Neandertals

Blaine Bettinger (the Genetic Genealogist) writes that some commercial test offerings are trying to sort out a way to tell you how Neandertal you are:

Once [the Max Planck] study came out, I knew it was only a matter of time before companies began offering tests that examined the percent of Neanderthal contribution to a test-taker’s genome.

This is one of the stickiest places to be a blogger. Bettinger links to a testing company's information on its product (including promotion of "Neandertal themed art" for the customer, sold at their Las Vegas gallery). Others have linked to Bettinger, drawing more attention.

I think that as a scientist, more promotion is the last thing I should be giving this company. So I won't be naming or linking to their advertising.

Ironically, the promotional material does not make any false statements of fact. The material makes it perfectly clear that the product does not test any gene variants that scientific research has shown may have come from Neandertals. Instead, the product reports on gene variants that we don't know about from Neandertals.

Huh?

You may wonder how a company can market such a product as a "Neanderthal Index". Since "Neanderthal Index" is not a scientific concept, a company can claim whatever it wants.

So what is it? According to the material, the Neanderthal Index is computed from (a very few) STR alleles shared with "archaic" populations. Those "archaic" populations aren't Neandertals, they're Basques, Turks, Syrians, and other living people. Anthropologists do not call these people "archaic", so this is not a scientific concept either. Nobody has demonstrated that the listed populations are more or less Neandertal-like than any other living people. Most of the differences between these living populations emerged during the last 10,000 years.

You'd do better putting calipers on your skull and measuring your cephalic index. At least that would tell you whether some real phenotype is Neandertal-like.

I don't imagine that customers beating down the doors for this product. I think it exists as a way of bringing attention -- Neandertals are in the headlines. That's a big reason to not give them any attention. The test has nothing whatsoever to do with Neandertals as we scientifically understand them.

Can you tell that I'm disgusted by this?

Here in my lab, we're in a very good position to say that no test today can accurately report on your individual proportion of Neandertal ancestry. Until we have characterized a broader set of gene trees than we have so far, we are really not able to give any answer about how similar any person's genome is to Neandertals. We can't say yet how heterogeneous the human population is today in its ancestry from different parts of the world during the Late Pleistocene. For the past thirty years most working geneticists completely ignored the possibility of such heterogeneity, we are only just beginning to investigate it seriously.

This kind of thing may not be why the FDA is looking to regulate personal genomics. Neandertal ancestry is not directly relevant to health. But if customers buy tests like this thinking that they are learning about Uncle Thag, just how much misinformation will they accept from other tests that purport to tell them something more important?

NEANDERTHAL MALES HAD POPEYE-LIKE ARMS

This isn't normally the kind of story -- oh, who am I kidding? I love to snark on these kinds of stories!

"Popeye-like arms". Hmmmm....

Neandertals had a low brachial index -- that is, with a short forearm were relative to the humerus. Popeye, well, you can see that he has the brachial index of a giant ground sloth. Neandertals were not built like Popeye.

The article itself reports the ideas of a group of Russian scientists, who think that hormonal changes may explain the Neandertal pattern of muscle development and cortical bone strength.

Remains of an early Neanderthal with a super strong arm suggest that Neanderthal fellows were heavily pumped up on male hormones, possessing a hormonal status unlike anything that exists in humans today, according to a recent paper.

...

The mixture [of big muscles and highly mineralized bones] is puzzling, because "Neanderthals demonstrate a markedly androgenic constitution," meaning they seemed to have a lot of steroids, yet these same hormones can cause reduced mineralization.

As a result, the researchers say "Neanderthals were characterized not only by peculiar biomechanical adaptations, but also by a specific hormonal condition which has no close parallels among modern human hormonal conditions either normal or pathological."

There's no mechanism being proposed here, the androgen system has effects all over the body. This is not a testable hypothesis, it's really just a speculation.

Or is it? The cool thing about having a Neandertal genome is that in principle we can look for differences in systems like the androgen receptor pathway. Looking for coding changes in androgen-associated genes is really just a browser window away.

So I did some checking.

Now, let me put some caveats here. This is good blog material, but the Neandertal genome sequencing has not reached a point where we can be at all certain about mutations. There are many gaps with no coverage at all in any Neandertal individuals. Most of the sequence of human coding regions is covered by at least one read, and a good fraction of sites have multiple Neandertal reads. As I've been looking through sequence, I tend to think a site may be interesting if it has a change in the Neandertal relative to the human sequence, and if it's not near the end of a read. If the same change is present in multiple Neandertal reads, that makes it a good candidate for a genuine change in Neandertals relative to the human sequence. A large fraction of those Neandertal-specific changes actually aren't Neandertal at all. They're shared with chimpanzees and represent new human-specific changes. Many of those are SNPs in humans where the genome draft has the derived version; there are also sites where the Neandertal shares a derived SNP allele with some other humans. Then there are ones not in chimpanzees or humans, which might be Neandertal-specific alleles or substitutions.

Looking at the androgen receptor gene and the 5-alpha-reductase gene, both central to the androgen pathway, there aren't any interesting-looking sites in the Neandertal sequencing reads. I don't think the data refute the hypothesis that the Neandertals were like humans for these genes. That's just a little bit of looking, of course, and that particular fishing expedition wasn't likely to turn up anything new. But that's the point! We shouldn't just go off speculating about fundamental changes in hormonal biology in Neandertals anymore. We can look.

That is just the beginning of answering a question like this. To test the hypothesis, we'd want to check many other genes that lie between the androgen receptor and its final effects on gene transcription. And of course, coding changes aren't the whole story of evolution in Neandertals. Promoter and enhancer changes, or even alternative splicing changes, may be more important than coding changes, especially for a system so broadly represented in different tissues. They're harder to look for by just firing up the genome browser.

But even these kinds of changes are potentially testable. It's not quite as fast as an interview with a reporter, but it doesn't take days to look.

Back in 2005, I reviewed the first description of fossil chimpanzee teeth, from the Middle Pleistocene of the Kapthurin Formation, Kenya, dating to around 500,000 years ago. At the time, I noted that no chimpanzees have lived in the area in historic times, and that mtDNA evidence then suggested that East African chimpanzees (Pan troglodytes schweinfurthii) may have been recently derived from Central Africa. Together, those observations raised a mystery -- if today's chimps had no ancestors anywhere near Kenya 500,000 years ago, to what group did these fossil chimpanzee teeth belong? I suggested an answer: a cryptic population of chimpanzees partially or completely replaced by the dispersal of Eastern chimpanzees. In other words, Neanderchimps.

Well, now that we know for sure that Neandertals are human, too... it's a good time to revisit the Neanderchimps. What can we say today about the population structure of chimpanzees in the past, and is it still possible that these chimpanzee fossil teeth are out of kilter with the population genetics of today's chimpanzees?

A few weeks ago, we had Jody Hey visiting here on campus, and he gave a talk about his recent work on chimpanzee population genetics. Together with Rasmus Nielsen and others, Hey has been developing Bayesian methods for estimating the times of divergence, migration rates, and effective population sizes of species.

The basic idea is that present-day samples of a species like chimpanzees reflect a branching process from an ancestral population. Each branch may exchange migrants with other branches, each branch has an effective population size, and each may begin with some kind of population bottleneck. That makes for a very complicated model -- for example, with only two populations, there are six parameters, not counting bottlenecks. With each additional population, the number of parameters is compounded by additional effective size, time of splitting, and migration rate to and from all other populations. The number of parameters increases faster than a factorial of the number of populations.

Hey began this work several years ago, initially limited to the two-population case. Together with Yong-Jin Won, he showed that West African chimpanzees (P. troglodytes verus) have a substantially smaller effective size than central African chimpanzees (P. troglodytes troglodytes). These two subspecies appeared to have diverged within the last 300,000-400,000 years. And while there was little evidence for gene flow from central into west African chimpanzees, there was clear evidence for gene flow the other direction, from west into central Africa.

Sound familiar?

In a series of two-way analyses, Won and Hey showed that bonobos diverged from chimpanzees approximately 400,000-800,000 years ago, that there was no substantial evidence of gene flow into or out of bonobos after their speciation, and that the efective size of bonobos was around the same as that of west African chimpanzees, a bit under 10,000 effective individuals.

Now, in 2010, Hey has extended both the data and method to encompass more than a single divergence between two populations. In the case of Pan, Hey has included three extant subspecies of common chimpanzees (P. t. troglodytes, P. t. verus, and P. t. schweinfurthii), together with bonobos (P. paniscus). Among those, in a bifurcating model of population divergence, there are three speciation times, ten effective sizes, and lots of asymmetrical migration rates, all scaled in one way or another to mutation rate. It takes a lot of data to estimate these parameters simultaneously. The study uses 73 loci from an average of 78 individuals split among the populations, which is apparently not quite enough data to get good parameter estimates for the migration rates, as the probability surfaces for these are shallow and relatively unresolved with a few exceptions.

