ancient DNA

Denisova the Menace

/ zcofran / Leave a comment

Johannes Krause and colleagues reported yesterday in Nature‘s advance online publication, on a new hominin mitochondrial DNA (mtDNA) genome. The genetic material is derived from a finger bone which lacks diagnostic morphology, from a southern Siberian site called Denisova dating to between 30 – 50 thousand years ago. Of note, the authors describe that the mtDNA is about twice as different from humans as any neandertal mtDNA is from modern humans. If the human-neandertal mtDNA divergence is accurately estimated at around 450 thousand years ago, that means this mystery specimen’s mtDNA lineage diverged from the human-neandertal line around 1 million years ago.

This is really interesting, because also around 40 thousand years ago, but from a site some 100 km to the west of Denisova, bones that were morphologically non-diagnostic yielded mtDNA basically identical to Neandertals.
Does this speak to the presence of at least 3 human species running around the Old World around 40 thousand years ago? Not necessarily. Most claims of a speciose recent human fossil record are based on cranial morphology. For example, modern human skulls are fairly different from “classic” neandertal skulls of western Europe (which is why the Skhul and Qafzeh hominins which display characteristics of both groups are so interesting). However, the mtDNA we have of most of these specimens comes from non-diagnostic specimens. The first Neandertal mtDNA studied came from a piece of tibia (shin bone); this bone is basically non-diagnostic morphologically between recent hominins, and the site it came from (Vindija, Croatia) has both human and Neandertal remains. The Denisova finger, similarly, is non-diagnostic in morphology so far as I can tell, and the archaeological layer contains both Middle and Upper Paleolithic cultural materials: we have no idea what these mtDNA bearers looked like.
I think people thinking “new species at Denisova” (NB: Krause and colleagues never make this claim!) would be shocked if it turns out that the Denisova remains, or those from which the Vindija specimens came, were morphologically modern humans, but this is entirely possible.
Humans today are not so diverse genetically as superficial appearances may suggest to many people. I wouldn’t be surprised if humans simply displayed more genetic diversity in the past. It is certainly interesting just how different the Denisova genome is from both humans and Neandertals. What exactly this difference means is just not clear. It is further interesting to note that the coding regions of the Denisova mtDNA show signs of strong purifying selection. Assumptions of neutrality are so important for genetic studies that I think people often forget that mtDNA actually serves functions necessary to survival, and is not actually neutral. Maybe this ancient mtDNA lineage lasted so long because the mitochondria provided some selective advantage, hence the purifying selection? Who knows?!
The authors make a funny deduction that I can’t quite follow, that because the Denisova specimen’s mtDNA diverged from humans-neandertals some 1 million years ago, “it was distinct from the initial radiation of H[omo] erectus that first left Africa 1.9 million years ago, and perhaps also from the taxon H. heidelbergensis,” which is the name given to mainly European but also African fossils between 1 and 0.5 million years ago. I just don’t follow this. We don’t know what mtDNA diversity was like at any of these times, so there is no reason to think that this specimen’s ancestors were from some undocumented dispersal from Africa. The implicit assumption is that mtDNA lineages arise sporadically and discretely from Africa and then spread to different parts of the world, repeatedly over the course of human evolution. If there’s gene flow all around from the get-go, then the Denisova specimen simply represents an especially ancient mtDNA lineage – not necessarily an ancient population (recall that mtDNA is only inherited from mothers).
Oh well, should be interesting to see the nuclear DNA from this specimen, surely to be described in the near future…
Reference
Krause J, Fu Q, Good JM, Viola B, Shunkov MV, Derevianko AP, Paabo S. 2010. The complete mitochondrial DNA genome of an unknown hominin from southern Siberia. Nature, in press.

Neandertal mtDNA genome sequenced

/ zcofran / Leave a comment

A neandertal mtDNA genome has been sequenced <!–[if supportFields]> ADDIN EN.CITE Green200840440417Green, Richard E.Malaspinas, Anna-SapfoKrause, JohannesBriggs, Adrian W.Johnson, Philip L. F.Uhler, CarolineMeyer, MatthiasGood, Jeffrey M.Maricic, TomislavStenzel, UdoPrüfer, KaySiebauer, MichaelBurbano, Hernán A.Ronan, MichaelRothberg, Jonathan M.Egholm, MichaelRudan, PavaoBrajkovic, DejanaKucan, ZeljkoGusic, IvanWikström, MårtenLaakkonen, LiisaKelso, JanetSlatkin, MontgomeryPääbo, SvanteA Complete Neandertal Mitochondrial Genome Sequence Determined by High-Throughput SequencingCellCell416-4261343CHEMBIODNAECO_EVOL2008http://www.sciencedirect.com/science/article/B6WSN-4T5BPWS-C/2/f0b90ab2a8efae1fa309863a20f37464 <![endif]–>(Green et al. 2008)<!–[if supportFields]><![endif]–>, the specimen coming from the Croatian site of Vindija, some 38 kya. The paper’s verdict: “Neandertal mtDNA falls outside the range of variation of modern humans.” So though they don’t explicitly say it, it sounds like the conclusion is that, based on mtDNA, neandertals were a separate species from the humans that inhabit the globe today. Is this the end of the story? Hardly.

