Evidence of ancient admixture between the Denisova and anatomically modern human from Southeast Asia, Oceania, and New Guinea

Reich, D., R. E. Green, et al. (2010). “Genetic history of an archaic hominin group from Denisova Cave in Siberia.” Nature 468(7327): 1053-1060.

Reich, D., N. Patterson, et al. (2011). “Denisova Admixture and the First Modern Human Dispersals into Southeast Asia and Oceania.” American Journal of Human Genetics 89(4): 516-528.

I went to a session that David Reich talked about his research on the Denisova during the American Society of Human Genetics annual meeting in Montreal last month and I had a chance to talk to him briefly after the session.

These articles are the results of collaboration of leading scientists, David Reich (Harvard University), Svante Paabo (Max Planck Institute), Mark Stoneking (Max Planck Institute), Montgomery Slatkin (University of California, Berkeley).  It is really a dream team of scientists.

The most important finding from this project is that they found the evidence of ancient admixture between the Denisova and anatomically modern human from Southeast Asian, New Guinea, Australia, and Oceania.  They estimated that the Denisova contributed up to 7% of genetic materials of modern people from the areas.

Considering that the Denisova was found in southern Siberia, the mechanism of interaction between the Denisova and modern human is difficult to understand.  From reading the articles and talking to David Reich, I am guessing that they considered many scenarios of interaction, but based on their available data, they believe the interaction took place in Southeast Asia.

Another important thing from this project is that now we have better understanding of the relationship between the Denisova and Neanderthals and between the Denisova and anatomically modern human.  The Denisova is more closely related to the Neanderthals than modern human, and they shared an ancestor about 640,000 years ago.  Modern human shared an ancestor with the Denisova and Neanderthals about 804,000 years ago.  The phylogenetic tree constructed from whole genome data was very different from the tree based on mtDNA genome data (See here).

Ancient genome data from archaic human is still limited, but current data favors the Multiregional model and suggests that both Denisova and Neanderthal (go here for the Neanderthal genome) contributed genetic material to the gene pool of anatomically modern human.  If we have a lot more ancient genome data, we may find evidence of substantial genetic contributions from archaic human, completely rejecting simplistic view of Out-of-Africa model.

Targeted Retrieval and Analysis of Five Neandertal mtDNA Genomes

Briggs, A. W., J. M. Good, et al. (2009). “Targeted Retrieval and Analysis of Five Neandertal mtDNA Genomes.” Science 325(5938): 318-321.

Briggs and his colleagues analyzed whole mtDNA genome sequence variation of five Neanderthal samples that they sequenced and one Neandethal sample that previously sequenced.  They found that Neanderthal sequence variation was much smaller than modern humans, even smaller than modern Europeans.  Of 6 total Neanderthal individuals analyzed, two had the exactly same sequence.  It is interesting because only two out of 30 modern Europeans had same mtDNA genome sequence.  Effective population was very small and did not exceed 3,500 females (mean Ne = 1476 and 95% confidence interval between 268 and 3510).  If we take the mean, the total Neanderthal population size is about 8,856 (1476 is multiplied by 2 assuming male-to-female effective population size was same and then multiplied by 3 because effective population size is about 1/3 of actual population size.  Note that effective population size is a long term average of number of people who contributed gene to next generation). 

The authors say that Neanderthal had small mtDNA diversity because they had a small effective population size for a long time during their existence, but their population size could have been reduced significantly, when anatomically modern human expanded into Europe.

This small mtDNA diversity and effective population size among Neanderthal is very interesting, first because Neanderthal population size estimated is smaller than many modern forager populations that are becoming extinct.  Second, lack of clear evidence of phylogeographic structure suggests that sparsely populated Neanderthals were highly mobile and high mobility of robust Neanderthals required high energy consumption.  Third, I wonder if skeletal morphology shows a similar pattern.  Do Neanderthals have less skeletal morphological variation than modern humans?

More information on Neanderthal genome can be found here and here.

Targeted Investigation of the Neandertal Genome by Array-Based Sequence Capture

Burbano, H. A., E. Hodges, et al. (2010). “Targeted Investigation of the Neandertal Genome by Array-Based Sequence Capture.” Science 328(5979): 723-725.