The parameters describing divergence times and effective sizes under the model have tighter posterior probability distributions, so that they are reasonably well estimated using these data. Here are the highlights:

1. Bonobos split from chimpanzees around 930,000 years ago (680,000-1.54 million).

2. The effective sizes of most populations were small (around 10,000 or less). The Pan ancestral population was moderately larger (around 17,000 effective individuals).

3. Only central African chimpanzees were substantially larger in effective size, upward of 25,000-30,000 effective individuals during the last 460,000 years.

4. All common chimpanzees (Pan troglodytes) descend from an ancestral population that existed 460,000 years ago (350,000-650,000).

5. East African chimpanzees split very recently, only around 93,000 years ago (41,000-157,000) from central African chimpanzees.

All these estimates result from a fairly restrictive model. Each population is described by two parameters, their interactions by an additional two parameters per population pair. The ideas of pulses of population mixture or founder effects are simply not possible in the model. I don't see this as a weakness -- I'd much rather begin with even simpler models. But it does mean that we cannot generalize the results past the model. In particular, we shouldn't compare these times and migration rates directly with those obtained under the model that Green and colleagues (2010) applied to the Neandertal genome.

But after those words of caution, what can we make of this proposed population history for chimpanzees? Here are some possible conclusions relevant to human evolution:

1. Eastern and central chimpanzee subspecies share a more recent history than would have been true of humans and Neandertal populations at the time the latter existed. Western chimpanzees are more distant from other chimps than the Neandertals and humans were from each other.

2. For that matter, population differences between MSA humans within Africa may have been nearly as great as those between eastern and central African chimpanzee subspecies.

3. Bonobos and chimpanzees split roughly a million years ago with little if any subsequent interbreeding. At least in the west (Africa, Europe and West Asia), Pleistocene human populations did not experience this kind of allopatric speciation. At the moment, I enter that as an assertion, which I'll follow up later by some discussion of the pre-Neandertal problem.

4. The effective sizes estimated for ancient human populations are not especially low.

5. Range expansions and partial or complete replacements were part of the population history of chimpanzees. They managed these dynamic events without handaxes, fire, projectile weapons, language, or any of the other proposed trappings of Pleistocene humans.

I want to follow up on a couple of these. First, effective size: You often hear people claiming that humans have much lower genetic diversity than chimpanzees. It is true only in a limited sense. Bonobos, west African and east African chimpanzees are populations with lower genetic variation than humans. The estimate for the effective size of the common chimpanzee ancestral population, 7100, is substantially lower than estimated for the human ancestral population during the same time period, a period stretching from roughly a million to 460,000 years ago. The common ancestral population of chimpanzees and bonobos is inferred to have had an effective size close to that of ancestral humans at the same time, around 17,000 effective individuals prior to a million years ago.

One may object that chimpanzees cover a much smaller area than Pleistocene humans, so we should expect their effective size to be much lower. But genetic variation can be related to population size only by assuming a population model, and Hey's analysis gives us a model quite starkly different from the usual. That doesn't mean it's correct, or that it is a better estimator of the census size of the ancient populations. But it reminds us that comparing the genetic variation of humans and chimpanzees is too simplistic; that the gene trees within each populations are very sensitive to the relative contributions of different parts of each species' range during the last 500,000 years. In chimpanzees, the high genetic variation mostly can be attributed to the central African subspecies; in humans, the extant genetic variation can mostly be attributed to Africa.

Let's ponder chimpanzee range expansions for a moment longer. We know that in the early Middle Pleistocene, chimpanzee-like apes lived in western Kenya. The only chimpanzees who live anywhere near that area today seem to have been much more strongly connected to chimpanzees in western Congo prior to 93,000 years ago, and that central African population still has much more variation than the eastern ones. That suggests a recent range expansion, Late Pleistocene in age, into East Africa.

We don't know that the earlier chimpanzees became extinct. They may have contributed genes into later P. schweinfurthii, just as Neandertals did into living humans. We can tell stories about climate change and the former East African chimpanzees, just as people have done about human origins, megadroughts and volcanoes. But one thing is clear about the chimpanzees: there was no modern chimpanzee revolution. The other chimpanzee subspecies, P. t. verus, is still here.

UPDATE (2010-05-20): "More on chimpanzee population structure" discusses a subsequent paper on the same topic.

References:

Gagneux P, Gonder MK, Goldberg TL, Morin PA. 2001. Gene flow in wild chimpanzee populations: what genetic data tell us about chimpanzee movement over time and space. Phil Trans R Soc Lond B 356:889-897.

Goldberg TL, Ruvolo M. 1997. Molecular phylogenetics and historical biogeography of east African chimpanzees. Biol J Linn Soc 61:301-324.

Hey J. 2010. The divergence of chimpanzee species and subspecies as revealed in multipopulation isolation-with-migration analyses. Mol Biol Evol 27:921-933. doi:10.1093/molbev/msp298

McBrearty S, Jablonski NG. 2005. First fossil chimpanzee. Nature 437:105-108. doi:10.1038/nature04008

Won Y-J. Hey J. 2005. Divergence population genetics of chimpanzees. Mol Biol Evol 22:297-307. doi:10.1093/molbev/msi017

I, for one, welcome my Neandertal ancestry.

It may not sound like a lot -- between 1 and 4 percent. But that's the equivalent of one great-great-great grandparent's DNA contribution. In the case of the Neandertal contribution, more than 1500 generations ago, it's an enduring legacy of an ancient group of people, spread across many lines of the genealogies of living people. Beyond their genealogical interest, Neandertal genes might have made a big difference to our evolutionary potential.

In case you wonder what the heck I'm talking about, here's the story: Two new papers in Science describe the full draft sequence of the Neandertal genome, and perform additional analyses to understand the pattern of adaptive evolution in the population ancestral to living people.

Richard Green and colleagues report on the genome, demonstrating very convincingly that present-day people have Neandertal ancestors. It is not entirely obvious when and where the gene flow between Neandertals and other ancient populations happened -- whether it was associated with the dispersal of most of our ancestry from Africa, or whether it may have been earlier. The gene flow was not limited to Europe, and evidence for Neandertal ancestry occurs in East Asian and Australasian populations.

The paper is full of other good stuff, including some evidence about which gene regions changed under selection in the ancestral human population.

Meanwhile, the second paper by Burbano and colleagues applies new microarray techniques to assess how much of the human legacy of amino acid changes has arisen in the latest, post-Neandertal period of our evolution.

So there's a lot about the pattern of evolution and gene flow leading to living people, and a lot about adaptive and functional evolution. That makes a lot for me to cover -- and while I have the papers a little early, time is short. Let's see how much I can help clarify what's in this new research.

If you had to sum up in a few words, what does this mean for paleoanthropology?

These scientists have given an immense gift to humanity.

I've been comparing it to the pictures of Earth that came back from Apollo 8. The Neandertal genome gives us a picture of ourselves, from the outside looking in. We can see, and now learn about, the essential genetic changes that make us human -- the things that made our emergence as a global species possible.

And in doing so, they've taken a forgotten group of people -- whom even most anthropologists had given up on -- and they've restored them to their rightful place in our heritage.

Beyond that, they've taken all of their data and deposited it in a public database, so that the rest of us can inspect them, replicate results, and learn new things from them. High school kids can download this stuff and do science fair projects on Neandertal genomics.

This is what anthropology ought to be.

What did they sequence?

The Max Planck group obtained most of their genomic sequence from three specimens from Vindija -- Vi33.16, Vi33.25, and Vi33.26. These are all postcranial fragments with minimal anatomical information. Green and colleagues were able to establish that the three bones represent different women, and that Vi33.16 and Vi33.26 may represent maternal relatives.

From these skeletons they got 5.3 billion bases of sequence. All this from an amount of bone powder about equal in mass to an aspirin pill.

Amazing. I mean, I know the folks at Max Planck are reading this. It's inspiring to see what they've been able to do. These are three pieces of barely diagnostic hominin bone, and they've obtained literally hundreds of times more information than we have ever gotten from the fossil record of Neandertals.

I'll describe the analyses of genetic similarity with humans in more detail below. As a brief summary, of those positions where the human genome differs from chimpanzees, Neandertals have the chimpanzee version around 12.7 percent of the time -- meaning that across the genome, a Neandertal and a human will share a genetic ancestor an average of around 800,000 years ago. This is a couple hundred thousand years higher than the same number if we compare two humans to each other. The higher age of genetic common ancestors reflects partial isolation between the Neandertal population and the African populations that gave rise to most of our current genetic variation.