First, a technical note. The team used the “high-throughput 454 sequencing technique”, and since I am not a geneticist and could barely understand what the technique involves when I looked into it, all I can gather is that the method creates more sequence copies than traditional PCR (polymerase chain reaction). Perhaps a colleague can enlighten me and other readers on this technique? Also, the team took strong precautions that pretty much ensured that the sample wasn’t (significantly) contaminated with modern human mtDNA. Cool beans, the future today.

Anyway, what’s important is that this complete sequence (from a single individual) allows researchers to do whole mtDNA comparisons of neandertals with modern humans, to try to answer a riddle that is hotly debated in Paleoanthropology—whither Neandertals? Was there admixture between the archaic humans endemic to Eurasia (Neandertals) and the immigrating modern humans coming from Africa?

Now, in general I don’t care that much about neandertals. In my mind, they’re just a form of H. sapiens, albeit probably a homely form. But what I do care about (lately) are patterns of speciation in primates and human origins, so the question of modern-human-neandertal admixture is an interesting one to me. Green and colleagues inferred from the Vindija mtDNA that humans and neandertals were distinct (i.e. probably separate species)—a level of separation I don’t know I can agree with. When the team compared sequence differences between the neandertal and 53 modern humans from around the globe, they found that there are more differences between the neandertal and each human than there are between any pair of humans. This is in contrast to previous studies that looked only at the HRVI and HRVII regions of mtDNA, which found more overlap (less difference) between humans and neandertals. So this underscores the importance of using whole genomes for analysis, rather than a few genes.

Next the team estimated the human-neandertal divergence, assuming a molecular clock with a Homo–Pan divergence of 6-8 mya. This yielded a divergence date of 660,000 years, with the 95% confidence interval of 800,000 to 520,00 years. I suppose this is not too unreasonable. Some 600 kya is roughly the time when H. heidelbergensis is running around Europe and Africa. Their Homo–Pan divergence estimate is not so much to my liking, however. They based this estimate on the fossil record, 8 mya being based on the ~7 my-old Sahelanthropus tchadensis cranium and 6 mya based on the ~6 my-old Orrorin tugenensis material. I might have just stuck with the 6 mya divergence, because Sahelanthropus is not convincingly a hominin or “pre-hominin,” really it’s not convincingly anything but an ape. And 5-6 mya is when we start seeing fossils that really look like hominins, be it the Orrorin femora or the dental and mandibular fossils from E. Africa.

Now, as I asked before, is this the end of the story? No. For starters, this paper only looks at mtDNA, which is only maternally inherited. So we could deduce from this paper that perhaps no neandertal females interbred with modern humans. What will be more informative is a look at nuclear DNA—which the team hopes to have sequenced by the end of this year. Moreover, this single neandertal falls outside the range of variation of modern humans. There are several human mtDNA haplotypes—different lineages of mtDNA (again, I’m not a geneticist, so I don’t know how many or how different—a little help, anyone?). From this single individual we cannot get a good picture of neandertal mtDNA variation (haplotypes). Plausibly if we had more samples of mtDNA from archaic humans (are there any from any Upper Paleolithic modern humans?) we may well see the gap between humans and this neandertal bridged. Of course, on the other hand, we might not. So this paper demonstrates considerable difference between human and neandertal mtDNA, but the case is anything but closed.

