mtDNA sucks for inferring hominin relationships

Ancient DNA studies keep on delivering awesome findings about human evolution. Continuing this trend, Matthias Meyer and colleagues report today in Nature nuclear DNA (nDNA) sequenced from  ~430,000 year old humans from the Sima de los Huesos (SH) site in Spain. SH is badass not only because the name translates as “pit of bones,” but also because the pit has yielded hordes of fossils comprising at least 28 people (Bermudez de Castro et al., 2004), and some of these bones preserve the oldest human DNA yet recovered (Meyer et al., 2013).

Point 1 in Northern Spain, is Sima de los Huesos. The rest of the points are other sites where hominin fossils preserve ancient DNA. Figure 1. From Meyer et al. 2013.

Point 1 in Northern Spain, is Sima de los Huesos. The rest of the points are other sites where hominin fossils preserve ancient DNA. Figure 1. From Meyer et al. 2013.

Anatomically, the SH hominins have been interpreted as “pre-Neandertals,” having many, but not all, of the characteristics of geologically younger fossils we know as Neandertals. Mitochondrial DNA (mtDNA) obtained from one of the SH femurs was found, surprisingly,to be more similar to Densivan than to Neandertal mtDNA (Meyer et al., 2013), not what would be expected if the SH hominins were early members of the Neandertal lineage. Meyer et al. interpreted this to mean that perhaps the SH hominins were ancestral to both Neandertals and Denisovans, though they noted that nDNA would be necessary to uncover the true relationships between these fossil groups.

Writing about the SH mtDNA in 2013, I noted that mtDNA has failed to reflect hominin relationships before. The distinctiveness of Denisovan mtDNA initially led to the idea that they branched off before the Neandertal-modern human population divergence (Kraus et al. 2010), and therefore that humans and Neandertals formed a clade. Later, nDNA proved Denisovans and Neandertals to be more closely related to one another than to humans (Reich et al., 2010). Then I’m all like, “Hopefully we’ll be able to get human nuclear DNA from Sima de los Huesos. When we do, I predict we’ll see the same kind of twist as with the Denisova DNA, with SH being more similar to Neandertals.”

I made that prediction right before telling Josh Baskin he’d be big.

And lo, Meyer et al. (2016) managed to wring a little bit more DNA out of this sample, and what do they find: “nuclear DNA sequences from two specimens … show that the Sima de los Huesos hominins were related to Neandertals rather than Denisovans” (from the paper abstract).

This is not a surprising outcome. The SH hominins look like Neandertals, and mtDNA acts a single genetic locus – the gene tree is unlikely to reflect the species tree. What’s more, this is similar to the story mtDNA told about human and Neandertal admixture. The lack of Neandertal mtDNA in any living (or fossil) humans was taken to reflect a lack of admixture between early humans and derelict Neandertals, but more recent nDNA analysis have clearly shown that our ancestors couldn’t help but become overcome with lust at the sight of Neandertals (and Denisovans) in Eurasia.

So here ancient DNA corroborates the anatomy that suggested the SH hominins were early members of the Neandertal lineage. This new study also raises the question as to what’s going on with mtDNA lineages – Meyer et al. suggest that the SH mtDNA was characteristic of early Neandertals, later to be replaced by the mtDNA lineage possessed by known Neandertals. They suggest an African origin for this new mtDNA, though I don’t see what that has to be the case. It also raises the question whether the difference in early (SH) vs. later Neandertal mtDNA reflects local population turnover/replacement, or a selective sweep of an adaptive mtDNA variant. Either way, Meyer et al. have done a remarkable job of making astounding discoveries from highly degraded, very short bits of super old DNA. I can’t wait to see what ancient DNA surprises are yet to come.

