multiregional

I'm just looking through the January/February 2008 Evolutionary Anthropology, which is all about modern human origins in Africa. The special issue resulted from a conference at Stony Brook, along with a few additions to round out the topic.

I'll have some things to say about these articles, but one thing struck me. I'll describe the problem:

Dan Lieberman's paper, "Speculations about the selective basis for modern human cranial form," discusses five categories of functional requirements that might have been involved in the evolution of the "modern" human cranial anatomy. Each of these imposes distinctive requirements on the form of the head -- not all of which are fully understood -- but all of which changed in ways that parallel the basic changes in cranial form of the Late Pleistocene.

But Tim Weaver and Charles Roseman's paper, "New developments in the genetic evidence for modern human origins," claims that the modern human cranial anatomy originated by genetic drift, without any substantial selection:

Evolutionary quantitative genetic analyses, in fact, show that Neandertal and modern human cranial differences can be explained by genetic drift, making it unlikely, at least for the cranium, that modern human anatomical features were spread by natural selection rather than a range expansion out of Africa. An important point is that these analyses do not simply compare the magnitude of the morphological differences between Neandertals and modern humans; they are multivariate tests of how the patterns of covariation across different cranial measurements compare to those expected for divergence by genetic drift. Natural selective hypotheses designed to account for Neandertal and modern human cranial differences would also need to show multivariate consistency with the observed patterns of variation. While it may be possible to imagine natural selective scenarios that mimic genetic drift for a single measurement, such as fluctuating directional natural selection, the scenarios become much less plausible for multivariate patterns of variation (Weaver and Roseman 2008:78).

Both these papers cannot be correct. A full text search of Lieberman's paper does not find the words "drift" or "random," and "neutral" only appears as part of "neutral horizontal axis." Yet Weaver and Roseman cite the neutrality of cranial form as the main evidence against Eswaran's model of an adaptive dispersal of cranial form. According to them, all of Lieberman's "speculations" must be wrong.

I thought maybe I could get some insight into this dilemma by reading Günter Bräuer's paper, "The origin of modern anatomy: by speciation or intraspecific evolution." That title sounds fairly clear -- if we're talking about a speciation of modern humans to explain their anatomy, that sounds like the kind of rapid change that ought to indicate selection of some kind.

Bräuer shows some skepticism toward Lieberman's ideas about cranial evolution:

In my view, Lieberman, McBratney, and Krovitz's interpretation that anatomical modernization can be boiled down to just a few autapomorphies or genetic changes will be difficult to accommodate within the current fossil evidence (Bräuer 2008:27-28).

OK, but does this disagreement mean that Bräuer is likewise skeptical of adaptive hypotheses to explain modern cranial form? Again, a full text search fails to find the words, "drift," "neutral," or "random." But neither does it find the word "selection." Bräuer is concerned with describing the pattern of evolution of the modern human cranial form, but is entirely noncommittal on the question of why it evolved. That would seem to be problematic in itself: wouldn't we expect a different pattern of evolution if natural selection caused the changes, than if genetic drift caused them? Wouldn't the two causes make different predictions about the role of speciation in the process?

I'll have more to write about Bräuer's interesting paper, but on this issue, I think that is all I can extract from it. Osbjorn Pearson's paper, "Statistical and biological definitions of 'anatomically modern' humans," has more to say on the issue. Pearson cites the work that suggests modern human cranial form evolved under random genetic drift, saying:

Ideally, one would like to partition morphological distance into differences due to genetic drift, adaptation, and environmental interactions with ontogeny. Recently, several promising studies have shed light on these issues, including the amount of morphological diversity in recent humans that likely reflects genetic drift and the effects of the toughness of foods on the cranial morphology and occlusion of nonhuman primates, retrognathic mammals (for example, hyraxes), and humans from different parts of the world. Nevertheless, much remains to be done before these relationships become completely clear (Pearson 2008:40-41).

He later suggests (p. 44) that "rapid morphological change due to drift during population bottlenecks" may be involved in the evolution of modern cranial form. On the other hand, Pearson also suggests that "selection for new, advantageous traits or genes, or some combination of the two [selection and drift]" may have occurred. That would seem fairly noncommittal.

However, Pearson's description of the series of events -- a stepwise, sequential series of anatomical changes ultimately in a worldwide context up to and including the Holocene -- seems pretty unlikely to result from genetic drift alone. Indeed, Pearson writes,

In common with many other parts of the world, [African] crania that have dimensions or suites of morphological traits that make them statistically indistinguishable from the living populations appear only during the Holocene (Pearson 2008:45).

If the evolution of modern cranial form is a process that continued into the Holocene, it is quite impossible to have been caused by drift alone, since the effective population sizes of human populations were too large, and drift could hardly have caused a "nearly universal pattern of gracilization" (ibid.). So Pearson's paper certainly heightens the contrast between the adaptive and drift scenarios. If the events are as Pearson describes them, the "genetic drift alone" hypothesis must be false.

Philip Rightmire's paper is about earlier events, and Chris Stringer and Nick Barton's paper is a conference review. That leaves only Ian Tattersall and Jeff Schwartz's paper, "The morphological distinctiveness of Homo sapiens and its recognition in the fossil record: clarifying the problem," to clarify the problem.

Tattersall and Schwartz direct their attention to the kinds of features that are suitable for identifying a species from the fossil record -- uniquely derived features, or "autapomorphies." In their view, species must be accurately diagnosed from sets of specimens ("alpha taxonomy") before any kind of evolutionary hypotheses can be tested.

Because of this, they don't talk very much about the kinds of evolutionary forces that might cause the patterns they see. The paper includes only one reference to "random" and "adaptive," both in a single sentence:

However, there are some materials of this period [the late Middle Pleistocene] that fall outside, but not far outside, the strictest definition of Homo sapiens as based on the living species. Most of these (for example, Border Cave 5, Boskop, Fish Hoek, Klasies River Mouth except for AP 6222, and maybe Cave of Hearths) form a generally poorly dated South African group in which cranial structure largely conforms to the modern Homo sapiens morphology except that, most notably, the bipartite brow and/or the inverted-T-shaped chin are lacking. Do such fossils represent distinctive and now extinct populations of Homo sapiens that lacked two or more of the most striking autapomorphies of the living species merely as a result of random (or even adaptive) population variation? Or did they belong in life to one or more distinctive reproductive entities whose histories did not impinge, at least biologically, on that of today's Homo sapiens? (Tattersall and Schwartz 2008:52, emphasis added)

The bolded sentence is important. Tattersall and Schwartz view adaptive and random variations as equivalent: small changes between populations that may occur even without the kind of significant isolation that would invite a taxonomic interpretation. They contrast these in the next sentence with "distinctive reproductive entities whose histories did not impinge." And they are correct; modern human populations have morphological differences as a result of both selection and drift, and their histories certainly have impinged on each other.

But it makes a difference whether selection or drift was the cause of changes, because selection is more powerful than drift. Weak selection can cause a level of morphological differentiation that would require long isolation by random drift alone. If selection were involved in African regional differentiation, there may be no reason to posit "distinctive reproductive entities whose histories did not impinge" -- in fact, their histories almost certainly would have impinged.

In other words, the relation of the pattern of features to the taxonomic status of the populations depends on the evolutionary forces that generated the pattern.

As Weaver and Roseman note, their hypothesis that modern human cranial form evolved neutrally depends on the pattern of evolution of different features, not the amount of evolution of any single feature. But the amount of evolution must still be explained; under their hypothesis, it must have occurred in small populations over a substantial period of time. In their hypothesis, the cranial differentiation of African late Middle/early Late Pleistocene fossils would have emerged during relatively long periods of parital or complete isolation. Under that hypothesis, Tattersall and Schwartz would be correct to place these fossils into different taxa, only one of which was ancestral to living people -- or at least principally ancestral, allowing for some small amount of hybridization and introgression.