Also, as paper commentator A. Clark noted, there are many genes in modern human nuclear DNA that appear to be over 1 my old <!–[if supportFields]> ADDIN EN.CITE Clark200840340317Clark, Andrew G.Genome Sequences from Extinct RelativesCellCell388-38913432008http://www.sciencedirect.com/science/article/B6WSN-4T5BPWS-8/2/ea3c7ee1a50fed191e907fcecd1cf481 <![endif]–>(Clark 2008)<!–[if supportFields]><![endif]–>, and this may suggest that modern humans and archaic populations (including neandertals) may have interbred at least sporadically. He notes, “The long period of coexistence of modern humans and Neanderthals, as well as the great depth of common ancestry of modern human nuclear genes, make it quite plausible that there was opportunity for interbreeding . . . If there had been admixture, say 100,000 years ago, giving modern humans small segregating pieces of our genome with Neanderthal ancestry, it would be nearly impossible to identify them as such, even with full genome sequences.” When two populations intermingle, their offsprings’ genomes will not necessarily simply be a mix of ½ one parent, ½ the other. Rather, often only adaptive genes are able to ‘sneak’ into the other population’s gene pool—a phenomenon known as introgression. It looks like the human FOXP2 gene may well be an example of introgression, and in fact may have introgressed from an archaic population into modern humans <!–[if supportFields]> ADDIN EN.CITE Coop200826526517Coop, GrahamBullaughey, KevinLuca, FrancescaPrzeworski, MollyThe Timing of Selection at the Human FOXP2 GeneMolecular Biology and EvolutionMol Biol EvolMolecular Biology and EvolutionMol Biol Evol1257-12592572008<![endif]–>(Coop et al. 2008)<!–[if supportFields]><![endif]–>. On an interesting aside, geneticist Chung-I Wu has formulated the “genic species concept,” in which species are formed when they can still interbreed and exchange genetic material, but adaptive regions are not exchanged; obviously this intriguing concept is also controversial <!–[if supportFields]> ADDIN EN.CITE Noor200240540517Noor, Mohamed A. F.Is the biological species concept showing its age?Trends in Ecology & EvolutionTrends in Ecology & Evolution153-154174species conceptsspeciationreproductive isolationadaptationhybridizationbiological species concept2002http://www.sciencedirect.com/science/article/B6VJ1-45BCHTS-1/2/befbc7badc90a2be01430b6c1390afd0 <![endif]–>(Noor 2002)<!–[if supportFields]><![endif]–>.

A final point to consider that didn’t come up in Green et al.’s paper is the growing body of evidence that human evolution is accelerating, and has been for the past 40 ky, but especially in the past 10-20 ky <!–[if supportFields]> ADDIN EN.CITE Hawks20071117Hawks, JohnWang, Eric T.Cochran, Gregory M.Harpending, Henry C.Moyzis, Robert K.Recent acceleration of human adaptive evolutionProceedings of the National Academy of SciencesProc Nat Acad SciProceedings of the National Academy of SciencesProc Nat Acad Sci20753-2075810452

20753

Adaptive evolutionhuman evolutionlinkage disequilibriumdemography2007December 26, 2007<![endif]–>(Hawks et al. 2007)<!–[if supportFields]><![endif]–>. This is interesting as the neandertal specimen is 38 ky-old, and other neandertal DNA has come from even older specimens (Krause et al. 2007). I’m not sure at the moment how to interpret this in the context of mtDNA and recent sequencing of neandertal mtDNA. But it should be very important when the team (or someone else) analyzes ancient nuclear DNA, especially given that neandertals (arguably) ‘disappeared’ before human adaptive evolution really began to sprint.

This is an exciting time for anthropological genetics. Techniques are being developed for the extraction and analysis of ancient DNA, which will help shed light on the nature of the emergence of modern humans, and their interactions with archaic populations. At the same time, I am always wary of papers in genetics because of the numbers of assumptions/parameters required by their models.

<!–[if supportFields]> ADDIN EN.REFLIST <![endif]–>Clark AG (2008) Genome Sequences from Extinct Relatives. Cell 134(3):388-389

Coop G, Bullaughey K, Luca F, Przeworski M (2008) The Timing of Selection at the Human FOXP2 Gene. Mol Biol Evol 25(7):1257-1259

Green RE, Malaspinas A-S, Krause J, Briggs AW, Johnson PLF, Uhler C, Meyer M, Good JM, Maricic T, Stenzel U, Prüfer K, Siebauer M, Burbano HA, Ronan M, Rothberg JM, Egholm M, Rudan P, Brajkovic D, Kucan Z, Gusic I, Wikström M, Laakkonen L, Kelso J, Slatkin M, Pääbo S (2008) A Complete Neandertal Mitochondrial Genome Sequence Determined by High-Throughput Sequencing. Cell 134(3):416-426

Hawks J, Wang ET, Cochran GM, Harpending HC, Moyzis RK (2007) Recent acceleration of human adaptive evolution. Proceedings of the National Academy of Sciences 104(52):20753-20758

Krause J, Lalueza-Fox C, Orlando L, Enard W, Green RE, Burbano HA, Hublin J-J, Hänni C, Fortea J, de la Rasilla M, Bertranpetit J, Rosas A, Pääbo S (2007) The derived FOXP2 variant of modern humans was shared with neandertals. Current Biology 17

Noor MAF (2002) Is the biological species concept showing its age? Trends in Ecology & Evolution 17(4):153-154<!–[if supportFields]><![endif]–>