The team were able to identify 111 candidate duplications, almost all of which have some evidence of copy number variation in humans or other primates. They tentatively show that Neandertals have a bit more copy number variation than present-day humans, and identify a few loci with substantially higher copy numbers in one group or the other.

A substantial part of the paper is dedicated to finding evidence of positive selection on the human lineage after the emergence of Neandertals. The idea is to look for fixed selective sweeps -- regions where humans are likely to have SNPs absent in Neandertals and a relatively shallow gene tree. They identify 212 regions like this -- as I discuss below, a surprisingly low number.

The second paper, by Hernán Burbano and colleagues, describes the application of a targeted microarray to probe Neandertal genetic samples for protein-coding variants that separate humans from chimpanzees. They identify 88 amino acid substitutions that seem fixed in the known sample of living humans, but not present in the Neandertal sequence. Those 88 are not necessarily all functionally important, although this list will include a number of "structural" genetic changes that make a difference to proteins expressed worldwide today. There is much to come in analyzing the categories and genes represented in both lists, which may tell us very interesting things about our Late Pleistocene evolution.

What is the evidence for interbreeding?

From their initial work sequencing the nuclear genome in Neandertals, the Max Planck group has followed a clever strategy: Don't look at the Neandertal sequence to see what humans share, look at human variation to see which version the Neandertal sequence has.

The strategy is smart because it helps to obviate some major problems with ancient DNA -- you don't have all the parts, and the parts you do have probably contain a lot of sequencing errors of various kinds. By looking first at sites that vary within humans (or, in some comparisons, between humans and chimpanzees), we can focus on a very simple question -- did the Neandertal have one version, or the other?

Applied to human variation today, there are several ways we might use a Neandertal genome test the hypothesis of no interbreeding. Green and colleagues focus on two complementary approaches.

1. If Neandertals contributed no genes to living populations, then they should be equally related to all living people, no matter where in the world those people live.

Green and colleagues show that the Neandertal genome is closer to some humans than others. People whose ancestry lies outside Africa are significantly more like Neandertals than are people who live in Africa today. In this study, the authors include whole genomes from people in France, China and Papua New Guinea outside Africa, and Yoruba and San inside Africa. The Africans are not as close to the Neandertal as any of the non-Africans.

That doesn't mean that non-Africans derive most of their genes from Neandertals -- in fact, as I describe below, the proportion is quite small. Living people are more like each other -- even non-Africans and Africans -- than any of them are like Neandertals.

The point is that despite this great similarity of living people, we have genetic variants that we share with the Neandertal genome, and that proportion is a lot higher outside Africa than inside it. The natural conclusion is the Neandertals contributed more genes to non-Africans than to Africans.

One thing is for sure: You can't explain this observation under the hypothesis that a small, African population expanded out of Africa without interbreeding with Neandertals along the way.

2. Look at the genes most likely to represent ancient population structure, the ones with deep roots outside Africa.

This is an idea that we came up with to look for genes in living humans that might have come in from Neandertals or other ancient populations (for example, we described it in our 2008 review). Look for the parts of the genome with the deepest genealogical roots outside of Africa. Those are candidates for Neandertal gene flow -- a high chance that one of the two sides of that deep root was present outside of Africa for hundreds of thousands of years.

Green and colleagues took this idea to the next level. They found parts of the genome where non-Africans have a deep root and Africans don't. Then they looked at the Neandertal sequence. Out of the 12 regions they identified with deep roots outside Africa, they found that the Neandertals had the deep, non-African specific version in 10 of those.

I mean, there's really not any other way you can explain this. We got those genes from Neandertals. Every one of those loci is a region where some people have a Neandertal-derived allele, and others don't. Those particular 10 loci are a small fraction of the overall Neandertal-derived element of our heritage -- because they used Perlegen SNPs to find them, they ended up with regions that are fairly long (100 kb or more in length). Those are probably all really interesting, but there will be more of them when we can reliably identify smaller segments with deep genealogies.

Could the results have been caused by contamination?

Green and colleagues are utterly convincing about the level of contamination in their sequence. They have employed several independent checks, all of which arrive at the same conclusion: The modern human contamination in almost all their comparisons is limited to significantly less than one percent -- and for autosomal sequence they can give a tight estimate of 0.7 percent contaminating sequence.

The methods that Green and colleagues used to test for a Neandertal contribution to non-African populations are not likely to be strongly influenced by contamination. The probe for deep roots in particular is extremely unlikely to be influenced by contamination in the Neandertal sequence.

The very low contamination rate, and methods that should be robust to some contamination, means that we can be very confident in their result.

How much Neandertal ancestry do we have?

The Neandertal contribution does not make up a major proportion of any population, even outside of Africa. Green and colleagues apply a population model that involves isolation between ancestral Neandertal and African populations, a dispersal from Africa into Eurasia, and subsequent mixture with the Neandertals. Under this model, the estimated fraction of Neandertal ancestry for non-African populations today is between 1 and 4 percent.

Now, let's put on our skeptics' hats. Is this the right model?

If Neandertal and African populations had not been isolated, then the amount of mixture after an out-of-Africa dispersal would be lower. On the other hand, the dispersing African population would already be part Neandertal, because of genetic mixture. The proportion of ancestry from ancestral Neandertals would be around the same amount, it would just be distributed across a longer time.

They did not examine the question of how much of the genome came in from Neandertals because of selection. The estimate they have, between 1 and 4 percent, is so high that this is not just a few genes introgressing in from Neandertals -- it is a big fraction of the neutral, non-coding part of the genome. So selection doesn't explain the similarity, nor can parallelism -- the similarity is genome-wide, not just coding or functional changes, and not as far as we know clustered into regions that might have hitchhiked with adaptive alleles.

But there's clearly a lot more to do, characterizing the functional implications of some regions, testing for selection, and finding Neandertal variants that might have reached very high frequencies in later populations. To the extent that selection has influenced the pattern, it will also throw off the simple population model. But it doesn't throw off the fraction of Neandertal ancestry -- if it's three percent, it doesn't matter whether it was selected or neutral, it's still three percent.

So the bottom line is, the fraction is going to be about right, regardless of the mechanism by which the genetic mixture happened.

Can we please take off our skeptics' hats? It's getting in the way of my Neandertal victory dance.

No. All the cool paleoanthropologists wear hats.

What about population structure within Africa? Could that explain the apparent Neandertal contribution?

We've known about the occasional deep-rooted genealogies outside Africa for a long time (and Jeff Wall's work, as an example among others, has explained that pattern as archaic human mixture into non-Africans). They've been talking about something like five percent of the human genome coming from admixture with ancient groups outside of Africa. So this shouldn't come as a shock.

Until now, though, it has been possible for some people to wave these results away. We didn't really know that any of those deep roots were in archaic humans, and after all, who's to say that they aren't variants that originated in Africa and have since been lost there, or that we haven't found them yet? African variation is great, and if you imagine that some variation might have once existed in northeastern Africa and was subsequently lost within African populations, that might look like admixture with archaic humans outside of Africa.

This line of argument is now special pleading. Why would we posit a cryptic mystery population in Africa, which happens to look genetically identical to Neandertals, but has subsequently disappeared? A big fraction of deep genealogies outside Africa really are in Neandertals. By far the simplest explanation is that today's non-Africans got them from ancient non-Africans. This is no surprise -- that's where the data have been pointing now for five years.

Yet Africans are a lot more diverse than other populations, and this diversity itself does reflect the dynamics of the ancient African population. The Neandertals aren't so different from that pattern that now still exists within Africa -- they're extending the notion that "modern" is something that's been evolving for a long time. I expect we'll be able to come to a better understanding of ancient population interactions within Africa, by understanding the parts of the genome that have come from Neandertals outside of Africa.

Could the gene flow be due to ancient interactions between West Asia and Africa?

Green and colleagues suggest that at most few genes from modern humans ended up in Neandertals.

That is, although they find lots of evidence of old-looking genes in us that are shared with the Neandertal genome, they find few cases of new-looking genes in us that are shared with that genome.

That might suggest several things about interactions between Africa and West Asia and Europe during the Middle to Late Pleistocene. For example, if there had been high gene flow from Africa into West Asia after the first appearance of a distinct Neandertal population, maybe 200,000 to 400,000 years ago, we might expect to find some new-looking genes in humans that Neandertals also got.

