is not a Platonic ideal or a pure category of human vs. non-human.

I bring this up because a few months ago I relayed the findings at a conference as to the evidence of lots of introgression into the human genome from archaic hominins on immune related loci. The paper reporting those findings is now out in Science, The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans:

Whole-genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic HLA class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems.

Introgression implies more than just ancestry. These results indicate that Denisovan ancestry at particular immunologically relevant loci is rather high amongst East Asian groups which have no discernible Denisovan ancestry across the total genome. Presumably that’s an artifact of the limits of statistical power in detecting very low levels of admixture. But out of tens of thousand of genes it is not unimaginable that there are some few gene copies from exotic sources which turn out to be adaptive, and so favored over “native” alleles (cultural analogs come to mind; the Roman language remains, but the Roman religion has been replaced by a Jewish derived sect). The paper has little new beyond the conference talk. Note this result:

From the combined frequencies of these six alleles, we estimate the putative archaic HLA-A ancestry to be >50% in Europe, >70% in Asia, and >95% in parts of PNG (Fig. 4, C and D). These estimates for HLA class I are much higher than the genome-wide estimates of introgression….

More precisely, the introgression estimates are around an order of magnitude greater than admixture. Intriguingly the authors note that though most Africans exhibit some evidence of introgression from Eurasian populations, Khoisan and Pygmies do not. This seems to point to the possibility that the generic class “African” may hide a lot of interesting population structure and history. It is clear that peoples from the Horn of Africa seem to have been recently influenced by Eurasian groups, but it may be that West and East Africans more generally have been touched by deep-time back-migrations. Though I’ve been skeptical of attempts to portray Khoisan and Pygmies as “ur-humans,” these results suggest that that characterization may be closer to the mark than I had argued earlier.

(Republished from Discover/GNXP by permission of author or representative)
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Razib Khan
About Razib Khan

"I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. If you want to know more, see the links at"