In contrast, Lieberman's adaptive hypotheses are consistent with the evolution of modern human cranial morphology within a broader, larger population. Patterns of selection may explain the variation among the fossils. Today's humans may have emerged from a population with substantial cranial polymorphism. That scenario would seem to be consistent with the patterns described by Pearson -- in which modern human cranial variation does not standardize until very late, perhaps even Holocene times. Only selection could cause this kind of evolution within the large populations of the last 10,000 years, or even within the large populations of the last 70,000 years.

I picked this problem first, because it was the first to stand out to me in the papers. It does seem a fairly glaring contradiction. I don't expect the authors to have noticed the contradiction in advance; I think that they approach the question of human origins from fundamentally different viewpoints.

As you can tell, two of the papers are not concerned with the causes of evolution at all -- their aim is to map the pattern of morphological variation onto putative speciation events. But it seems to me that if we approach the fossil record with the idea that speciation is the major cause of such patterns, then we have already assumed how the evolution happened. It may not have escaped your notice that this is the major reason for disagreement about modern human origins: One group of authors wants to assume the conclusion, foreclosing further discussion.

I don't have any complaints about the papers that were chosen for the issue -- in fact, I'm interested in reading the current opinions of all these authors. So far, I would say that each paper is a well-written expression of its authors' ideas, and I appreciate having all that in one place.

But it does seem a little strange that a special issue devoted to modern human origins in Africa doesn't have more, um, diversity of opinion. Several of the papers discuss multiregional evolution. They apparently believe that it is an important enough viewpoint to include their reasons for disbelieving it. One of the papers (Weaver and Roseman) includes a section about genetic introgression, kindly citing my work. Another (Bräuer) claims that it is reasonable to include all Middle Pleistocene humans in Africa and Europe as part of "one polytypic species, Homo sapiens" (Bräuer 2008:32).

So the work of those of us who write about evolutionary mechanisms seems to be making an impact. Still, it's kind of like "dark matter" -- you only know about the ideas because of their effects on what you can read! In this case, you can read a lot of peoples' opinions about these ideas -- you just can't read them from the people who thought of them.

What boring meetings these must be, with everybody agreeing with each other all the time, and nobody to point out all these contradictions!

References:

Bräuer G. 2008. The origin of modern anatomy: by speciation or intraspecific evolution? Evol Anthropol 17:22-37. doi:10.1002/evan.20157

Lieberman DE. 2008. Speculations about the selective basis for modern human cranial form. Evol Anthropol 17:55-68. doi:10.1002/evan.20154

Pearson OM. 2008. Statistical and biological definitions of "anatomically modern" humans: Suggestions for a unified approach to modern morphology. Evol Anthropol 17:38-48. doi:10.1002/evan.20155

Tattersall I, Schwartz JH. 2008. The morphological distinctiveness of Homo sapiens and its recognition in the fossil record: Clarifying the problem. Evol Anthropol 17:49-54. doi:10.1002/evan.20153

Weaver TD, Roseman CC. 2008. New developments in the genetic evidence for modern human origins. Evol Anthropol 17:69-80. doi:10.1002/evan.20161

A flush of papers this week (two today in Nature, one tomorrow in Science) describe new analyses of SNPs across the genome. Two of the papers sample SNPs in global samples numbering more than 500 individuals.

This Reuters story by Maggie Fox is typical of the press coverage:

Gene studies confirm 'out of Africa' theories

WASHINGTON - Two big genetic studies confirm theories that modern humans evolved in Africa and then migrated through Europe and Asia to reach the Pacific and Americas.

...

The studies, published in the journal Nature on Wednesday, paint a picture of a population of humans migrating off the African continent, and then shrinking at some point because of unknown adversity.

Later populations grew and spread from this smaller genetic pool of founder ancestors -- a phenomenon known as a bottleneck.

These studies have very, very exciting potential. Here in my lab, we will be immediately using the data from these papers to test hypotheses about recent human evolution.

But it is beyond me to understand why anyone thinks that the "serial founder effect" story is news!

For one thing, the idea is based on 12-year-old research demonstrating that human diversity declines for some genetic loci with distance from Africa. This observation was replicated for genome-wide STR loci in a well-publicized paper three years ago. This paper clearly demonstrated how a model involving a chain of bottlenecks could result in a cline of diversity -- one population leaving Africa, a small group from this population moving to Jordan, another small group moving from Jordan to Mesopotamia, another small group from Mesopotamia to the Zagros, etc.

In other words, there's nothing new here. It's no surprise that genome-wide SNPs and copy-number variants (CNVs) should replicate the pattern already shown for genome-wide STRs.

What's worse, all these papers from the Stanford school of genetic orthodoxy fail to even test the hypothesis! I pointed out this problem three years ago:

The data that the paper attempts to explain are (1) the correlation of genetic distance and geographic distance among human populations, and (2) the decrease in genetic diversity in populations farther from Africa. We may ask, what other hypotheses would explain the same data? And what kind of evidence could test these hypotheses, instead of just asserting that they "match" the pattern of evidence.

One scenario that matches the evidence is multiregional evolution with a recent African dispersal of some adaptive genes. This is the hypothesis presented by Eswaran (2002). The idea is that human populations interacted for a long time in Africa and Eurasia, and that during the Late Pleistocene, adaptive changes within Africa allowed those populations to spread alleles into existing populations in Eurasia. The strength of the "founder effect" in this scenario depends on the genetic structure and selective advantage of the new African adaptive complex. Ramachandran et al (2005) actually cite Eswaran (2002) as an example of a serial founder effect. So the idea that there was widespread genetic movement out of Africa does not necessarily imply an out-of-Africa population replacement. The data do not require a replacement, and some -- even many -- of the genetic variants outside of Africa may have nothing to do with recent genetic movement out of Africa.

A second hypothesis is presented by Templeton (2002), who proposed that several founder effects happened at different times in the Pleistocene, each carrying one or more genetic variants out of Africa. The pattern of genetic variation appears to indicate that some genes left Africa during the Lower or Middle Pleistocene, while others dispersed later, during the Late Pleistocene. For Templeton (2002), this pattern indicates multiple dispersals, none of which was sufficient to wipe out the genetic contribution of earlier dispersals. This scenario also would lead to a pattern of correlation of genetic and geographic distance (because most genes have been affected by isolation-by-distance for a long time), while the recurrent dispersals would explain the decline in genetic variation outside of Africa.

A third hypothesis is that population size was simply greater within Africa than within Eurasia. The smaller population size (along with isolation-by-distance) would explain the difference in genetic variation; the correlation of genetic and geographic distance would be explained by isolation-by-distance. We may consider a fourth hypothesis also: that natural selection has tended to create slightly more genetic uniformity within Eurasia and slightly more genetic diversification in Africa. Such a scenario might be justified on ecological grounds: African populations cover a wider range of ecologies and have historically had a greater exposure to zoonotic disease, for example.

Except for the serial founder effect with population replacement, none of the other hypotheses are mutually exclusive. In other words, some genes might have been influenced by natural selection, most might have been somewhat influenced by differences in population size, but the largest effect might have been recurrent population dispersals.

Reading over the whole post, I think it did a good job of laying out the situation with serial founder effects in 2005, and there is little reason to change it now. Still nobody has tested the model! Again, this is a case of science by consistency -- the results of simulations generate the same kind of correlations as the observed data, so the authors claim support for their hypothesis.

But the necessary test should be carried out by dating haplotypes, finding the ages of "founder mutations" and eliminating the possibility of introgression from ancestral Eurasian populations. One of the key points in my earlier post is that the model proposed by Eswaran (2002) would generate exactly the distribution expected for serial founder effects -- despite the fact that it describes a wave of genetic change within an already-established pan-Old-World population.

This study doesn't support an out-of-Africa migration; it merely assumes it. Now, I'm one who thinks that there was an important trend of strong gene flow out of Africa in the Late Pleistocene. But data showing a correlation between diversity and distance from Africa just cannot show the critically important facts about the timing and magnitude of such gene flow.

Somebody will eventually straighten all this out. What I wonder is why it never seems to be the reviewers!