Bermudez de Castro, JM., Martinón-Torres, M., Lozano, M., Sarmiento, S., & Muela, A. (2004). Paleodemography of the Atapuerca: Sima De Los Huesos Hominin Sample: A Revision and New Approaches to the Paleodemography of the European Middle Pleistocene Population Journal of Anthropological Research, 60 (1), 5-26 DOI: 10.1086/jar.60.1.3631006

Krause, J., Fu, Q., Good, J., Viola, B., Shunkov, M., Derevianko, A., & Pääbo, S. (2010). The complete mitochondrial DNA genome of an unknown hominin from southern Siberia Nature, 464 (7290), 894-897 DOI: 10.1038/nature08976

Meyer, M., Fu, Q., Aximu-Petri, A., Glocke, I., Nickel, B., Arsuaga, J., Martínez, I., Gracia, A., de Castro, J., Carbonell, E., & Pääbo, S. (2013). A mitochondrial genome sequence of a hominin from Sima de los Huesos Nature, 505 (7483), 403-406 DOI: 10.1038/nature12788

Meyer, M., Arsuaga, J., de Filippo, C., Nagel, S., Aximu-Petri, A., Nickel, B., Martínez, I., Gracia, A., de Castro, J., Carbonell, E., Viola, B., Kelso, J., Prüfer, K., & Pääbo, S. (2016). Nuclear DNA sequences from the Middle Pleistocene Sima de los Huesos hominins Nature DOI: 10.1038/nature17405

Reich, D., Green, R., Kircher, M., Krause, J., Patterson, N., Durand, E., Viola, B., Briggs, A., Stenzel, U., Johnson, P., Maricic, T., Good, J., Marques-Bonet, T., Alkan, C., Fu, Q., Mallick, S., Li, H., Meyer, M., Eichler, E., Stoneking, M., Richards, M., Talamo, S., Shunkov, M., Derevianko, A., Hublin, J., Kelso, J., Slatkin, M., & Pääbo, S. (2010). Genetic history of an archaic hominin group from Denisova Cave in Siberia Nature, 468 (7327), 1053-1060 DOI: 10.1038/nature09710

Dawn of Paleoepigenomics

It was only a matter of time. In the 1990s scientists started extracting, sequencing and analyzing mitochondrial DNA from Neandertal fossils. In the 2000s they made major advances in obtaining and analyzing ancient nuclear DNA, which is much trickier than mtDNA. In just the past year, paleogeneticists pushed the envelope in sequencing truly ancient DNA, announcing hominin and horse genomes from 400 and 700 thousand years ago, respectively. As I mentioned a few months ago, the burgeoning field of paleogenomics is revealing things about human evolution that could hardly be dreamt of only a few decades ago.

But world of DNA is so much more than just ceaseless sequences of four letters, and the field of ‘epigenetics’ has emerged to investigate the complex way that chemical alterations to DNA structure (not sequence) affect gene expression. Melding epigenetics & paleogenomics, David Gokhmen and colleagues report in Science, “Reconstructing the DNA methylation maps of the Neandertal and the Denisovan.” For a review of what DNA methylation is and does, check out this Scitable overview. In short, DNA methylation is part of the reason why not all of your genes in your genome are expressed at all times throughout your body, even though all of your genes are physically present in all of the cells of your body. Methylation plays an important role in turning genes on or off during development. It’s nuts. Now, the structure of DNA breaks down over time after an animal dies, obscuring original methylation patterns. But the decompositoin process is becoming better understood, including patterns at methylated vs. unmethylated sites. As Gokhmen et al. write, these patterns “may serve as a proxy for the levels of methylation in ancient DNA.”

This brilliant insight allowed Gokhmen and colleagues to identify some 2000 genomic regions in bone cells that differed in methylation between a living human, a Neandertal and a Denisovan (2000 less than 1% of all regions). One such region was the HOXD cluster, which is known to be involved in embryonic limb development. Neandertals and Denisovans were more methylated than humans at the HOXD9 and HOXD10 loci. Whether and how these epigenetic differences might be responsible for anatomical differences between these populations is not at all clear yet. But Neandertals are known to differ from humans in some aspects of arm and leg anatomy – authors point out that Neandertals generally have larger and more robust joints but shorter limbs. They state, “together, these findings suggest that the HOXD cluster might have played a key role in the recent evolution of human limbs.”

