eFfing Fossil Friday: Frozen Femur

A 45,000 year old human femur from Siberia provides new information about genetic mutation rates and modern human origins. As Quiaomei Fu and colleagues report in this week’s issue of Nature, this seemingly simple leg bone carries so much information, not because of its gross anatomy, but because of the ancient DNA it preserves.

The femur wasn’t discovered by paleontologists, but by an artist/historian looking for fossils around the Irtysh River. The bone came from from a site called Ust’-Ishim, only some 650 km north of the snowy capital where I work in Kazakhstan:


The site in question, Ust’-Ishim is marked by the yellow star. The red and blue sites to the southeast are other Upper Paleolithic sites. Okladnikov (3) and Denisova (4) have also yielded fossils preserving ancient DNA. Modified from Fu et al. figure 1.

The bone was directly radiocarbon dated to around 45,000 years ago. With a fairly precise age of the bone, Fu et al. could estimate the rate at which genetic mutations arise, by counting the number of new mutations in recent humans that aren’t shared by the Ust’-Ishim femur. This led to an estimate of around 0.43×10−9  new mutations per site per year. This is a relatively low rate compared to estimates based on geologically older fossils, but consistent with more recent estimates that directly compare parents and offspring.

The Ust’-Ishim individual had levels of Neandertal ancestry comparable to living Eurasians (~2.3% of the genome), but there is no evidence of any Denisovan ancestry. Because this individual lived closer to the date of modern-Neandertal admixture, the Neandertal segments of its genome are longer than in modern people (recombination over generations breaks these regions apart into shorter segments). Knowing about recombination rates, Fu et al. could infer that admixture between Neandertal and modern human populations occurred between 50-60,000 years ago.

This eFfing Friday fossil provides more tantalizing evidence for DNA-bearing human fossils just across the Kazakhstan border. With Ust’-Ishim to the north, Denisova and Okladnikov caves to the east, and Teshik Tash to the south, my colleagues and I are very keen to find similar sites here on the KZ side.

Reference: Fu et al. 2014. Genome sequence of a 45,000-year-old modern human from Siberia. Nature 514: 445–449. doi:10.1038/nature13810.

And so the plot thickens

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.

I’m sure it will turn out to be more complex still. Onward and upward!

Freely available online through the PNAS open access option.”


Here you go
Skoglund P and Jakobsson M. Archaic human ancestry in East Asia. Proceedings of the National Academy of Sciences in press. doi:10.1073/pnas.1108181108.

Neandertal mtDNA genome sequenced

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 HomoPan 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 HomoPan 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


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]–>