References:

Jakobsson M and 23 others. 2008. Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451:998-1003. doi:10.1038/nature06742

Eswaran V, Harpending H, Rogers AR. 2005. Genomics refutes an exclusively African origin of humans. J Hum Evol 49:1-154.

Ramachandran S, Deshpande O, Roseman CC, Rosenberg NA, Feldman MW, Cavalli-Sforza LL. 2005. Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa. Proc Nat Acad Sci USA 102:15942-15947.

Templeton AR. 1998. Human races: a genetic and evolutionary perspective. Am Anthropol 100:632-650.

Templeton AR. 2002. Out of Africa again and again. Nature 416:45-51.

This week, Johannes Krause and colleagues from the Max Planck Evolutionary Anthropology institute announced that they had tickled FoxP2 out of two Neandertal specimens from El Sidrón, Spain. The bones were excavated in sterile (clean-cave?) conditions, immediately frozen and then shipped to Leipzig, where extracts were taken in clean-room conditions.

Here's an FAQ about what they found.

Why is this paper really important?

Isn't it obvious? It's important because it demonstrates that more than one Neandertal is suitable for nuclear genome recovery. We will know about genetic variation in Neandertals, sooner rather than later. These two bones come from different individuals, because the Leipzig group found two different mtDNA sequences in them. Together with the Vindija Vi 33.16 specimen in the original Neandertal genome papers, this makes three nuclear genome Neandertals. There will be more.

It also shows the possibility of probing ancient skeletons for specific genes. Here, they went in looking for Y-DNA, X-DNA and particular sites on FoxP2, and they found them. That is definitely the way to go if you want to test a biologically significant hypothesis fast -- otherwise, you just have to wait until the sequence comes up in your genome project.

However, I question the value of probing for individual genetic variants in this way. Every probe takes a bit of sample, which might be more efficiently used in whole-genome sequencing. We have 25,000 genes, and every one is potentially interesting. Every small sample used to assay only one of those genes may destroy many sequences from the others. It would be one thing if samples were trivial and easily replaced, but they obviously aren't.

Still, we will certainly see additional probes for genes that are of particular interest. I wouldn't be surprised to see MC1R results soon, to probe whether there were pigmentation variants in Neandertals. The same has already been done for woolly mammoths.

So, Neandertals had the human-specific FoxP2 form. Did they talk?

I think the genetic observation leans toward that direction, but doesn't really change our understanding. Consider:

Neandertals have a hyoid bone with humanlike anatomy, as did the Atapuerca people at more than 300,000 years ago, even though A. afarensis did not. So something related to vocalization evolved in humans by the Middle Pleistocene. Although Neandertal vocal tracts may not have been identical to recent humans, there is nothing about them that would preclude speech. The only paleoneurological observation about language puts a developed Broca's area on the KNM-ER 1470 endocast, Homo habilis.

Like other Middle Paleolithic/MSA people, their technology required more information to learn than earlier, Lower Paleolithic industries, leading to regional differentiation and more task-specific facies. Late Neandertals made use of some technology otherwise used only by Upper Paleolithic modern humans. Their hunting methods must have required cooperation and may have been impossible without a more sophisticated communication strategy than used by other primates.

All of these things argue for some kind of Neandertal language irrespective of FoxP2.

Then again, most of the arguments against humanlike language facility in Neandertals also have nothing to do with FoxP2, either. The slow technological progress, limited collection strategies, the rarity of any artistic or symbolic expression, their high mortality rate, and -- of course -- the fact that they no longer exist have all been considered as evidence that Neandertals lacked some essential aspect of "behavioral modernity." If language is a prerequisite for the modern human pattern of behavior, then Neandertals may not have talked, at least not in the way we do.

I think the FoxP2 story has really confused people much more than necessary. But in this case, the confusion is the same that results from every other gene study: when the press says we've found a gene "for" something, what it ought to say is that we've found an allele that affects something.

No macromutation happened. Language did not spring full-formed into the mind of some ancient African. All members of Homo used communication systems including some (possibly minimal) elements of language, and the evolution of the human brain, along with technological changes throughout the Paleolithic, reflect the evolution of communication. Human language evolved -- like all things -- over a long time, and like all complex phenotypes it required a series of mutational changes. Many of these mutations became fixed during recent human evolution, some may still be changing in frequency today. Language evolution is probably a continuing process.

That means that it must have involved many more genes than FoxP2 -- which after all experienced only two amino acid substitutions in all of human evolution. I would imagine the number of genes involved in language evolution is more than 500, and I wouldn't be surprised if it were much more. In that context, it seems quite silly to say FoxP2 is the "critical" evolutionary change for anything.

Then you agree with Language Log. They told me that FoxP2 isn't a "language gene."

The case is strong that the two FoxP2 coding substitutions in humans were selected because of their role in language. The gene sequence is strongly conserved in most mammals, and shows similar changes in some other species with unusual vocal adaptations, such as echolocating bats (Li et al. 2007). Its expression pattern delineates areas related to vocalizations in both humans and birds, and the pattern itself differentiates between song-learning versus nonlearning bird species (Haesler et al. 2004, Teramitsu et al. 2004, Webb and Zhang 2005). And of course, mutations to FoxP2 can result in specific language impairment (SLI) in humans.

Still, that case is only circumstantial. We know that FoxP2 was under selection, that it became fixed in humans, probably during the Late Pleistocene, and that breaking the gene changes brain development and damages language skills. But we don't know what a human would be like with the chimpanzee form of the protein. We don't know whether both of the human-specific amino acid substitutions have a different effect than one. Most important, we don't know what other genetic changes may have been necessary backgrounds for selection on FoxP2.

This means Neandertals were really modern humans, right?

This study should put an end to the "sudden mutation" model of modern human origins.

There was not a single mutation that made the critical difference in the ancestry of today's people. There was no cognitive Rubicon leading to modern human evolution. I would analogize the process as a slow-motion avalanche: at first a few small sands began to tumble, and then selection on a large number of genes became inevitable. FoxP2 is one of those genes, and as yet we don't know whether it was near the beginning or near the end of the process.

But it is clear that the process began before the Neandertals were gone. Some aspects of behavioral complexity did begin to evolve rapidly sometime after 70,000 years ago. This rapid evolution was multiregional in context -- it was not limited to a single human population. In particular, it was not limited to Africans: the last Neandertals clearly manifested technological and behavioral strategies otherwise defined as "behaviorally modern" (d'Errico 2003). There's a reason why the Neandertal-produced Châtelperronian industry of France and Spain was historically considered the first Upper Paleolithic industry.

But we have undergone light-years of change since the last Neandertals lived. This is not a question of "modern human origins" anymore. We can now show that living people are much more different from early modern humans than any differences between Neandertals and other contemporary peoples. I think that "modern humans" is on its way to obsolescence. What matters is the pattern of change across all populations. Possibly that pattern was initiated by changes in one region but the subsequent changes were so vast that the beginning point hardly matters.

We all know that the Neandertal genome is riddled with contamination from modern humans. Isn't the null hypothesis that we have a modern human sequence here because it is a modern human?

Well, as you know, I'm not all that convinced that contamination explains the interpretive discrepancies between last year's genome papers. But still, this study has done some things to address the problem of contamination.

It is notable that Green et al. (2006) found 25% modern human mtDNA in one of the El Sidrón bones: this shows that even "sterile" excavation, immediate freezing and extraction under clean-room conditions cannot exclude contamination. There is at the moment nothing more that can be done. We will always have the problem of a contamination fraction in ancient Neandertal skeletons. So we have to judge each study by the extent to which we can exclude contaminants with statistical analysis.

For this study, Krause et al. (2007) developed a test of nuclear DNA contamination: they identified seven gene variants that differ between the recovered Vindija Vi 33.16 nuclear genome and all known living humans. In other words, these are human-derived mutations that are absent from the only known Neandertal nuclear genome. Then, they probed the El Sidrón bones for these sites. They found only the ancestral form in their extracts of both bones -- presumably because no human contaminants were present in their samples.

That seems like a pretty good indication that the other sites in their sample represent the true gene variants of the ancient Neandertals. I wouldn't go so far as to say that contamination is ruled out, but it seems like these are good results.