Importantly, “Denisovans” are only known from 2 teeth and part of a finger bone, no other limb fossils are known (or at least published) for this ancient population. This leads us to a prediction – if the similarly hypermethylated HOXD sites in Denisova and Neandertals are functionally important, then Denisovan limb fossils, if ever found, should be more like Neandertals than like humans. If this prediction is borne out, this would provide evidence of specifically how HOXD9-10 affect limb development, and how HOXD epigenetic regulation has changed in human evolution. This hypothesis can be tested, but only with the discovery of the right fossils (i.e., genetically attributable to Denisovans). Well, the functional importance of hyper/hypomethylation at these sites could probably also be assessed with transgenic mouse experiments…

There is truly remarkable work being done in paleogenomics – and now paleoepigenomics – which will probably begin to form the basis of some exciting new human evo-devo research.

This human DNA is old as hell

If hell were around 400,000 years old. The people who salvaged ancient DNA from fossil Neandertals and “Denisovans” now present mitchondrial DNA (mtDNA) from a human-ish fossils from the Spanish site of Sima de los Huesos (SH; this translates as “pit of bones,” by the way, which is pretty badass). DNA-bearing Neandertal sites and Denisova cave date anywhere from around 30-100 kya, while Sima de los Huesos has been dated by various methods to 300-600 thousand years ago. So the newly announced mtDNA is the oldest human DNA ever recovered…


Now, we know what Neandertals look like, since they are perhaps the best known group of fossil humans. We don’t really know what Denisovans look like, as their unique DNA came from fossils that are anatomically ambiguous (a large molar and the end of a tiny fragment of the bone at the end of your pinky finger) – they could look like anyone. Even you! The SH fossils predate Neandertals by a few hundred thousand years, but their skulls look pretty similar; quite possibly the SH populations were ancestors of Neandertals, and you’d expect the DNA to be similar in the two groups.

So researchers were surprised to find this SH mtDNA to be more similar to Denisovan than to human or Neandertal mtDNAs. But this actually shouldn’t be that surprising, since we saw the same twist when Denisovan mt and nuclear DNA was sequenced – mtDNA first made it look like humans and Neandertals were more closely related, and the ancestors of Denisovans separated from the human+Neandertal lineage in the deep past. However, mtDNA essentially acts as a single genetic locus – a gene tree isn’t necessarily a species tree – and the more informative nuclear DNA later showed Neandertals and Denisovans to be more closely related to one another than either was to living humans (yet each of these ancient populations contributed some genes to some living people today). Denisovans held on to a very ancient mtDNA lineage, and apparently so did the people represented at Sima de los Huesos. And let’s not forget, we don’t know what Denisovans looked like – maybe they looked just like the older SH fossils.

Hopefully we’ll be able to get human nuclear DNA from Sima de los Huesos. When we do, I predict we’ll see the same kind of twist as with the Denisova DNA, with SH being more similar to Neandertals. But if I’m wrong, maybe we’ll be a step closer to knowing what the bones of the the mysterious “Denisovans” looked like…

Here’s that paper: Meyer et al. in press. A mitochondrial genome sequence of a hominin from Sima de los Huesos. Nature. doi:10.1038/nature12788

Ancient DNA & admixture: One of Science’s breakthrough in 2011

The high-profile journal Science has compiled a list of the top breakthroughs of 2011, some of the most major discoveries and and advances across scientific fields. The top breakthrough was research finding that antiretroviral drugs can act not only to treat patients infected with HIV, but also these antiretrovirals significantly reduce the likelihood of transmission of the disease. This is a pretty effing big deal, as HIVand AIDS are tragically rampant in many parts of the world.

One of the runners-up to this breakthrough: “Archaic Humans’ DNA lives on.” The brief exposé highlights the studies from this year that corroborated the 2010 evidence for Neandertal and “Denisovan” DNA in living people. The exposé concludes with a short and rather out-of-the-blue paragraph about the Australopithecus sediba fossils from Malapa. How about that – anthropological research as a major scientific breakthrough; FL governor Rick Scott certainly didn’t see that one coming.
See for yourself:
Anonymous (2011). The Runners-Up Science, 334 (6063), 1629-1635 DOI: 10.1126/science.334.6063.1629

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.