This is the third post on the reports of Neanderthal Genome Project published on Science last week (to read previous post, click here and here).  On the same edition of the science magazine that Green and colleagues published their Neanderthal genome draft sequence, Burbano and colleagues (Note that both Green et al. and Burbano et al are Paabo’s group at Max Planck Institute) address the technical issues analyzing Neanderthal genome.

Burbano et al. used different sequencing method to analyze different Neanderthal remains from Green et al.  Burbano et al. used microarrays to analyze a Neanderthal remain from El Sidrón, Spain, while Green et al used shotgun sequencing technique to analyze three individuals from Vindija cave, Croatia.  There are several disadvantages using the shotgun method.  First, with this method, Green et al. got low coverage of Neanderthal genome sequence.  Second, it is costly to have sequences of many specific loci of your interests from multiple individuals, since sequences are obtained from random fragments of DNA assembled together.  Third, the shotgun sequence method does not work well, when a large amount of microbial DNA is present. 

Burbano et al., on the other hand, demonstrated with microassay method that they can sequence the target locus and have more genome coverage, even with a large amount of microbial DNA.  They found 88 none-synonymous substitutions in 83 genes that alter amino acid sequences, though functional consequences are not known.

Now, I understood that they could not use the shotgun sequencing method to analyze the El Sidrón individual, but I wonder why Green et al. and Burbano et al. did not combine shotgun sequencing and microassay method to analyze the three individuals from Vindija to get more genome coverage and better understanding of Neanderthal genome from these Neanderthal individuals (maybe, they are already doing it).  Probably, we have to wait for a while for them to analyze more Neanderthal individuals and get more genome coverage from each.  Then, we can reevaluate the genes that are unique to human and went through selective sweep.  Also, we can reevaluate Neanderthal-Modern Human admixture pattern. 

In addition to Neanderthal, we also have to wait to see, if they can analyze other archaic humans using either methods.  Better understanding human evolution requires how other archaic humans and modern humans interacted in other parts of the world.

A Draft Sequence of the Neandertal Genome

Green, R. E., J. Krause, et al. (2010). “A Draft Sequence of the Neandertal Genome.” Science 328(5979): 710-722.

Green and his colleagues demonstrated what scientists can do and what kind of information you can get by applying advanced genomic technology to study of Neanderthal remains, but at the same time, we have to remind ourselves that what the Neanderthal genome tell us is still limited and hypothetical, because of small amount of DNA preserved, possible contamination from modern DNA source, chemical damage on the nucleotides, small coverage of genome, and small sample size.  Another reason why it is difficult to understand Neanderthal genome is that Neanderthals are genetically very similar to modern humans.  Several places in the article, the authors say that the Neanderthals are not genetically very different from modern human.

Despite the similarity, from three way comparisons of Neanderthals, modern humans, and chimpanzee, they found many genetic changes occurred only among modern human including 78 nucleotide substitutions that change amino-acid sequence (see the list on Table 2 of the article) and substitutions at regulatory area.  They also found 212 regions that could have changed significantly among modern humans through strong positive selection, or selective sweep.  The top 20 candidate region that selective sweep affected are listed on Table 3 of the article.  These regions include genes that are responsible for metabolism, cognition, and skeletal development.  However, the list will probably change, as they have more Neanderthal genome sequencing coverage and more Neanderthal individual analyzed.

Based on the closer genetic similarity between non-Africans and Neanderthal compared to between modern Africans and Neanderthals that they observed, the authors proposed that gene flow between Neanderthal and ancestors of modern non-Africans occurred.  They estimated the 1 to 4 % of modern human genome is from Neanderthal and according to the authors the most likely scenario is that gene flow between Neanderthals and anatomically modern human occurred possibly in the Middle East, before ancestors of non-Africans radiated from there (Scenario 3 of Fig. 6).  However, the authors also point out that actually Neanderthal genetic contribution could be smaller, if there was surfing effect, or larger, but later migration events erased evidence of ancient admixture.