Did FoxP2 introgress into Neandertals?

It sure looks that way to me. Let's consider the evidence:

FoxP2 recently fixed in humans. According to Enard et al. (2002:871):

Under a model of a randomly mating population of constant size, the most likely date since the fixation of the beneficial allele is 0, with approximate 95% confidence intervals of 0 and 120,000 years.

Now, Enard et al. (2002) noted that human populations have grown over time, and that they are not randomly mating, so that this date estimate might be too recent. Allowing for population growth since "10,000--100,000 years ago," they asserted that fixation of FoxP2 must have happened "during the last 200,000 years of human history." But this is not quite accurate. Unlike genetic drift, positive selection can and often does fix genes rapidly in a growing population. It simply doesn't matter that the human population has been rapidly growing: FoxP2 may still have just become fixed yesterday.

Last year, Green and colleagues (2006) considered that the Neandertal-modern population divergence time might have been quite recent, depending on the ancestral population size. According to the estimates of Wall and Kim (2007), the Green et al. data are consistent with a Neandertal-modern population divergence time as recent as 30,000 years ago. Of course, that date would predict substantial admixture between contemporary Neandertal and non-European populations -- they would have been exchanging genes up to the very lifetimes of the last Neandertals. According to those data there would be nothing surprising about Neandertals and living people sharing the human-derived FoxP2 allele. But as mentioned above, Wall and Kim (2007) used the recent divergence estimate as evidence that the Neandertal genome data from Green et al. must be contaminated.

So, if we cannot trust the data, then we have to fall back on some other estimate of the divergence date. Noonan and colleagues (2006) estimated a divergence date between Neandertals and modern populations between 170,000 and 570,000 years ago. If we accept that, then the confidence intervals of the Neandertal-human divergence and the FoxP2 selective sweep might barely overlap. Might. But I will note that a minimal overlap between the 95% confidence intervals of two point estimates does not mean that they are not significantly different. Only if the expected value of one estimate falls within the 95% confidence interval of the other do they fail to be significantly different. It is pretty unlikely that the most recent FoxP2 sweep is older than 170,000 years ago and the Neandertal-modern population split is as recent as 170,000 years.

That is, unless the "split" time reflects widespread genetic introgression.

The current paper (Krause et al. 2007) goes to some contortions to try to establish that the FoxP2 sweep could really have been older than 300,000 years ago (where they place the lower confidence limit on the N-M split):

The third scenario is that the selective sweep started before the divergence of the ancestral populations of Neandertals and modern humans around 300,000-400,000 years ago

Let me just say that I was surprised to read this explanation in a paper from this group. One of the main arguments they have been posing as a scientific value of the Neandertal genome sequencing is that conventional methods don't detect selection at 300,000-400,000 years ago. But here, they consider such an ancient mutation to be the most likely hypothesis. This seems like quite a shift just to avoid the unpleasant idea of Neandertal introgression. Ooooh -- can't have those Neandercooties!

In reality, there is no reason to think the fixation of FoxP2 happened as early as 300,000 years ago, and indeed the very high frequencies of the linked derived alleles (over 97% for six of the linked alleles) suggest strongly that the sweep probably happened within the last 100,000 years -- otherwise, subsquent genetic drift should have caused these linked derived alleles to show more dispersion in their current frequencies. The same features that make the inference of selection so strong at FoxP2 -- it is far (>286 kilobases) from the nearest gene and it includes many high-frequency derived alleles in addition to reduced polymorphism -- make it very unlikely that the selective sweep was ancient.

So, considering that the El Sidrón samples both share the human-derived amino acid substitutions on the same haplotype as modern humans, complete with all the high-frequency derived SNPs, it seems almost certain that the gene introgressed into Neandertals from modern humans.

Or, there's one other option. One of the El Sidrón bones includes a relatively rare (in humans) ancestral SNP allele at one of those linked sites where the derived allele is at very high frequency in humans. One explanation: the selected mutation arose in Neandertals and introgressed into other humans. That would explain why this Neandertal didn't have a SNP variant on its FoxP2 haplotype that later became very common in humans: Neandertals had the new FoxP2 first.

What about that Y chromosome thing?

The El Sidrón bones both tested positive for the Y chromosome site assayed in the study. That means they were both male (duh!). But more important, the Y chromosomes of both individuals lacked the human-specific derived mutation that the researchers tested for. Since all human males yet surveyed have this human-derived mutation, this means that a Y chromosome variant has fixed in modern humans that Neandertals did not have. Since the entire nonrecombining portion of the Y chromosome is completely linked, we can infer that the entire modern human Y chromosome has undergone at least one fixation not shared with the ancestors of these Neandertals.

Here's the text (from page 2):

Both Neandertals yielded products for Y chromosomal primer pairs, indicating that they were males. Strikingly, all 15 Y chromosomal products for the five assayed positions show the ancestral allele. This includes two polymorphisms that define the deepest split among current human Y chromosomes (Y2 and Y4, Figure S1) as well as two polymorphisms that cover less common African Y chromosomes (Y3 and Y5, Figure S1). These Y chromosome results must derive, then, either from Y chromosomes that fall outside the variation of modern humans or from the very rare African lineages not covered by the assay (Figure S1). For our purposes, this result shows that neither the maternally inherited mtDNA nor the paternally inherited Y chromosome shows evidence of gene flow from modern humans into Neandertals or of subsequent contamination of their mortal remains.

That's not such a big surprise. Already we knew that the fixation of the human Y chromosome was very recent -- probably within the last 70,000--100,000 years, and possibly even more recently. Every man on earth shares recent Y chromosome mutations that were completely absent in Middle Pleistocene humans. That is one radical recent evolutionary change.

The paper elsewhere suggests that this absence of the human-derived Y chromosome in Neandertals as evidence that they did not contribute other genes to us. I could not disagree more.

The very recent fixation of the Y chromosome in an expanding human population is extremely unlikely to have resulted from genetic drift. Drift does not eliminate rare variants as quickly in an expanding population. Instead, one or more Y chromosome mutations must have been positively selected, resulting in the fixation of the entire NRCY in recent humans.

In that context, the Neandertal result is quite expected: they had an earlier Y chromosome lacking one or more mutations later selected in the other ancestors of living people.

References:

Briggs AW, Stenzel U, Johnson PLF, Green RE, Kelso J, Prüfer K, Meyer M, Krause J, Ronan MT, Lachmann M, Pääbo S. 2007. Patterns of damage in genomic DNA sequences from a Neandertal. Proc Nat Acad Sci USA doi:10.1073/pnas.0704665104

d'Errico F. 2003. The invisible frontier. A multiple species model for the origin of behavioral modernity. Evol Anthropol 12:188-202. doi:10.1002/evan.10113

Green RE, Krause J, Ptak SE, Briggs AW, Ronan MT, Simons JF, Du L, Egholm M, Rothberg JM, Paunovic M, Pääbo S. 2006. Analysis of one million base pairs of Neanderthal DNA. Nature 444:330-336. doi:10.1038/nature05336

Haesler S, Wada K, Nshdejan A, Morrisey EE, Lints T, Jarvis ED, Scharff C. 2004. FoxP2 expression in avian vocal learners and non-learners. J Neurosci 24:3164-3175. doi:10.1523/JNEUROSCI.4369-03.2004

Krause J, Lalueza-Fox C, Orlando L, Enard W, Green RE, Burbano HA, Hublin J-J, Bertranpetit J, Hänni C, Fortea J, de la Rasilla M, Rosas A, Pääbo S. 2007. The derived FoxP2 variant of modern humans was shared with Neandertals. Curr Biol 17:1-5. doi:10.1016/j.cub.2007.10.008

Li G, Wang J, Rossiter SJ, Jones G, Zhang S. 2007. Accelerated FoxP2 Evolution in Echolocating Bats. PLoS ONE 2(9): e900. doi:10.1371/journal.pone.0000900

Noonan JP, Coop G, Kudaravalli S, Smith D, Krause J, Alessi J, Chen F, Platt D, Pääbo S, Pritchard JK, Rubin EM. 2006. Sequencing and analysis of Neanderthal genomic DNA. Science 314:1113-1118. doi:10.1126/science.1131412

Wall JD, Kim SK. 2007. Inconsistencies in Neanderthal genomic
DNA sequences. PLoS Genet 3:e175. doi:10.1371/journal.pgen.0030175.eor

Hawks sightings in the news.