A species by any other name…would leave us with the same problem

This is a great big week for anthropology coverage. The sequencing of the orangutan (Pongo species) genome made the cover of Nature. It’s grant-writing-dissertation-formulating-prelim-studying time for me so I haven’t had a chance to read this one yet. Science has a couple paleoanthropology-related stories, including two by Ann Gibbons. The first is about recent research on ancient DNA, and how this informs the debate about ‘modern human’ origins. But there’s also a short blurb on what the eff “species” means.

This is a great effing question! The textbook species definition is that proffered by Ernst Mayr: populations of actually or potentially interbreeding individuals, capable of producing viable (and fertile) offspring. Cool, so a dog and a cat are different species because if they mated (ew) no ungodly animal would come from this monstrous union. Expensive high-tech multivariate Scientific reconstruction simulations show the abomination would probably look like this:
But there are many “good” plant and animal species that do mate and reproduce successfully (‘hybridize’). Very often these hybrids are sterile, but then very often they’re not. This has led researchers to come up with scores of other ways to define species (Holliday (2003) has a great discussion on the matter).
Worse, there’s no way to measure, genetically or morphologically, just how different things should be before they can be called different species. The late Morris Goodman and others (Wildman et al. 2003) argued that humans and chimpanzees are so genetically similar that chimps, now in the genus Pan, should be moved to our genus Homo to denote how similar we are. But any other, non-genetic comparison would put our chimp cousins in a very different group from us. Moreover, the effects of hybridization seem, to me at least, to be fairly unpredictable, at least superficially. That is, the outcome of hybridization is highly contingent on what animals are hybridizing, and on these lineages’ own evolutionary histories (this is the intractable problem that made me abandon doing hybrid work for my dissertation. Some day though…).
A major issue relates to what I blogged about yesterday: both ‘species’ and ‘hybrid’ are terms we’ve found ourselves with, but they have no inherent meaning in themselves, other than whatever we give them. So it’s funny to read this from Gibbons’ story:

In the real world, [Jean-Jacques Hublin] says, Mayr’s concept doesn’t hold up: “There are about 330 closely related species of mammals that interbreed, and at least a third of them can produce fertile hybrids.”

But is it Mayr’s species concept that’s flawed, or was it misguided to have put these hybridizers into different species in the first place? Should we delineate species based on our a priori conception about whether two things are different, or should a definition of ‘species’ determine what we call them? Or does it even matter?
To this end, Gibbons’s other story describes the morphologically-unremarkable Denisova fossils as belonging to “a new type of human.” Well, now what the eff does that mean? We’re back to “The Species Problem” (the title of Gibbons’s article), but with a new term. And pretend for a moment that the Denisovan fossils didn’t yield DNA: the pinky and tooth probably would not have made headlines. Pretend they did have diagnostic cranial remains – would we have recognized them as being so distinct as their genes indicate?
For that matter, I wonder how many arguably ‘modern’ human fossils would still retain the modern moniker if we could analyze their genes…
Gibbons, A. (2011). The Species Problem Science, 331 (6016), 394-394 DOI: 10.1126/science.331.6016.394
Gibbons, A. (2011). A New View Of the Birth of Homo sapiens Science, 331 (6016), 392-394 DOI: 10.1126/science.331.6016.392
Holliday, T. (2003). Species Concepts, Reticulation, and Human Evolution Current Anthropology, 44 (5), 653-673 DOI: 10.1086/377663
Wildman, D. (2003). Implications of natural selection in shaping 99.4% nonsynonymous DNA identity between humans and chimpanzees: Enlarging genus Homo Proceedings of the National Academy of Sciences, 100 (12), 7181-7188 DOI: 10.1073/pnas.1232172100

01/01/2011: Looking forward and backward, so fast you may barf

2010 was a big year for anthropology and lawn-chair-anthropologists. There was laughter and crying, and maybe also some yelling. And smiling. Let’s take a look back at some of the big events of the past year.