On the other hand, the data are from European Neandertals, who are at the end of a fairly long chain of populations from Northeast Africa. If gene flow had been ongoing into the Levant or further into West Asia during the last 200,000 years, it's not obvious how many of these genes would have made it into Europe. The rapid mitochondrial DNA coalescence of Neandertals does suggest substantial mobility in the population across Central Asia to Western Europe. But maybe that apparent dynamism had a boost from mtDNA selection.

So just on the data, I don't think we know yet whether this is gene flow in the Levant 200,000 or 100,000 years ago, or whether it's genes coming from West Asian Neandertals into dispersing Africans after 100,000 years ago. I expect all are likely. I have some ideas how to test some of these things, and we will get started immediately.

The lack of apparent mixture of "modern" genes into Neandertals -- what does it mean?

It means that a model of one-way gene flow from Neandertals into us can explain the pattern of genetic similarity.

The authors explain this as a function of population expansion. The expanding population (us) picks up some Neandertal genes that expand in numbers, while the contracting population (Neandertals) doesn't have a chance to pick up as many genes because it is declining in numbers. That model seems plausible, particularly in comparison with historical cases of population contact.

On the other hand, the three Neandertals from which most of the genome sequence was derived all date to before 40,000 years ago. There weren't any modern humans around for them to have interacted with around Vindija at that time. So should we be surprised that they don't have genes of modern humans?

A more interesting question was posed to me by a very sharp journalist: What would we expect the result to have been if they had sequenced a Near Eastern Neandertal, like Amud, for example?

The answer seems obvious -- the admixture fraction should have been higher. That population, which is the most likely to have been the source of mixture, must have been somewhat genetically different from the European Neandertals. Any extent of genetic differentiation between them would make the European Neandertals look less like non-Africans today than the Near Eastern ones.

I'll have more to say about these Near Eastern Neandertals in the next few days.

But wait a minute. I thought the mitochondrial DNA proved that Neandertals are extinct!

Selection. Selection. Selection.

I've been saying it for years. I've published it. Will you learn to listen to me, already?

The mtDNA of Neandertals is gone because it conferred some disadvantage. There are many reasons to suspect this -- the Neandertal variation is itself apparently recently derived; the human variation is clearly in disequilibrium, especially outside Africa; the mtDNA genes affect functions that differ greatly in Neandertal and recent populations, including energetics, longevity, and brain; there are clear signs of mtDNA selection in many recent human populations.

Mitochondrial DNA is useful for a lot of reasons, but nobody should ever have relied on it alone as evidence of Neandertal population dynamics.

Is it really true that there is no variation in Neandertal ancestry outside Africa?

The comparisons in the paper are highly convincing because of the sheer amount of sequence taken from the sampled individuals. A single gene locus from an individual may be unrepresentative of the person's population, but averaged across the whole genome, the difference between two people from distant populations is very, very close to the difference between the two populations.

But they sampled very few individuals. So we are left with a question -- do we really know we've sampled variation outside Africa enough to make regional estimates of Neandertal gene flow?

I think we could do better with more genomes. For example, when it comes to finding deep genealogies, we need to be able to find shorter regions than the ones used by Green and colleagues. That will expand the sample of candidate loci, and will catch some Neandertal-derived genes that we're missing now. Moreover, if gene flow was really around 1-4 percent, many SNPs that came in from Neandertals will be rare enough to be missing from the big SNP genotyping samples. We may find some variants with whole-genome sequencing on larger samples that will be worth examining.

But most important, we'll be able to develop strategies based on this success to find ancient population structure involving groups where we don't yet have the DNA -- like populations of South and East Asia. Some of those may give us the chance to test those methods soon, as for the Denisova individual.

Is this multiregional evolution, or just out-of-Africa with some leakage of earlier Eurasian genes?

Out-of-Africa movement was a major mechanism of recent human evolution. The genetic ancestry of living people is multiregional.

I see no contradiction between those statements. From now on, we are all multiregionalists trying to explain the out-of-Africa pattern.

There was clearly a dispersal of African genes into the rest of the world during the Late Pleistocene, sometime between 50,000 and 100,000 years ago. Living people everywhere on Earth derive more than 90 percent of their genes from African populations who lived 100,000 years ago. That much is plain.

(Why did I not write "more than 96 percent?" See below.)

These genetic observations require some kind of out-of-Africa event. This event was not limited to a few genes, and selection of a few genes even with substantial hitchhiking of surrounding genome cannot account for the pattern. There must have been some kind of demographic expansion including African-derived populations and preferentially excluding the genes of Eurasian populations like the Neandertals. Selection on a gene network might have mediated the expansion, as suggested by Eswaran (2002). Or the expansion might have been culturally or technologically mediated, as many other people have suggested.

Those are hypotheses about mechanisms. How did it come to be that living people trace the overwhelming majority of their ancestry to Africa within the last 100,000 years? These explanations may answer that question.

The present study shows that Neandertals were at a minimum partially isolated from their contemporaries in Africa, and that the genetic divergence between those populations was larger than the genetic differences between European, Asian, and African populations today.

Yet those Neandertals are among our ancestors. Late Pleistocene humans had multiregional origins, and the evolution of the Neandertals was itself a case of relatively recent population dispersal from Africa or West Asia. Human and Neandertal genes mostly derive from common genetic ancestors between 400,000 and a million years ago -- much, much later than the initial habitation of Eurasia 1.8 million years ago.

But 1-4 percent is so minor, can it be an important part of our evolution?

There are three things you have to ask about the fraction of Neandertal ancestry.

1. How much gene flow would it take to guarantee that anything adaptive in the Neandertal population survived into later people?

The answer to that question is simple -- it takes a few dozen matings to get most adaptive genes into our population. If there was a lot of interference with the genetic background, it might take more -- just to make sure that the advantageous alleles had a chance to be de-linked from the genetic background.

If Neandertals are one percent of the ancestry of non-Africans, we can be very sure that any gene in a Neandertal that had adaptive value in the later population is here now. That means they were important in an evolutionary sense.

2. What fraction of the human population 50,000 years ago were Neandertals?

This is very important -- when it comes to neutral genetic loci, the essential question is how much the Neandertals may be underrepresented today relative to their numbers in the past. Is three percent too low? It seems very unlikely that the fraction of Neandertals compared to the rest of humans was as high as 10 percent -- we know that Africa already had a large population 50,000 years ago, and everything we know about Neandertals suggests a very low population density, an effective size much smaller than 10,000 individuals. Were five percent of the people on Earth 50,000 years ago Neandertals?

We don't really know the answers, but now we have a chance to test hypotheses about ancient population size and expansion in Neandertals. My point at the moment is only this: If today Neandertal genes make up only one percent of the gene pool of the 5 billion people outside Africa, that's the genetic equivalent of 50 million Neandertals.

In relative terms, their contribution to our population may be a reduction from their fraction of the Late Pleistocene population. Not that great a reduction, not a massive crash to zero. A reduction in the wake of the out-of-Africa movement, possibly from five percent to three.

You might think the answer to this is obviously zero. But in genetic terms, we can ask, how many times has the average Neandertal-derived gene been replicated in our present gene pool? Those aren't Neandertal individuals -- that is, a forensic anthropologist wouldn't classify them as Neandertals. They're the genetic equivalent.

The answer to this is also simple: In absolute terms, the Neandertals are here around us, yawping from the rooftops.

There are more than five billion people living outside of Africa today. If they are one percent Neandertal, that's the genetic equivalent of fifty million Neandertals walking the Earth around us.

Does that sound minor? If I told you that your average gene would be replicated into fifty million copies in the future, would you be satisfied? Maybe your ambition is greater, but I think the Neandertals have done very well for themselves.

Does this mean that Neandertals belong in our species, Homo sapiens?

Yes.

Interbreeding with fertile offspring in nature. That's the biological species concept.

Now, some paleontologists might still disagree -- maintaining that species are units that can be distinguished morphologically, or by one or more derived features, or any number of other definitions. That's fine with me, as long as they're clear. But understand: It does define all non-Africans today as an interspecific hybrid population.

So maybe they want to rethink that one?

If Eurasians got less than 4 percent from Neandertals, doesn't that mean that they got more than 96 percent from Africa?

I look at the 1-4 percent estimate as a minimum, for several reasons. As I'll note below, this estimate mainly refers to the excess Neandertal ancestry outside Africa, which means there may be some additional amount that both recent African and non-African populations share.

But more important, Neandertals weren't the only people living in Eurasia 100,000 years ago. China didn't have Neandertals, nor did Southeast Asia and Java. India was full of hominins, which might or might not have shared substantial genetic similarity with Neandertals. They're close enough to the known Neandertal range to speculate that they may have been close, but the only available fossil, the Middle Pleistocene Narmada skull, is not very informative. Any of these populations might have been genetically different from Neandertals, and might have also contributed genes to present-day human populations -- genes that wouldn't show up by scanning the Neandertal genome.