I've been in the midst of a grant proposal -- yes, I actually do write those from time to time! Yes, you can support the site by giving my grant proposals glowing reviews...

Anyway, there hasn't been much time for me to follow up on that "Skull study deals death blow to multiregional evolution" story that's been going around this week. But I've written a few notes:

Charles Roseman makes the essential point in Michael Balter's article about the study:

Charles Roseman, an anthropologist at the University of Illinois, Urbana-Champaign, says that he is not convinced that the Nature authors have adequately tested the Out of Africa model versus its multiregional rival. The researchers assumed that the multiregional model requires that modern humans arose more than once. "Proponents of the multiregional model have been very clear for some time that their models do not posit multiple origins, as suggested in the paper," Roseman says.

The thing that irritates me is that the phrase "multiple origins" is right there in the abstract: (emphasis added)

The origin and patterns of dispersal of anatomically modern humans are the focus of considerable debate [1, 2, 3]. Global genetic analyses have argued for one single origin, placed somewhere in Africa [4, 5, 6, 7]. This scenario implies a rapid expansion, with a series of bottlenecks of small amplitude, which would have led to the observed smooth loss of genetic diversity with increasing distance from Africa. Analyses of cranial data, on the other hand, have given mixed results [8, 9, 10, 11, 12], and have been argued to support multiple origins of modern humans [2, 9, 12]. Using a large data set of skull measurements and an analytical framework equivalent to that used for genetic data, we show that the loss in genetic diversity has been mirrored by a loss in phenotypic variability. We find evidence for an African origin, placed somewhere in the central/southern part of the continent, which harbours the highest intra-population diversity in phenotypic measurements. We failed to find evidence for a second origin, and we confirm these results on a large genetic data set. Distance from Africa accounts for an average 19-25% of heritable variation in craniometric measurements - a remarkably strong effect for phenotypic measurements known to be under selection.

Really, they could have gotten this right with very little effort. It would have taken away the headline-grabbing part; but I can hardly believe that this kind of thing is headline-grabbing any more. I mean, Hanihara's craniometric database is awesome, sure, but they haven't done anything with the data that Bill Howells didn't do 35 years ago. This is a simple regression of variance against distance, with a second multiple regression including "climate," meaning a variable consisting of mean annual temperature and precipitation. It is a lot less sophisticated than the analyses that Roseman (2004) did, or Katerina Harvati and Tim Weaver (2006).

OK, so here are some of my notes about the paper (Slashdot wanted to know...):

1. There was a theory of "multiple origins" of modern humans. It was called polygenism, it was rejected by Darwin and was utterly discredited more than 50 years ago. One of the cited papers above for the idea of "multiple origins" [ref. 9] is one of my papers, titled "Multiregional, not multiple origins." Now, I know that some people might write a paper with the words, "not multiple origins", in the title, and secretly, in their heart of hearts, have meant to send the message that "multiple origins" is the way to go. But that wasn't what we had in mind! How could we have been any clearer?

Now, you might think, well this is just a semantic quibble. So they shouldn't have written "multiple origins" -- just ignore that. They did test multiple evolution, didn't they?

No. They conclude that a single origin is the best explanation, because adding a second origin somewhere else doesn't improve the explanatory power of their model. This "second" origin is assumed to be from a long-isolated population -- otherwise, they wouldn't say this:

[W]e cannot distinguish between single and multiple exoduses from Africa, because both scenarios would lead to a major cline from Africa (347).

Of course, "multiple exoduses" is precisely the prediction of multiregional evolution.

2. The main result of the study is that there is a trend toward lower within-population phenotypic variance as populations are farther from Africa. This trend does provide a good match to the cline of reducing genetic variance outside of Africa. However, the genetic cline in diversity itself is utterly uninformative about the geographic origin of recent humans. The diversity cline may just as easily be explained by population size (larger long-term within Africa), migration (biased in one direction), or selection. These are not obscure facts, I can't really believe that anyone conversant in modern human origins and genetics isn't aware of them.

Well, it's a short paper -- maybe that's why these problems slipped past Nature's reviewers...

3. A lot of people know about human genetic variation, and they are aware that a series of sequential founder effects can yield a cline of reducing genetic diversity. But here's the problem: what works for allele frequencies ain't necessarily true for quantitative features.

The phenotypic variance of craniometric characters is somewhere between 25 and 75 percent environmental. So from the outset, there is a large component of variance that isn't explained by allele frequencies. More problematic, although phenotypic variance is the sum of genetic and environmental variances, reducing the genetic variance does not tend to reduce the phenotypic variance by an equal amount. This is because a reduction in variation in the genetic background tends to increase a third component of the variance, the genotype-environment interaction variance.

Consider a field of hybrid corn. All the plants are genetically uniform, and this elimination of genetic variance tends to vastly decrease the phenotypic variance. At least, as long as the environment is also uniform. But introduce variation in the environment -- low spots in the field with standing water, patches toward the edge with greater pest damage, and so on -- and the variance in the genetically uniform field may be disproportionately great compared to the effects of the same factors in a genetically diverse field.

All this is to say that if you want to use phenotypic variance to measure genetic variance, then you have to ensure that the environmental variance is equal. Of course, that's a problem for human crania, since people manifestly live in different environments, arguably with greater variability (at least with respect to diet and climate) in Africa.

4. So, variability in these samples declines further from Africa. What does that mean?

Well, if I wanted to answer that question, then I would look first at exactly which measurements show the trend.

As a whole, except for three measures that actually increase in variability with distance from Africa, the rest show a quantitatively slight trend toward lower variation out of Africa. For most it is not significant (with R² < 0.03), but for a few it reaches statistical significance even with a slight negative correlation (R² < 10%). Since all of the comparisons include New World populations, I would want to see the data scatter for these characters to see if most of the slight negative correlation of variability with distance was explained by these far-flung populations that probably really did experience a strong bottleneck within the last 15,000 years.

That leaves five measurements with strong negative correlations between distance from Africa and variability: Basion-prosthion length, upper facial breadth (fmt-fmt), nasion-prosthion height, nasal height, and zygomaxillary subtense (a measure of facial projection).

It seems to me that the recent evolution of the face is mostly a consequence of selection on the dentition, which has evolved rapidly in the last 15,000 years throughout the world. That has little, if anything, to do with modern human origins.

But it has a lot to do with my grant application.

References:

Manica A, Amos W, Balloux F, Hanihara T. 2007. The effect of ancient population bottlenecks on human phenotypic variation. Nature 448:346-348. doi:10.1038/nature05951

Israel Hershkovitz, Liora Kornreich, and Zvi Laron think they know the problem with Liang Bua 1. Almost 40 years ago, Laron began studying patients with a congenital deficiency of IGF-I (insulin-like growth factor, I). This deficiency occurs because of a defect to the growth hormone receptor, which then does not respond to growth hormone (GH). Hence, patients have a high circulating level of GH, but a low level of IGF-I. After Laron's description, this type of dwarfism was called Laron syndrome, or "Laron-type dwarfism". Since 1970, the disorder has been identified in families throughout the world, caused by a large variety of mutatations to the GHR gene. Much of this is reviewed in OMIM.

In the last few decades, a large number of clinical cases of Laron syndrome have been compiled. Hershkovitz, Kornreich, and Laron (2007) review the characteristics of the LS sample. Patients were dwarfed -- significantly short in stature for their age -- by more than 4 standard deviations (SD) below the average for their population. Moreover, they had small endocranial volumes, as much as 5 SD below the average for their population.