  1. Ancient DNA. What a great year for ancient human DNA! In April, Krause and colleagues (2010) announced the sequencing of mitochondrial DNA from a ~50,000 year old girl from Denisova in Siberia. This sequence was twice as divergent from humans as Neandertal mtDNA, which really shocked a lot of people. Then just a week or so ago Reich and colleagues (2010) announced nuclear DNA from the site. The big news was that these ancient humans contributed genes to modern day Melanesians, but not other modern humans sampled. In May, Green and the Pääbo lab announced a draft sequence of the Neandertal nuclear genome. Like with the Denisova story, Neandertal mtDNA is fairly distinct from that of modern humans, and the nuclear genome revealed contribution to some modern humans but not to others. Basically, ancient DNA came out supporting the multiregional model of modern human origins.
  2. Malapa hominids. Lee Berger and researchers announced a new fossil site, Malapa, in South Africa. This site yielded 2 partial skeletons (and others forthcoming), including a very well-preserved skull of a subadult. Superficially the thing looked to me like Australopithecus africanus, though the authors argue that it shows some features derived toward the condition of early Homo. But at an estimated 1.9-1.7 million years old, it’s a little too young to have anything to do with the origin of Homo – not to mention its small 400 cubic centimeter cranial capacity. I really don’t know what to do with Malapa yet.
  3. Woranso-Mille Australopithecus afarensis. This site dates to around 3.6 million years ago, so it’s roughly contemporaneous with Laetoli afarensis, or intermediate in age between Laetoli and later afarensis sites like Maka and Hadar. Haile-Selassie and colleagues described a partial skeleton from the site. This male includes part of the pelvis, which didn’t get much coverage. But it has a 1st rib, scapula and clavicle, indicating a fairly human-like (rather than ape-like) torso shape. So even for how well we know A. afarensis, we’re always learning more about our ancestor.
  4. Saadanius hijazensis and catarrhines. I didn’t blog about this one at the time as I was getting ready to hit the field. But this was exciting because Iyad Zalmout and friends here at UM discovered and analyzed it. Saadanius was found in ~29 million year old deposits in Saudi Arabia, right around the estimated time of origins of apes. The fossil looks like an Aegyptopithecus to my untrained eye, but apparently may be similar to the last common ancestor of apes and old world monkeys.
  5. Field work. I had my first (of hopefully more!) field season at Dmanisi in Georgia. Paleoanthropology would be nothing without fossils, so an important aspect of the job I’d like to do more of is increasing the fossil record. Dmanisi is an amazing place for this, being among the oldest human sites outside Africa, and the interesting ‘intermediacy’ of the Dmanisi hominids between early Homo and more classic H. erectus. We found some great stuff last year, and I anticipate the site will produce more great fossils in the future. Who knows, maybe more fossiliferous deposits will be found in nearby regions?
So it was a helluva year, 2010. What excitement will 2011 bring? Here are some things I’d like to, or expect to, see this year:
  1. More ancient DNA – the surprise that many researchers got from Denisova and Neandertal ancient DNA clearly warrants more work on other ancient DNA. What does that of other fossil humans look like? Will the picture of human origins become further complicated (that is, different from paradigmatic out-of-Africa replacement)? In this regard we need to analyze DNA from more late Pleistocene fossils regarded as ‘anatomically modern.’
  2. a) More about Malapa. I want to say I heard somewhere that there were more hominids than just the 2 presented in the Science paper. These additional specimens will provide further evidence, including what variation within the site was like, and how it fits with other South African specimens. From the appearance of things, these fossils may be late-persisting A. africanus, somehow contemporaneous (roughly sympatric?) with A. robustus and possibly early Homo. Perhaps more work on the geology and taphonomy of Malapa will show it to be older, contemporaneous with the nearby site of Sterkfontein known for abundant A. africanus fossils? Probably not.

    b) More hominid sites and fossils in South Africa. One thing that was neat about Malapa was that it was from slightly outside the rest of the South African ‘cradle’ sites like Sterkfontein, Kromdraai, Drimolen, and Swartkrans. When I was in the area in 2008 I went with some researchers on survey of the Sterkfontein valley, new sites are definitely being sought. Perhaps 2011 will see the discovery of more Malapa-like sites?
  3. Human fossils from East Asia. Maybe even ancient DNA recovery from the region. East Asia has long been thought to be a potential ‘center’ of human origins. Earlier in the year, fossils coming from Zhirendong suggest some of the earliest evidence of chin, arguably a ‘modern human’ feature. Recent fossil and genetic discoveries ought to usher a renewed vigor in examining human evolution in Asia.