The recent genetic sequencing of the Denisova pinky (a.k.a. the X-woman) from the Altai Mountains reminds us that these populations outside of Africa may have been quite a bit closer to us, genetically, than we might have expected from the 1.8-million-year record of humans outside Africa. These populations were dynamic in ways that many paleoanthropologists haven't yet appreciated.

Do living Africans have Neandertal ancestry, too?

I think that the present study doesn't have the power to answer this question, at least with the design that the authors used. The fact that living Africans are less genetically similar to the Neandertals is extremely important evidence of the Neandertals' genetic contribution to populations outside Africa. But it doesn't bear on how much back-migration into Africa may have happened.

We know that the answer is nonzero, because Africa has received immigrants from other parts of the world during historic times. The same genetic patterns that reflect population contacts up and down the East African coast, and across the Sahara into West Africa, show the possible conduits for the flow of Neandertal-derived genes into African populations.

But how much genetic dispersal into Africa happened in LSA or late MSA times? Mitochondrial and Y chromosome distributions in Northeast Africa suggest there was been some. Nevertheless, Africa would have been a very difficult place to return, for humans who had begun adapting to different ecological and disease environment.

I think that some Neandertal genes might have made it back into Africa, even in ancient times, but I wouldn't be surprised if that number was small.

The big shoe left to drop is the extent of population differentiation within Africa during MSA times. So far we've seen hints that these populations might have been nearly as differentiated from each other as they were from Neandertals, with substantial gene flow homogenizing them in the last 30,000 years. This paper includes an additional Bushman genome, after the four published earlier this year. Comparing that new genome to the Neandertals, its modal difference from the human reference (Hg18) genome is between the other humans and the Neandertal. Not quite halfway between, but nearly so. There's a lot of genomic variation within Africa, and exploring the population history that explains that variation may turn up some surprises.

What about recent selection?

One of the really exciting aspects of this work is that both Green and colleagues and Burbano and colleagues look for things that all humans today share but Neandertals lack.

You might call these "the genes that make us modern," although functionally we have little idea what any of them do.

Both papers show one thing that is extremely interesting: There aren't very many such genetic changes.

Burbano and colleagues put together a microarray including all the amino acid changes inferred to have happened on the human lineage. They used this to genotype the Neandertal DNA, and show that out of more than 10,000 amino acid changes that happened in human evolution, only 88 of them are shared by humans today but not present in the Neandertals.

That's amazingly few.

Green and colleagues did a similar exercise, except they went looking for "selective sweeps" in the ancestors of today's' humans. These are regions of the genome that have an unusually low amount of incomplete lineage sorting with Neandertals, and therefore represent shallow genealogies for all living people. They identify 212 regions that seem to be new selected genes present in humans and not in Neandertals. This number is probably fairly close to the real number of selected changes in the ancestry of modern humans, because it includes non-coding changes that might have been selected.

Again, that's really a small number. We have roughly 200,000-300,000 years for these to have occurred on the human lineage -- after the inferred population divergence with Neandertals, but early enough that one of these selected genes could reach fixation in the expanding and dispersing human population. That makes roughly one selected substitution per 1000 years.

Which is more or less the rate that we infer by comparing humans and chimpanzees. What this means is simple: The origin of modern humans was nothing special, in adaptive terms. To the extent that we can see adaptive genetic changes, they happened at the basic long-term rate that they happened during the rest of our evolution.

Now from my perspective, this means something even more interesting. In our earlier work, we inferred a recent acceleration of human evolution from living human populations. That is a measure of the number of new selected mutations that have arisen very recently, within the last 40,000 years. And most of those happened within the past 10,000 years.

In that short time period, more than a couple thousand selected changes arose in the different human populations we surveyed. We demonstrated that this was a genuine acceleration, because it is much higher than the rate that could have occurred across human evolution, from the human-chimpanzee ancestor.

What we now know is that this is a genuine acceleration compared to the evolution of modern humans, within the last couple hundred thousand years.

Our recent evolution, after the dispersal of human populations across the world, was much faster than the evolution of Late Pleistocene populations. In adaptive terms, it is really true -- we're more different from early "modern" humans today, than they were from Neandertals. Possibly many times more different.

More?

That's what I have time for now, if I want to get this posted. There is much, much more to say on the topic, and you can bet it will be all Neandertals all the time here for the foreseeable future.

References:

Green RE and many others. 2010. A draft sequence of the Neandertal genome. Science (in press) doi:10.1126/science.1188021

Burbano HA and many others. 2010. Targeted investigation of the Neandertal genome by array-based sequence capture. Science (in press) doi:10.1126/science.1188046

I had a great session with my advanced students yesterday running through different evolutionary scenarios for the X-Woman. This and some later posts will follow up on my initial thoughts ("Hobbit version 2.0: the undiscovered hominin").

May I just say, "X-Woman" is one of the more dopey nicknames for an ancient piece of bone? I mean, it's better than "Twiggy", but jeesh. I can't be the only one who thinks of John Singer Sargent:

Meanwhile, I have some great e-mails about Madame X, some of which I can share. First, an exchange on the topic of incomplete lineage sorting:

I'm confused by your suggestion of an ancient divergence among Neanderthals. Wouldn't that lead to a tree with the Siberian DNA and other Neanderthal DNA samples forming their own clade, to the exclusion of human DNA? As things stand, the Neanderthals are closer to humans than to the Siberian DNA.

Not at all; it could be either way.

Consider humans today. Africans have mtDNA lineages (the L clades) that are deeper in the human tree than any outside of Africa and basically absent elsewhere except for recent migration. But Africa also contains many of the mtDNA lineages that are present in Europe, India and West Asia.

Now imagine that the human population divides into two species, Africans and non-Africans, and those species persist for 100,000 years. Assuming no huge bottlenecks in either of these species, they both ought to retain the major clades present today. If we sample their genes at that time, 100,000 years in the future, we'll discover that Africans will be more genetically diverse than non-Africans. And the Africans will have L clades that are outgroups to the clades (M and others) that include *some* Africans and *all* non-Africans.

Subsequent population bottlenecks or selection could eliminate those ancient clades, but they will hang around unless they are eliminated. That's also the explanation for why humans and gorillas are more genetically similar at some loci than either is to chimpanzees, even though humans and chimpanzees speciated more recently. The variation in that ancestral H-C-G population was retained in the ancestral H-C population, to some extent, and lineage sorting sometimes gave humans the more gorilla-like clade.

An interesting question is whether the rest of the Neandertal sample would be so relatively invariant, if some part of their population included this quite divergent mtDNA haplotype.

It's quite hard to answer that question given the small sample of Neandertal mtDNA -- only less than twenty individuals, sampled from a range of times. A "lopsided" tree, with a lot of similar sequences and a few divergent ones, is not an unlikely genealogy in a small sample. The variance in the lengths of the deep branches in a genealogy is intrinsically high, even in the simple Wright-Fisher model with no population structure or selection. A "lopsided" tree is just one possibility on a continuum, in which the deepest coalescence time in the sample is high relative to the next deepest -- not an unlikely event at all.

For those who would like to explore this process, I put together a Mathematica demonstration ("Coalescent Gene Genealogies") that generates random gene trees under the neutral Wright-Fisher model. Strange-looking trees are normal, in the sense that they occur often enough that they are not statistically unlikely for a single gene locus.

Obviously what you'd want to do is compare multiple gene loci -- in this case, to get nuclear genomic sequence. Since the Max Planck group is actively pursuing further sequencing (and already has had some success, according to their press conference), I expect they're already making progress toward testing the neutral hypothesis.

If mtDNA proves to be unusual compared to other loci, then it's either intrinsic coalescent variability, or selection. Testing those two alternatives would require a larger sample of Neandertal mtDNA.

If, on the other hand, the nuclear genetic diversity is also substantially not shared with Neandertals (or living people), then the hypothesis of population structure in Late Pleistocene-age Eurasia would be strongly supported. It's a bit more complicated to test whether a speciation had occurred, but with whole genomes such a test can almost certainly be done.

In this week's copy of Nature, Johannes Krause and colleagues [1] report on the complete mitochondrial sequence of a pinky bone from Denisova Cave, in the Altai Mountains of Siberia.

You might expect this sequence would look like a Neandertal. After all, two other specimens from a little further to the West have both produced mitochondrial sequences very similar to those of Neandertals from Europe.

But you would be wrong. This sequence turns out to be a surprise.