Here, I have reproduced Table 1 of the paper, including the list of similarities between Laron syndrome patients and the LB 1 skeleton:

There are two notable features of this list, besides its sheer length. First, it includes characters from around the skeleton. This is the first substantial examination we have seen of the LB 1 features that compare the full body to the effects of any kind of human dwarfism. Evidence from the postcrania are especially important, because they form a constellation that may be the result of a common developmental cause. Second, the list includes a broad range of features that are not "outside the range" of modern human variability -- the kinds of rare features that a clinician would recognize as symptomatic in combination with other features, but that by themselves may be found within otherwise normal humans.

If you've been following closely, you may remember that Richards (2006) also proposed that the features of LB 1 might be explained by a mutation to the IGF-I pathway, possibly in combination with other changes affecting brain size. Richards pointed out that pituitary dwarfism, including Laron syndrome, may alter the proportions of the limbs in a way similar to LB 1, and I view that as an important conclusion of the current paper (Herskovitz et al. 2007) as well. In fact, Hershkovitz and colleagues argue that many of the purportedly "unusual" features of the skeleton are straightforward consequences of its small size. This includes not only the proportions of the limb bones, but other details such as their slight muscle markings.

Interestingly, the low humeral torsion of LB 1 also figures into the LS diagnosis, and they spend nearly a page reviewing this feature. The torsion increases with age up to around 16, and developmental abnormalities including LS may cause it to fall below the general adult range. But this has become a very equivocal feature. Larson and colleagues (2007) reported that the humeral torsion exhibited by LB 1 was within the range of contemporary Australians. There's a huge range of torsion included within normal human populations, now -- extending as low as macaque values. The more comparisons are included, the more the LB 1 specimen seems to fall in the human range. This is not too surprising; if every unusual skeleton could be diagnosed by comparison with a small number of specimens, there would be no need for pathologists!

Brain size

Richards (2006) considered Laron syndrome briefly, but concluded that Laron syndrome patients have a cranium that is "near-normal in size." In the present paper, Hershkovitz et al. claim that the brain size is reduced by "up to 5 SD" in Laron syndrome. What gives?

Here is the relevant text from Hershkovitz et al.:

There is no doubt that the most striking characteristic of LB1 is not small stature but rather the minute cranial capacity. Despite the fact that the cranial volume in patients with LS is usually not decreased to the same degree as observed in LB1, three points should be mentioned: a) skulls of LS patients manifest most of the unique LB1 cranial features, b) a small head is a major characteristic of LS patients (up to 5 SD below the norm) and in IGF-I gene deletion (Woods et al., 1996). Jacob et al. (2006) reported that the LB1 cranial volume falls 5.5 SD below the combined sex Rampasasa mean, similar to what has been reported for LS patients, and c) there is a high degree of association between microcephaly and growth failure in general (O’Connell et al., 1965; Pryor and Thelander, 1968), GH deficiency (Dacuo-Voutetakis et al., 1974), and congenital IGF-I deficiency (Laron et al., 1968; Woods et al., 1996) in particular.

Additionally, many of the unique anatomical landmarks left by the brain of LB1 on the endocranial bony surface (Falk et al., 2005), are seen also in LS patients, and derived from the reorganization of the brain to fit into a small cranial space... (Hershkovitz et al. 2007:7).

Additionally, they point out that the genetic background of their sample of LS patients is different from that of recent and archaeological Southeast Asian islanders, which may also produce differences in the manifestation of growth deficiencies.

Is this fully convincing? The radiographs in the paper do not show skulls as reduced in cranial volume as LB 1. As far as I know (they do not present a range) there are none. Perhaps Richards (2006) is correct that a second explanation is necessary besides GH/IGR-I to explain the small brain, or perhaps the manifestation of such disorders in this population really is different. Plausibly, an archaeological specimen from anywhere is simply not comparable to the development of modern agricultural populations. I think the brain size remains a big hole in the hypothesis.

The hypothesis is testable!

The best thing about the LS hypothesis is that it is testable. There are other features of the skeleton that reflect LS that have not yet been reported for the LB 1 skeleton, but that ought to be observable.

Hershkovitz et al. (2007) point to the pneumatization of the mastoid region as possibly the most important test. LS patients have minimal or no pneumatization of this part of the cranial base; meaning that instead of spongy bone and open sinuses, they have dense compact bone:

Unfortunately, no radiographs of LB1's skull are as yet available and therefore appreciation of the extent of pneumatization in the LB1 skull is impossible. Non-pneumatized (acellular) mastoid process (Fig. 4), lack of (or minimal) frontal sinus (Fig. 2), and small paranasal sinuses are characteristic of LS (Kornreich et al., 2002) (Hershkovitz et al. 2007:3).

CT scans of LB 1 do exist, and they should be easy to check. Very easy. As in, somebody already knows the answer. That somebody just isn't me.

But is it a species?

What would it tell you if the hypothesis were true -- if LB 1 actually does have a mutation inducing a GH/IGR-I defect and this explains its stature, morphology, and brain size? For instance, does it represent a real ancient hominid species or just a pathological member of our own?

Hershkovitz, Kornreich, and Laron agree with Jacob et al. (2006), that many of the "unusual" characteristics of the skeleton actually are normal or reasonably common within the regional population of modern humans. For that reason, they find that the skeleton possesses no features that preclude it from membership in our species. So the short answer is, they think H. floresiensis is sunk.

But their longer answer is quite interesting as a defense of taxonomic conservatism, and is worth reading closely:

It is not the numerous conundrums that have been located by us and other researchers (Jacob et al., 2006; Martin et al., 2006a,b) in the Homo floresiensis publications which refute its status as a new species, but rather the wrong arguments brought to support it.

The combination of "modern" and "primitive" morphological characteristics is one of the major arguments raised by Brown et al. (2004) to differentiate LB1 from Homo sapiens. Nobody would argue, however, that LS patients who also manifest a similar combination (e.g., an extremely oval-shaped pelvic inlet, or a "bell-shaped" form of the thoracic cage), are direct descendents of Homo erectus (an idea advocated strongly for LB1 in the first paper) nor of the australopithecines (a notion which appears in the second publication). Based on morphological comparison between LS patients and normal short children, it is clearly evident that many of the "unique" primitive morphological traits seen in LB1 are due to her small stature (Takano et al., 1986). This also explains why LB1 shares most of her features, including the most "unique" ones (e.g., the deep fissure separating the mastoid process from the petrous crest of the tympanic bone; the absence of a true chin etc.) with local pygmoid populations (Jacob et al., 2006). Ignoring the possibility that LB1 is derived from a small stature population (Rampasasa pygmies are good candidates, as suggested by Jacob et al. in 2006) with its own distinct morphological features may lead to erroneous conclusions. For example, recently Larson et al. (2006) reported on a clavicle (short relative to humeral length) and scapula (normal) of LB1 and suggested that "A short clavicle may indicate a more protracted scapular position, raising the possibility of a previously unsuspected transitional stage in the course of hominin pectoral girdle evolution" (p A21). However, the length of the clavicle is mainly dictated by the shape and diameter of the upper thoracic cage. This is why both LS patients and KNM-WT 15000 H. erectus (both manifesting a very similar fan-shaped thorax) have a relatively short clavicle.

In contrast to Morwood's statement (2005) that LB1 manifests a combination of primitive and derived features that dictate exclusion from the species sapiens, we have herein offered evidence to suggest that LB1 is but a local individual in a highly inbred, probably pygmy-like population (of Homo sapiens) in whom a mutation of the GH receptor had occurred. (Hershkovitz et al. 2007:9).

In short, the persuasiveness of any combination of features as evidence depends on their correlation with each other. If they are all strongly correlated -- for instance, if they are effects of a common cause -- then the combination of features is best interpreted as evidence for that cause, rather than as multiple instances of evidence for some other hypothesis. In this case, Hershkovitz et al. argue that the common cause explaining the data does not require a species interpretation. Instead, they argue (following Jacob et al. 2006) that LB 1 and other specimens share many features with recent local people. So, the hypothesis that the LB hominids are Homo sapiens is well supported.

Now, what could contradict that hypothesis? In other words, what would be the right argument to support a new species?