That’s all I feel like doing for now. Happy New Year, all!
Berger, L., de Ruiter, D., Churchill, S., Schmid, P., Carlson, K., Dirks, P., & Kibii, J. (2010). Australopithecus sediba: A New Species of Homo-Like Australopith from South Africa Science, 328 (5975), 195-204 DOI: 10.1126/science.1184944
Cann, R., Stoneking, M., & Wilson, A. (1987). Mitochondrial DNA and human evolution Nature, 325 (6099), 31-36 DOI: 10.1038/325031a0
Green, R., Krause, J., Briggs, A., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M., Hansen, N., Durand, E., Malaspinas, A., Jensen, J., Marques-Bonet, T., Alkan, C., Prufer, K., Meyer, M., Burbano, H., Good, J., Schultz, R., Aximu-Petri, A., Butthof, A., Hober, B., Hoffner, B., Siegemund, M., Weihmann, A., Nusbaum, C., Lander, E., Russ, C., Novod, N., Affourtit, J., Egholm, M., Verna, C., Rudan, P., Brajkovic, D., Kucan, Z., Gusic, I., Doronichev, V., Golovanova, L., Lalueza-Fox, C., de la Rasilla, M., Fortea, J., Rosas, A., Schmitz, R., Johnson, P., Eichler, E., Falush, D., Birney, E., Mullikin, J., Slatkin, M., Nielsen, R., Kelso, J., Lachmann, M., Reich, D., & Paabo, S. (2010). A Draft Sequence of the Neandertal Genome Science, 328 (5979), 710-722 DOI: 10.1126/science.1188021
Haile-Selassie, Y., Latimer, B., Alene, M., Deino, A., Gibert, L., Melillo, S., Saylor, B., Scott, G., & Lovejoy, C. (2010). An early Australopithecus afarensis postcranium from Woranso-Mille, Ethiopia Proceedings of the National Academy of Sciences, 107 (27), 12121-12126 DOI: 10.1073/pnas.1004527107
Krause, J., Fu, Q., Good, J., Viola, B., Shunkov, M., Derevianko, A., & Pääbo, S. (2010). The complete mitochondrial DNA genome of an unknown hominin from southern Siberia Nature, 464 (7290), 894-897 DOI: 10.1038/nature08976
Liu W, Jin CZ, Zhang YQ, Cai YJ, Xing S, Wu XJ, Cheng H, Edwards RL, Pan WS, Qin DG, An ZS, Trinkaus E, & Wu XZ (2010). Human remains from Zhirendong, South China, and modern human emergence in East Asia. Proceedings of the National Academy of Sciences of the United States of America, 107 (45), 19201-6 PMID: 20974952
Reich D, Green RE, Kircher M, Krause J, Patterson N, Durand EY, Viola B, Briggs AW, Stenzel U, Johnson PL, Maricic T, Good JM, Marques-Bonet T, Alkan C, Fu Q, Mallick S, Li H, Meyer M, Eichler EE, Stoneking M, Richards M, Talamo S, Shunkov MV, Derevianko AP, Hublin JJ, Kelso J, Slatkin M, & Pääbo S (2010). Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature, 468 (7327), 1053-60 PMID: 21179161
Zalmout IS, Sanders WJ, Maclatchy LM, Gunnell GF, Al-Mufarreh YA, Ali MA, Nasser AA, Al-Masari AM, Al-Sobhi SA, Nadhra AO, Matari AH, Wilson JA, & Gingerich PD (2010). New Oligocene primate from Saudi Arabia and the divergence of apes and Old World monkeys. Nature, 466 (7304), 360-4 PMID: 20631798