Alternatively to ancient admixture, the authors also suggest that ancient population structure within Africa can also cause to have closer genetic similarity between Eurasians and Neanderthal, if the population source of the out-of-Africa had a great amount of old genetic variation that Neanderthals and modern human shared.

Now, there are several important questions that need to be addressed.  If anatomically modern humans mated with Neanderthals and other archaic humans, should we considered modern humans, Neanderthals, and other archaic humans as sub-species of a single species, Homo sapience, not different species?  Then, Home Sapience once had a great genetic and morphological variation, but today they are lost somehow.  Should we reconsider who these archaic humans were?  Once anthropologists thought intellectually superior modern humans could not be a same species as Neanderthals that had more primitive culture.  However, archaeological evidence suggests that Neanderthals were capable of more complex thoughts than we originally thought.  How about other archaic humans?  Were they capable of having more complex culture?  Are we so biased and we tend to think we are so unique and Neanderthals and other archaic humans were so different?  Just like the 19th century evolutionary anthropologists who tried to theorize that Europeans were intellectually superior based on the cultural traits that they observed.

For more information, read my post on Neanderthal genome (here and here) or go to my YouTube AnthroGenetics Channel.  I have a playlist on Neanderthal DNA (here).  You can find videos of Green, Krause, Briggs, and Paabo talking about Neanderthal Genome project.

Neanderthal Genome show the evidence of ancient admixture: what are the possible implications?

Last week, two articles on the Neanderthal genome were published on Science.  These articles report the results of Neanderthal genome analyses that many anthropologists and human geneticists were waiting for a long time.  Probably, not many anthropologists and geneticists believe the two extreme opposite view (complete replacement of archaic humans by anatomically modern humans came out of Africa within 100-200,000 years ago vs. continuous gene flow among our ancestors living in different parts of the world from the time of Homo erectus until today), but many wanted to know if archaic humans really disappeared without genetically contributing to modern human gene pool and how much gene flow, or genetic exchange, took place between anatomically modern human and archaic human, if there was.  From human genetics point of view, the important question is what genetic variation is unique to modern human or what genetic variant make us human?

I am going to read through the reports and write about them this week (here for Green et al. and here for Burbano et al.), but on this post, I am going to write about the featured Science Magazine webpage, the Neandertal Genome.  This webpage is recommended for non-geneticists, anthropologists, students, and general public who do not have training in genetics, because the science articles contains full of genetic terms and sophisticated analytical methods.  It provides a basic background on Neanderthal and Neanderthal genome research, summary of the articles, and references.  Also, it has videos of Svante Paabo, Chris Stringer, and Sarah Tishkoff talking about the methods, findings, significance,and implication of the Neanderthal genome project.

Here are some important things that these three specialists talking about the Neanderthal genome, including my comments.  First, because of technical issues as well as small sample size (n=3), at this point, we do not know enough about the Neanderthal genome variation, yet, to examine, for example, if we can find evidence of our gene in the Neanderthal populations.  Second, we have to understand the technical problems that they encountered, because the procedures they chose to fix the problems actually may have biased the results.  Third, they estimated between 1 and 4 % of modern Eurasian genome come from Neanderthal (assuming that contamination from researchers was not problem?).  This raises another question.  Did ancestors of modern humans exchanged genes with other archaic humans, such as new species recently identified in Siberia?  Then, how much can genetic contribution of archaic human to modern human add up?  10%?

However, this research project changed the course of how the field of anthropological genetics progress toward future.  In the near future, I think the focus of the anthropological genetic research will shift from single locus non-gene coding markers, such mtDNA hypervariable region sequence and Y chromosome STR to genomics.  Along with ancient genome study of extinct Eskimo individual, this project has show genomic technology can be applied to ancient DNA analysis to understand pattern of population structure as well as natural selection, hopefully at population level, not individual level.

You can find my comments on Green et al. here and Burbano et al. here and more information on Neanderthal Genome Project at Max Planck Institute Neanderthal genome project webpage, Anthropology.net, John Hawks Weblog, YouTube GenomeTV, and many other sites.


Green, R. E., J. Krause, et al. (2010). “A Draft Sequence of the Neandertal Genome.” Science 328(5979): 710-722.