Instead of falling within the Neandertal clade, the sequence in this pinky bone lies as an outgroup to Neandertals and as an outgroup to modern humans.

Assuming an average divergence of human and chimpanzee mtDNAs of 6 million years ago, the date of the most recent common mtDNA ancestor shared by the Denisova hominin, Neanderthals and modern humans is approximately one million years ago (mean = 1,040,900 years ago; 779,300–1,313,500 years ago, 95% highest posterior density (HPD)), or twice as deep as the most recent common mtDNA ancestor of modern humans and Neanderthals (mean = 465,700 years ago; 321,200–618,000 years ago, 95% HPD) (Fig. 3). Although the absolute dates depend on several assumptions and are subject to uncertainty (Supplementary Information), the fact that the divergence of the Denisova hominin mtDNA is about twice as old as the divergence of Neanderthal and modern human mtDNAs is robust to most assumptions (Krause et al. 2010: 2).

If you are sharp-eyed, you may notice that mean value from the Neandertal-human comparison, at 465,700 years ago, is rather substantially lower than has previously been reported -- Green and colleagues [2] put this divergence at 660,000 years ago. Including the new Denisova specimen into the comparison provides a much more recent branch point than the human-chimpanzee divergence date. That means some of the ambiguity in the long branch between the chimpanzees and the human-Neandertal ancestor can be resolved, effectively pushing the Neandertal a little bit closer to us.

As you might have guessed from the paper's title, the authors interpret the deep divergence of the new Denisova sequence as evidence of a previously unknown, "genetically distinct" lineage of hominins. I want to be very precise about what they say and don't say, because it is a very short paper. Nowhere in the paper do they use the word "species". But in the conclusion, they do discuss lineages and "forms".

We note that the stratigraphy and indirect dates indicate that this individual lived between 30,000 and 50,000 years ago. At a similar time individuals carrying Neanderthal mtDNA were present less than 100 km away from Denisova Cave in the Altai Mountains, whereas the presence of an Upper Palaeolithic industry at some sites, such as Kara-Bom and Denisova, has been taken as evidence for the appearance of anatomically modern humans in the Altai before 40,000 years ago. Although these dates are associated with large and unknown errors, this temporal concurrence suggests that complete and successive replacements of distinct hominin forms, similar to what occurred in Western Europe, may not have taken place in southern Siberia. Rather, representatives of three genetically distinct hominin lineages may all have been present in this region at about the same time. Thus, the presence of Homo floresiensis in Indonesia about 17,000 years ago and of the Denisova mtDNA lineage in southern Siberia about 40,000 years ago suggest that multiple Late Pleistocene hominin lineages coexisted for long periods of time in Eurasia.

The mention of Homo floresiensis in this conclusion seems unlikely to be an accident, particularly in Nature, the hobbits' birthplace. I haven't seen any press coverage of this yet, obviously, as I'm writing before the embargo breaks. But I can only imagine the likely spin: just as Homo floresiensis has demonstrated the diversity of archaeologically recent hominins in Asia, this new mitochondrial sequence adds even more to that diversity.

One of my long-time correspondents is already calling it "the Yeti".

Is this a new species?

As my students have heard me say many, many times, gene trees are not species trees. The different genetic loci within a population have diverse genealogies. Often, when two populations diverge from each other, their gene genealogies will show similar patterns of divergence. But not always.

When we look within a single population, gene genealogies are likewise diverse. but within a single population, there is no population divergence. There must be an oldest branch point in the genealogy of any single gene. Here's a question: how many individuals do you have to sample so that you are sure you will find this deepest branch point? The answer to that question depends on the frequencies of the lineages on either side of that branch. If one of them happens to be rare, you're unlikely to find it unless you sample lots and lots of individuals.

And if the population is spread across a substantial amount of space, it is very likely that one of the clades will be geographically limited compared to the other.

Put these two things together, and apply them to a widespread population like the Neandertals. It is pretty likely that if we sample a dozen Neandertals across a subset of their range, that we will miss the deepest divergence in the genealogy of a single gene. That may be what has happened here. By extending the known mitochondrial sample of Neandertals even further to the east, this study may have discovered a deeper branch point than was previously known within the Neandertal population.

Indeed, a million-year-old clade divergence would be entirely normal for a large mammal. That's what we see in chimpanzees, and as I pointed out yesterday, it's smaller than the clade divergence we see among mammoth mtDNA across a similar time range and geographic extent.

I think the mammoth paper makes a really nice comparison to this one. In that case, they discovered a deep clade divergence in an ancient population, one branch of which was geographically restricted within a part of northern Siberia. They didn't conclude that multiple species of mammoths had been sampled -- despite the fact that one mtDNA lineage significantly outlasted the other. That was variation within one geographically diverse species, consistent with what we know about other species' mtDNA variation.

So it is unnecessary to posit the existence of an unknown species of hominins in southern Siberia, based on the mitochondrial evidence alone. Whether we're talking about an unexpected diversity of forms -- well, I want to see something other than a pinky bone.

Does it add to our understanding of Neandertal phylogeography?

Well, first we need to know if it's a Neandertal. We don't. It's a pinky bone.

But if it were a Neandertal, then the appearance of a deep clade at the very eastern extent of the population's range might suggest something about its diversification. The western Neandertals in that scenario have relatively restricted diversity, as if they had descended from a recent mtDNA ancestor. That pattern would be consistent with a range expansion from the east to the west. So maybe the Late Pleistocene Neandertals invaded Europe from elsewhere?

Could this be Homo erectus?

Of course, at the very furthest eastern extreme of the Neandertal range, we might well be running out of Neandertals and running into another kind of hominin. Even as recently as 40,000 years ago, it is not entirely obvious who those hominins would have been. The archaeological transition is nowhere near as clear in the east as in Europe, and even in Europe the archaeological transition to Upper Paleolithic industries is not the same as the biological transition.

Before 100,000 years ago, the humans in China could plausibly be assigned to Homo erectus. It seems likely that much, if not most, of the genetic heritage of the pre-40,000 year population of China would have been derived from these ancient Chinese hominins. It is unknown how much genetic exchange there would have been between east and west at this time. I suspect that there were substantial genetic exchanges, both along the southern coast of Asia and across Central Asia. So China might well provide an alternative geographical origin for this mitochondrial clade.

If we look to China as the ancestor population for this mitochondrial sequence, we can ask whether the roughly million year divergence date makes sense. As a marker of populations, a single gene can inform us about the maximum time of population divergence, not the minimum. The minimum is in effect zero: in other words, a million-year-old divergence genetically could occur within a single human population. So a widespread human population across much of Asia could contain such a deep branch, just as Neandertal's -- equally widespread across West an and Central Asia -- could have contained such a branch.

But a million-year-old divergence does tell us one thing: this cannot represent a Homo erectus population that originated in Africa 2 million years ago, colonized Asia around the time of Dmanisi, and was isolated after that time.

In other words, it would argue strongly against the hypothesis of a deep divergence of eastern and western hominin species, starting with the initial dispersal of humans from Africa in the Early Pleistocene. It argues in favor of continued genetic exchanges or a more complex history of population movements.

I hesitate to take this line of reasoning too far. It's a pinky bone.

Could this be a modern human?

Even though the date of the cave could be as recent as 30,000 years ago, it is very unlikely that this mitochondrial sequence would have occurred within the growing population of "modern" humans. A growing population is relatively unlikely to lose mitochondrial variants. An ancient clade like this one, which survived in the population for a million years, might have been just at the edge of extinction at the time the population started to grow and therefore might just have missed its opportunity to survive. But it seems sort of unlikely.

Do they know more than they are letting on?

In the back of my mind I'm thinking this: if Krause's team has done enough sequencing to do the entire mitochondrial genome, they surely already know something about what the nuclear genome looks like. The increasing success of DNA recovery from these very fragmentary fossils has been stunning over the last several years. It is incredible that we are likely to recover a substantial amount of autosomal sequence from the distal phalanx of a (did I mention?) pinky. A quick comparison against raw data, without much systematic analysis, would be enough to check the mtDNA result.

I wonder if this is only the first shoe, and there is another left to drop? These guys know as well as I do the gene trees are not species trees, and that such an obvious point that -- even though this is Nature we're talking about -- the reviewers should have caught it.

So maybe there are already hints that the autosomal comparison will fall in the same direction as the mitochondrial comparison with Neandertals: different from them, different from us.

Maybe it's a Yeti after all.

UPDATE (2010-03-24): Man, the press is worse than I imagined. Nature's news article goes fully with the "new species" interpretation -- even though the paper itself does not include the word "species" -- and every other outlet I've seen is following suit.