Here, the morphology of the other specimens besides LB 1 come into play. It seems very unlikely that multiple archaeological individuals over many thousands of years would have had the same rare mutation(s) of the GH/IGR-I axis unless that mutation were very common in the local population. Richards (2006) accepted at face value the argument that these archaeological individuals were in fact of the same short stature and small size as LB 1, and suggested that the ancient Flores population of H. sapiens simply had a high frequency of this variant (in his view, possibly along with another variant affecting brain size). Hershkovitz and colleagues appear willing to accept this hypothesis, pointing out that LS patients have normal reproductive potential and are relatively more common in some populations:

As LB1 replicates most of the diagnostic features of LS patients (Table 1), as well as those of pygmoid Australomelanesians (Jacob et al., 2006), it can be assumed that the findings from the island of Flores represent a local, highly inbred, low stature Homo sapiens population in whom a mutation in the GH receptor had occurred. The long time presence of LB1-type humans on the island of Flores is not surprising considering that LS patients, and derived dwarfed populations with GHRH-R defect, reproduce normally (Laron, 2004) (Hershkovitz et al. 2007:9).

But it is not necessary to take this view of a long-term population with a variant GH/IGR-I allele, if the other specimens are not actually unusual for modern humans. That is the argument put forward by Jacob et al. (2006), and it doesn't yet seem to have been contradicted. The most persuasive commonalities among this collection of fragments are (1) that they are all small, and (2) that the second mandible LB 6/1 shares several features with the first. But Jacob et al. (2006) claim (1) that the local population was small anyway, and (2) that these features are regionally common and not persuasive as evidence for a distinct lineage.

An alternative claim might be that H. floresiensis was a genuine evolutionary species on Flores (and possibly other islands), and that local people today retain features from this ancient species due to local introgression. But of course, local ancestry of some features might occur whether the ancient Flores population was another species or not. We call the latter hypothesis "multiregional evolution." So any distinctiveness of the local people is in no respect evidence that ancient people on Flores were a different species; if anything, the long-term retention of local features into living populations is a refutation that they were a different species. There is nothing impossible about introgression -- as I've said many times -- but it actually is a bit easier if speciation has not occurred!

Picky details

As in many clinical descriptions of dwarfism, there is a lot of "SD" talk in this paper. That substitutes an absolute measure (e.g., meters) for a relative one (compared to the population variability). And in some ways, that confounds two different kinds of change. For example, after a very good discussion of the problems estimating proportions and stature of LB 1, the paper includes this:

Finally, Jacob et al. (2006) estimated that the stature of LB1 falls 3.3 SD below the local Rampasasa pygmy average stature of 1.46 m, within the range of the deviation in stature reported in some of the Israeli LS patients (Laron, 2004).

This is not really a valid comparison. If pygmy populations of humans already have a variant of the GH/IGF-I axis that results in reduced stature, then a further mutation on that axis should not exert the same proportional effect. We ought to expect a dwarf in a population of pygmies to be close to the stature of dwarfs elsewhere.

Instead, the important comparison is the stature itself, not the number of standard deviations below mean. Hershkovitz et al. (2007) report that the stature of female Laron syndrome patients in their sample ranges as low as 95 cm, which is smaller than the minimum stature estimate of 106 cm for LB 1. Hence, it is consistent with the diagnosis.

Also, the genetic heterogeneity of LS means that there can be substantial variations among people with different mutations:

So far 57 mutations have been described in LS patients residing in various parts of the world including South Asia (Rosenfeld et al., 1994; Rosenbloom and Guevara-Aguirre, 1998; Laron, 1999; Shevah et al., 2005). These numerous molecular defects on the GH receptor gene or the postreceptor cascade (Elders et al., 1973; Godowski et al., 1989; Laron et al., 1992; Rosenbloom et al., 1999; Laron, 2004; Woods and Savage, 2004) produce a large variety of short stature phenotypes and a wide spectrum of intellectual abilities and deficits (Shevah et al., 2005), which may also explain the differences between the LS patients and LB1 (Hershkovitz et al. 2007:9).

This is the kind of quote that can drive a person crazy. The disorder is genetically heterogeneous. As reflected in OMIM, it may even include individuals with normal GHR function, but with other downstream problems that decrease IGF-I. But it is unsatisfying because it means that no comparison can necessarily capture the effects of the disorder. So for something like the exceptionally small brain size of LB 1, it is quite possible to say, "Well, there are at least 57 different ways to have this disorder, and maybe the 58th will be manifested with even smaller brain size.

On the other hand, with 57 different varieties (hmm....) we can probably say that the sample space of genetic mutations is now very large, so we are seeing possibly a good representation of the possible phenotypic effects of changes to this axis. At least, that's my optimistic answer.

Summary

This is a powerful paper. The overlap between the morphology of LB 1 and Laron syndrome symptoms is very extensive.

To my mind, much of the credibility of the species hypothesis -- that H. floresiensis really existed on Flores for a long time and evolved a mean phenotype including derived features absent in other populations -- depends on finding more specimens from earlier time intervals. If the archaeology of the island could be extended into the period after 500,000 years, it would document the long-term persistence of some hominid population across the interval from 700,000 years ago to 90,000. At 90,000 years, given ambiguities in dating, it is entirely possible that remains may be attributed to modern humans. So documenting a persistence in between those dates is important.

Likewise, the anatomical evolution of those populations would be a key piece of evidence. Were they, as Jacob et al. (2006) suggest, connected by gene flow to the Asian landmass by recurrent connections? Or were they really isolated on Flores or possibly other islands? Only a trace of the evolutionary history, through morphology or DNA, can provide evidence of this isolation.

I don't view any of this as impossible, but naturally it remains to be demonstrated. Likewise there is nothing impossible about such a population having a unique GH/IGR-I variant, either by drift or as an adaptation to the island. But we are waiting for the evidence that they were there throughout that time.

References:

Hershkovitz I, Kornreich L, Laron Z. 2007. Comparative skeletal features between Homo floresiensis and patients with primary growth hormone insensitivity (Laron Syndrome). Am J Phys Anthropol (early) doi:10.1002/ajpa.20655

Richards GD. 2006. Genetic, physiologic and ecogeographic factors contributing to variation in Homo sapiens: Homo floresiensis reconsidered. J Evol Biol 19:1744-1767. doi:10.1111/j.1420-9101.2006.01179.x

Jacob T, Indriati E, Soejono RP, Hsü K, Frayer DW, Eckhardt RB, Kuperavage AJ, Thorne A, and Henneberg M. 2006. Pygmoid Australomelanesian Homo sapiens skeletal remains from Liang Bua, Flores: Population affinities and pathological abnormalities. Proc Nat Acad Sci USA. 103:13421-13426. DOI link

In a less recognized article in Current Biology, Fischer et al. (2006) report on the genetic diversity of ape subspecies.

Here's the meaty part of the abstract:

Finally, we find that the extent of genetic differentiation among "subspecies" of chimpanzees and orangutans is comparable to that seen among human populations, calling the validity of the "subspecies" concept in apes into question.

Previous studies of ape population structure have mostly been based on one locus (mtDNA), with a few using the Y chromosome and nuclear microsatellites. This study adds nuclear sequences to the mix, from 16 to 26 loci. The multiple-locus perspective is important, because demographic structure can be tested only through its similar effects on different unlinked loci. The use of sequence adds a time depth that may not be as evident from microsatellites, since they have markedly faster mutation rates. For instance:

The two orangutan populations have a significantly positive Tajima's D, because of an excess of intermediate frequency alleles, which is best explained by a recent reduction in population size or by population subdivision. Using 14 microsatellites, Goossens et al. [3] showed that the excess of intermediate allele frequencies in an orangutan population from Borneo can be explained by a very recent decline in population size, mainly as a result of human activity. Because it would take much more time to be able to detect this effect in nuclear DNA, and because our orangutan samples come from different local groups (see Table S1), population structure is a more likely explanation of our observation (Fischer et al. 2006:1134).