Burbano, H. A., E. Hodges, et al. (2010). “Targeted Investigation of the Neandertal Genome by Array-Based Sequence Capture.” Science 328(5979): 723-725.

DNA genome of an unknown hominin from southern Siberia

Krause, J., Q. Fu, et al. (2010). “The complete mitochondrial DNA genome of an unknown hominin from southern Siberia.” Nature advance online publication.

This article is very interesting and also covered by Anthropology.net and Prancing Papio.  I believe the research findings presented in this article provide an interesting perspective on the human evolution and genetic diversity existed in the past.

The complete mitochondrial DNA genome of the fossil remain from Denisova Cave in the Altai region of Russia dated to 48 to 30 kyr ago was analyzed.  Their results of analyses show that the Denisova individual was genetically very different from Neanderthals or modern humans.  An average of nucleotide position differences was 385 between the Denisova individual and modern human, which is about twice as many difference between Neanderthals and modern human (202 positions) (Figure 2).

The phylogenetic treesof complete mtDNA show that the ancestors of the Denisova individual sprit from the ancestors of Neanderthals and modern human, before archaic human lineages began diverge (Figure 3).  TMRCA of all three lineages is about one million years ago (mean=1,04,900 with 95% C.I. ranging 779,300-1,313,500).

So, who is this Denisova individual?  Home erectus left Africa and around 1.9 myr ago and was in Asia by 1.7 myr ago, so the Denisova individual was probably not H. erectus (TMRC of three lineages is about one myr ago.  That is after H. erectus spread into East Asia).  If the Denisova is H. erectus much older TMRCA is expected (> 1.9 myr?).  Homo heidelbergensis, probable ancestors of Neantherthals, emerged after divergence of three lineages.  However, since the 95% C.I. of TMRCA slightly overlaps with the time that H. heidelbergensis existed, so we cannot reject the hypothesis of the Denisova individual = a descendant of H. heidelbergenesis, but if H. heidelbergenesis were ancestors of Neanderthals, the ancestors of Neanderthals and the Denisova individual were genetically quit different.

The findings from this project generally support Huff et al. (2010) and these two projects have shown that great genetic diversity existed in the past (> 30,000 years ago).  It is very interesting that there were many species or subspecies of Home may have co-existed in some parts of the world.  Around time the Denisova individual lived, there is also possible existence of Neanderthal and anatomically modern human in the area (Don’t forget H. erectus existed in East Asia about same time).  However, only anatomically modern human survived and others disappeared without leaving clear genetic evidence of ancient admixture.

Update (April 1, 2010)

I forgot about H. ergaster and that is another possibility in addition to H. heidelbergensis.  If we believe that Asian H. erectus was a different species from African H. ergaster who were direct ancestors of H. heidelbergenesis, H. neanderthalensis, and H. sapiens, the Denisova individual could be a descendant of H. ergaster who took very different evolutionary path from Neanderthals and Anatomically modern human.  The 95% C.I. of TMRCA (1.-0.7) also slightly overlap with the time H. ergaster existed in East Africa (1.8-1.3 mya).  If we believe this scenario, first there was an out of Africa event of H. erectus into Asia and then another out of Africa event of H. ergaster into Western Eurasia.  However, TMRCA is too young for Asian H. erectus and all others to share the common ancestor that recent, so mtDNA of the Denisova individual is not that of H. erectus.  Of course, we are talking about only maternal side of evolutionary history.

Updata (April 3, 2010)

I considered the possibility of an unsampled Neanderthal, but I thought that the TMRCA is too old, considering that Neanderthals analyzed so far is genetically not diverse and effects of drift affecting mtDNA is strong because of small effective population size of mtDNA.  If, in fact, the Denisova individual was a Neanderthal, Neanderthal was genetically much more diverse than many genetic researchers thought and phylogenetic tree suggests that Neanderthals were ancestors of modern human.   Judging from the genetic evidence we have, this is unlikely scenario.  Of course, we should not conclude that the Denisova individual was not Neanderthals, because we do not know enough about this individual or human evolution.