I have to teach my class this afternoon where we'll be talking about this mtDNA sequence, so I don't have time for a longer update. Let me say very clearly: nothing about this sequence requires there to have been an undiscovered hominin species.

UPDATE (2010-08-10): References updated.

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References

I had the neat experience yesterday of talking to a class about scientific illustration, from my point of view as a scientist who does a lot of illustrating my own work.

The students' questions ranged widely. Some were very technical -- what tools do I use, why do I hatch in a particular style? Others were more conceptual -- how do artists put flesh onto bones in their reconstructions?

In that light, Carl Zimmer has a nice article in the Science Times today about the work of artist reconstructors of fossils: "Artists Mine Scientific Clues to Paint Intricate Portraits of the Past". I get asked about artist reconstructions every so often -- "How accurate are they? Are they scientific? Are they just made up?"

Zimmer discusses many kinds of fossils, from dinosaurs to humans. For ancient humans, one new aspect is that we have details from their genomes about possible phenotypes, based on associations in living human populations. This came into play for the reconstruction of the "Paleo-Eskimo" individual whose genome was published in Nature last month:

Mr. Godtfredsen’s picture is plausible, rather than photographic. It’s impossible to pick out an individual from a police lineup based on nothing but a genome. Dark hair, brown eyes and a stocky build could describe thousands of people who live in the Arctic today. It’s also important to bear in mind that genes rarely guarantee any particular traits; instead, they tend to be associated with them. So we can’t know for sure that having a so-called baldness gene meant that Inuk actually ended up bald. It’s certainly possible that he died too soon to find out.

Zimmer also discusses Jay Matternes' reconstruction of Ardi:

Mr. Matternes worked for years with the scientists on his reconstruction of Ardipithecus. First he drew its skeleton. Onto the skeleton he added muscles, and finally skin and hair. Mr. Matternes infused the picture with a deep artistic understanding of anatomy. But it is also a scientific hypothesis.

This is the point I try to emphasize -- an artistic reconstruction is a hypothesis. It is communicated visually, unlike hypotheses that are expressed verbally or mathematically. Elements of it are testable -- they can be refuted by making further observations. I was explaining this to my introductory anthropology students yesterday as well -- that Matternes reconstruction of Ardi is a hypothesis about posture and locomotor mode. Looking at the reconstruction helps to frame further tests of that hypothesis in a way that complements the verbal description of the anatomy, although it doesn't supersede or substitute for the anatomical description.

But there is another aspect to the artistic representation of fossils: It conveys the reality of the objects.

I find that these two aspects of artistic representation are in tension.

Clearly communicating about the anatomy of a fossil requires a representation that highlights some anatomical aspects and glosses those that are irrelevant. Having the experience of the reality of an object requires a different kind of representation. On a surface level, for example, one may consider that fossils are broken and discolored in various ways. A true-to-life rendering of the discolorations will accurately convey something about the objects, but may obfuscate the anatomy. The very act of representing a fossil in a way that corrects for breakage and distortion is a kind of reconstruction -- a kind of hypothesis, in other words. It conveys information about the way the artist or scientist conceives of the object's relation to other objects.

Likewise, an artist's fleshed-out reconstruction of a fossil skull communicates the artist's hypothesis about the relation of the skull to ancient flesh and the living flesh that the artist knows through study and observation. It obfuscates some details of the fossil, and highlights others.

All art has this tension. We understand that an artistic representation of a living person is a kind of fiction -- it can never capture the person herself, only some aspect of the person. It may exaggerate some and gloss others.

So it is natural for some viewers to see an artistic representation of a fossil with suspicion. The agency of the artist is apparent, and we may not trust that the artist is an appropriately skeptical observer. When we look at multiple reconstructions of the same fossil, the power of convention is apparent.

Just think -- how many reconstructions of Neandertals have you seen in the last few years that weren't red-headed? Gurche's new one isn't, but almost all have been. The red-headed Neandertal clearly conveys the information about the genomics of MC1R, and yet the color itself is just a hypothesis. As I discussed upon the discovery, even if the variant has the postulated functional effect on melanocortin reception by melanocytes, there may well have been modifier genes that made Neandertal hair blonde. The convention of the red-headed Neandertal follows the needs of museums and textbook authors, all of whom need to tell the story about genetics. But in that sense, it's rather like the convention of a bearded Jesus -- making the Neandertal iconic triggers our recognition, but may subtract the need to scrutinize closely, to experience the form anew.

I have some more to write about this topic, using Jay Matternes' Ardi reconstruction as case study -- so check back later!

UPDATE (2010-03-24): I'm reminded of a post from last year, "Paleo-artists in the spotlight", which pointed to a well-illustrated Michael Balter profile of several artists in Science last July.

Reuters correspondent Zoran Radosavljevic reports on the recent opening of the new museum at Krapina, Croatia. The museum is devoted to Neandertals, and represents the long work of Croat paleoanthropologist Jakov Radovcic.

Visitors can touch parts of a digital Neanderthal body to get a medical explanation of their diseases and ailments - most of them very similar to our own, like knee and shoulder problems at a later age.

The central scene -- a big Neanderthal family gathered in a cave around the fire -- is particularly impressive because of the accompanying acrid smells of sweat and burning meat, and sounds meant to recreate those typical of the Stone Age.

The article includes a few photos of the reconstructions in the museum. This one gives an impression of the space:

I can't wait until I get a chance to visit, it looks truly impressive!

Anne-Laure Daniau, Francesco d'Errico and Maria Fernanda Sánchez Goñi went looking for signs that Upper Paleolithic Europeans were using fire to control ecosystems, similar to what is believed to have happened in Southeast Asia, Australia, and the New World under human agency during the terminal Pleistocene.

They didn't find any.

Our results show that contrary to Southeast Asia, no major increase in fire regime is recorded in Southwestern Iberia or in Western France at the onset or after the colonisation of these regions by Modern Human populations. CCsurf values associated in Southeast Asia with Modern Human impact are twice as great as the highest figures recorded in the same sequences for the period before colonisation by Modern Humans. Such a dramatic increase is not observed in our records. Also, no shift is observed in the vegetation apart from that expected by the impact of the millennial scale climatic variability on plant communities, and no increase in taxa that might be related to an increase in fire. Although the Southeast Asian and the European trends are difficult to compare considering the different latitudinal, paleoclimatic and vegetation settings, the coincidence in the former area between the peopling event and the increase in biomass burning makes it conceivable that the two phenomena are related in some way.

Our results strongly argue against the view that Neanderthals and Modern Humans were the driving factor of the large scale variations in fire regime observed in our records, which were clearly governed by the D-O millennial-scale climatic variability and its impact on fuel load. However, we cannot rule out at this stage the possibility that either one or both populations used fire for ecosystem management in ways that did not significantly affect the natural fire trend.

This is a great study. They sure looked hard, sampling microcharcoal particles from a deep sea core covering the span from 70,000 to 10,000 years ago. It's a nice record of fire on the European continent, and shows fluctuations on a millennial timescale. No sign of any other influence -- in particular, no sign that the Upper Paleolithic made any difference at all.

Negative results are in some ways more interesting than positive ones. In this case, it's not so unexpected that the humans didn't burn systematically -- Europe just ain't so easy to burn. Getting some confidence about that gives another kind of climate record. Plus it tells us one thing that didn't hurt the Neandertals.

References:

Daniau A-L, d'Errico F, Sánchez Goñi MF (2010) Testing the Hypothesis of Fire Use for Ecosystem Management by Neanderthal and Upper Palaeolithic Modern Human Populations. PLoS ONE 5(2): e9157. doi:10.1371/journal.pone.0009157

By popular request from scads of readers:

Was Neanderthal man the original metrosexual? New study suggests he wore make-up

That's in The Daily Mail. I actually like the window title even better, which I assume was an older draft of the story's headline:

Neanderthal 'make-up' discovered: Proof the human subspecies were not the 'half-wits'?

It's like something from the Onion. The story is more or less reasonable, and I love the quote at the end:

Professor Chris Stringer, a palaeontologist from the Natural History Museum in London, supported the findings but added that the view of Neanderthals as 'dim-wits' would be hard to change.

He said: 'I agree that these findings help to disprove the view that Neanderthals were dim-witted. It's very difficult to dislodge the brutish image from popular thinking.

'When football fans behave badly, or politicians advocate reactionary views, they are invariably called "Neanderthal", and I can't see the tabloids changing their headlines any time soon.'

Well, let's see how many of those football fans are wearing makeup!

I got to sit down and watch most of the first episode of "The Human Spark" on PBS tonight (my earlier post). Our local station shows these things later than the national release dates, and I missed out on the first ten minutes or so as I was putting the kids to bed. The host is Alan Alda, and here are my live-blogging thoughts after I sat down to watch:

8:16: Svante Pääbo interview. Alda watches Adrian Briggs drilling into ancient bones. Explains the problems with contamination.

"But that small difference between us could be crucial, couldn't it?"

8:18: Now, on to protein extraction from Neandertal bones to do isotopic analysis. Alda sits down in the cafeteria with Michael Richards, explaining the high proportion of animal protein in the Neandertal diet.

8:19: On to Grenoble. Nice shot from an Alp. The European synchotron. Tanya Smith is here beaming X-rays into them to get micro-CT data from inside the teeth. The skull here is from Roc de Marsal.

Some interesting animations of human versus chimpanzee cranial growth. Human brains develop slowly, etc.

"Neandertal children ... seem to have grown up more quickly..."

We're in the archaeological site of Roc de Marsal, with Harold Dibble and Shannon McPherron. How many Neandertals were there at any one time. They banter about 20,000, decide that's too many.

8:23: Dan Lieberman is showing Alda the original Skhul 5 skull. We've got a graphic of modern humans evolving in Africa, like little campfires from a night view of the Earth. And then they spread out to light little campfires in Europe. It's like the George Bush version of human evolution -- "a thousand points of light!"

Close shots of archaeological levels with Randall White.

8:27: "Even if Grandma kept her teeth in a glass..." Pierced human molars, being worn as ornaments. They go through the little museum near the site. "Microscopic analysis that we've been doing shows that they were sewn on, like to articles of clothing." This is a nice conversation they're having.

It's a little unfortunate that the film pushes the "no Neandertal ornaments" angle, particularly since this week's paper with the pierced shells.

"Here's what I don't get: The Neandertals survived, but didn't change. They came from the same people that we came from, and at some point we started changing; we became able to change.... Having come from the same background, why were we able to change and they weren't?"

White's answer -- Neandertals have a generalized technological approach; modern humans invent new technologies to address every problem that comes along. You can't separate society from technology (as a response to a followup about social organization). Population numbers may have limited lines of communication among Neandertals. With moderns, "once somebody invents something, everybody knows about it."

8:35: John Shea is teaching undergraduates how to knap. Explaining the value of projectile technology. Ooooh -- time to hit a deer decoy with an atlatl dart. "A hunter who's using this kind of thing would have to work with a group...it takes planning, cooperation...I can't imagine this functioning without the prior existence of language."

I find myself thinking wondering why this wouldn't have been true of Neandertals hunting the same animals? And didn't we hear a little while ago that it was the small animals and fish that set modern humans apart? There is a problem with the presentation here -- these seem contradictory.

8:40: Now, we're in Nairobi with Veronica Waweru. Looking at arrows with reusable shafts. Alda is narrating -- did modern humans start using poison?

8:43: Olorgesailie. Alison Brooks and (an unnamed) Rick Potts are there. Brooks has points that are 150,000 years old that may be arrow points (although the one they handle on camera is bigger than Shea's atlatl point...). Three different excavations, each representing a different age. Another small point "has just been unearthed". This one looks a likelier arrow point than the other. Then, 320,000 years old, they have left a bunch of small stone flakes on pedestals for the film crew. The stone raw material is taken from at least 45 to 50 km distance. Alda: "These people were choosy about their materials...quite unlike the Neandertals."

This is unfortunate, too -- there are some clear instances of Neandertals transporting raw materials over 250 km.

Now they're looking at a possible anthropogenic accumulation of pigment minerals. Brooks stresses human "inventiveness" as a cause of the success of modern humans.

8:50: Back to Ian Tattersall. I didn't see his earlier appearance. "When did people who would fit into human society now first appear?" Tattersall puts it down to 50,000 years ago or so. He suggests that the biological ability to behave in modern society might date back to 150,000 years ago, but lay latent until culture developed much later to bring out the modernity.

Whoa -- the points of light again. People are swarming like tiny sparking ants, and all the yellowish Neandertal fires are going out.

Not a bad program. Alda was a great host for this. You can tell he's genuinely interested in this stuff, and he really put the scientists at ease in the interviews. It's great that they got usable material again and again just having him talking with the archaeologists. And having one host actually travel to these field sites was great -- much better than the usual disembodied narration.

I was really liking it until around halfway through, but as the film went on, it started to raise contradictions that bothered me. Very one-sided about Neandertal behavior, too simplistic.

I don't think the interviewees were the problem here, I think in particular Shea and White were making fairly nuanced statements about Neandertals. I can guess that if either had given any black-and-white quotes, the editors would have included them. My impression was that the choice of topics dictated the result -- ornaments, pigment, and projectiles were chosen to emphasize the "behavioral modernity".

Where I think that approach fails in in the specifics. Projectiles may have been technically more difficult than large-point weapons, but they should have been socially easier. Does it take less cooperation to bring down large animals with close-contact weapons? I think it's the opposite -- I think Neandertals must have been under more pressure to cooperate in their hunts. The transport across long distances is important in MSA contexts, but it's also present in Mousterian France. Neandertals didn't spend hours and hours making beads, but they did wear ornaments and use pigments. If there's a distinction, it's the frequency of these behaviors -- which is a lot harder to measure or estimate.

It's too bad in a way -- it really wasn't necessary to talk about the "human spark" as a human versus Neandertal comparison. This didn't have to be a "modern human origins" program. The DNA segment was interesting, but it didn't really contribute anything to the show's theme -- the narration concluded the segment by saying that the genes don't tell us about the "spark" yet.

I'd have emphasized some older stuff, which is new science that actually does tell us about the emergence of humanness. The Brooks segment would fit into that theme, with the much earlier material from Olorgesailie (and this week we have 500,000-year-old blades from the Kapthurin Formation...). I'd have emphasized the new stuff from Atapuerca, especially the evidence about language. An earlier focus would bring a little more credible use of genetics, either FOXP2 (which I really don't need to see again...) or some human-accelerated genes.

It's curious to compare this program with the NOVA series last fall. The themes were very different (NOVA emphasized climate, this one technology). There was very little overlap of scientist lists -- although it never hurts to be based in New York. I think the programs go well with each other, but it sort of forces the casual viewer to notice that the same evidence can be read almost at cross-purposes, depending on what the scientist assumes is fundamental.

Bruce Bower reports on excavations by Thomas Strasser on the Mediterranean island of Crete: "Ancient hominids may have been seafarers".

At Preveli Gorge, Stone Age artifacts were excavated from four terraces along a rocky outcrop that overlooks the Mediterranean Sea. Tectonic activity has pushed older sediment above younger sediment on Crete, so 130,000-year-old artifacts emerged from the uppermost terrace. Other terraces received age estimates of 110,000 years, 80,000 years and 45,000 years.

These minimum age estimates relied on comparisons of artifact-bearing sediment to sediment from sea cores with known ages. Geologists are now assessing whether absolute dating techniques can be applied to Crete’s Stone Age sites, Strasser says.

I would set a high bar for evidence on this one. No details are available; it was a conference presentation.

One possibility: According to Alexandra van der Geer and colleagues (2006), there was a faunal turnover on Crete 300,000 years ago. The earlier fauna included a 1.5-meter dwarf mammoth and dwarf hippos. The hippos were hoof-walkers apparently adapted to a "more terrestrial" activity pattern. Sometime after 400,000 years ago, this fauna was replaced. No more hippos or mammoths, and new, larger, mainland-derived elephants. As they wrote (125):

The dwarf elephant may be large compared to the mammoth of the previous period, but it is still about 30% smaller than its mainland ancestor E. antiquus, which has a shoulder heigth of 3.7 m. The dwarf elephant has strongly curved tusks. It is still a matter of debate why this elephant did not reach a pygmy size.

The arrival of humans is one possibility. Sondaar and van der Geer (2002) suggested that Sardinia-Corsica might have undergone similar turnovers induced by human arrivals during the Middle and Late Pleistocene.

But that's entirely speculation. I want to see some dating and good descriptions of the artifacts and their context.

If the artifacts found by Strasser represent a genuine occupation, the Cretans would presumably have been seafaring Neandertals. Or Preneandertal-derived hobbits. Man, I wish I'd made that one of the 2010 predictions!

References:

van der Geer A, Dermitzakis M, de Vos J. 2006. Crete before the Cretans: The reign of dwarfs. Pharos: Journal of the Netherlands Institute in Athens 13:119-130.

Sondaar PY, Van der Geer AAE 2002. Plio-Pleistocene terrestrial vertebrate faunal evolution on Mediterranean islands, compared to that of the Palearctic mainland. Annales Géologiques des Pays Helléniques 1e Série 39, A: 165-180.