Despite the conclusion and abstract, there is not too much different in this study compared to previous work. For instance, the F_ST estimated between orangutan subspecies is 0.28, which is at least double that estimated between human races for the same loci. Similarly, the F_ST between Eastern and Western chimpanzees (Pan troglodytes schweinfurthii and P. t. verus) is 0.32. These estimates show a considerably higher degree of population structure in these ape species compared to humans. The F_ST between orangutan subspecies doesn't represent quite the high division between these two groups, because of the extensive sequence variation within each of the subspecies.

One difference is surprisingly slight: the F_ST between central and eastern chimpanzees is only 0.09. This is the same as estimated between Chinese and Italians in the study, placing chimpanzee subspecies differences inside the range of human racial differences.

Or does it? The study also obtains the average pairwise difference between these populations, finding that the average difference between central and eastern chimpanzees (0.20 percent) is about the same as that between central and western (0.21) and eastern and western populations (0.20). Now, again as for the orangutans, the average pairwise difference among chimpanzee populations is inflated by the relatively great diversity within chimpanzee populations -- but not so much. F_ST is a measure of how many variants are shared by two populations (formally, it measures a reduction in heterozygosity attributable to population structure). So the results tend to indicate that eastern and central chimpanzees share a lot of alleles, amid a relatively high amount of diversity.

Why should that be? One explanation is a recent colonization of the eastern range (or more narrowly, the part represented by their sample of reserve chimpanzees from Kenya) by chimpanzees of central African origin. A widespread recent colonization might also explain the evidence of mtDNA disequilibrium in eastern chimpanzees.

Or, the low F_ST could represent a history of gene flow between central and eastern African chimpanzees. Fischer et al. apply a mixture of these explanations, which they also apply to the orangutans:

With respect to the duration of physical separation, the Dahomey gap that separates western and central chimpanzees was covered with rainforest until about five thousand years ago, and Sumatra and Borneo were physically connected until ten to twenty thousand years ago. Thus, the time of separation of the "subspecies" by geographical barriers has certainly been too short for complete lineage sorting by genetic drift and shorter than the separation of many human groups. In addition, migration between the groups may have occurred subsequent to the emergence of these geographical barriers. Indeed, we speculate that a more geographically complete sampling of chimpanzees and orangutans with noninvasive samples from the wild as well as samples from museum specimens in areas where apes are now extinct will eventually demonstrate that the overall picture of genetic variation within chimpanzees and orangutans is one of isolation by distance, as is largely the case among humans (Fischer et al. 2006:1135, citations omitted).

Naturally, both factors are important -- the initial movements of these apes to their current locations, sometime during the Pleistocene, and the subsequent movements of individuals between populations. The question of gene flow is important because it delimits the extent to which adaptive variants can spread from their point of origination -- and thereby circumscribes the degree to which all chimpanzees today may be different from their common ancestors. In other words, gene flow would allow multiregional evolution of these ape species over time.

But there's no real reason to say that these weren't subspecies. They were genetically differentiated after their initial origin and retained substantial genetic distinctions between them over time. "Subspecies" is a nebulous category, but it is generally defined as an evolutionary lineage within a species, which these populations would appear to be. They're not species, after all.

The only real question is what the spatial differentiation of these populations looks like -- are there long clines of genetic variation within chimpanzees as there are within human populations? For that, we will have to sample many more chimpanzees. For orangutans, the answer today is presumably "no", because the subspecies are on islands, and themselves are highly fragmented into small populations.

References:

Fischer A, Pollack J, Thalmann O, Nickel B, Pääbo S. 2006. Demographic history and genetic differentiation in apes. Curr Biol 16:1133-1138. DOI link

OK, I was reviewing hypotheses about sinus anatomy for a student, and I ran across this one, which I must admit was news to me:

Nitric oxide (NO), a substance produced in the paranasal sinuses, is thought to defend against pathogens among other functions. High levels of NO increase mucuciliary activity. NO levels in both the nasal cavity and the maxillary sinus seem to depend on the size of the paranasal ostia [i.e., the openings of the sinuses into the nasal cavity]: As ostia [sic] size increases, NO levels decrease. It has been hypothesized that the purportedlarge sinuses of Neandertals are a consequence of their need for high NO production to support a vigorous way of life (Rae and Koppe 2004:216).

No, nitric oxide is not laughing gas -- that's nitrous oxide (N₂O)! Although for excellent pictures of laughing Neandertals, I highly recommend Kennis and Kennis (whose website, sadly, seems to have disappeared).

Rae and Koppe (2004) draw their account from this meetings abstract by Sam Marquez and colleagues (2002):

The anatomy and function of the Neanderthal upper respiratory tract (URT) has been a topic of great interest, particularly as a possible window on their lifestyles. Neanderthal paranasal sinuses (pns) have been described as expansive although the precise reasons for this are not well understood. However, the pns are the prime site for production of nitric oxide (NO), a gas with neurotransmitter-like functions. In the URT, NO exerts functions on ciliary activity, gland stimulation, and acts as an aerocrine messenger between the upper and lower airways that selectively reverses hypoxic pulmonary vasoconstriction without causing systemic vasodilation. NO also functions in host defense (Fliegelman, Gannon, and Lawson, 1998) insuring sterility of the pns permitting mucus drainage through their ostia into the airflow pathway thus serving as a valuable adjunct in the air-conditioning process of humidification (Gannon et al., 1997).

This qualitative and quantitative study examined pns morphology via CT imaging in a multiregional sample of 125 human skulls and compared them to assessments of the nasal complex in archaic Homo sapiens. Modern groups exhibited population specific pns morphology with respect to ecogeographic localities. Notably, Neanderthal pns dimensions differed from European modern populations. This suggests that Neanderthal pns volumes may reflect a different clade trajectory, perhaps due to differing NO production rate and utilization. We hypothesize that the idiosyncratically large size of Neanderthal pns is related to greater production of NO. This sinonasal / aerocrine adaptation was selected to meet the critical cardiopulmonary system demands imposed by the vigorous lifestyle of Neanderthals (Marquez et al. 2002:107).

Hopefully that research will come out somewhere. The beauty of the sinus production of NO is that it is localized to the respiratory tract. NO metabolism is very important to different systems -- its role as a vasodilator makes it an important regulator of blood pressure, it has a role in the reproductive system, and a role as a neurotransmitter. So it is important for its effects to be localized rather than systemic.

For Neandertals, one could imagine different kinds of balances -- for example, since NO concentration decreases with ostium size, a larger Neandertal ostium might require greater NO productivity to maintain the same function. It doesn't seem too likely that greater productivity was an adaptation to activity level, at least not unless high-activity modern populations were shown to have large sinuses. The Neandertals otherwise are a bit of a contradiction, since in general sinus size seems to decrease with latitude -- apparently a structural side effect of having larger nasal cavities in colder climates. I guess ostium size becomes a pretty crucial parameter to examine, since if large maxillary sinuses were merely a side effect of large faces in Neandertals, the nasal and sinus systems would presumably have evolved to maintain a constant function.

Rae and Koppe (2004) have a good review of other adaptive hypotheses for sinuses. I guess it will take some convincing to get me to think they are specifically adaptive in humans, since their morphology and size is so variable.

References:

Kirihene RKDRA, Rees G, Wormald P-J. 2002. The influence of the size of the maxillary sinus ostium on the nasal and sinus nitric oxide levels. Am J Rhinol 16:261-264. IngentaConnect

Marquez S, Gannon P, Lawson W, Reidenberg J, Laitman J. 2002. Were Neanderthals full of "NO" gas? The relationship between paranasal sinus morphology and nitric oxide production. Am J Phys Anthropol 34(suppl):107.

Rae TC, Koppe T. 2004. Holes in the head: evolutionary interpretations of the paranasal sinuses in catarrhines. Evol Anthropol 13:211-223. DOI link

It's that time of the semester -- exam time -- and I'm getting a lot of questions from my students by e-mail. One of the most common is how to differentiate the Multiregional evolution hypothesis from the Out of Africa hypothesis. So I'm posting a nutshell version to help with studying.

The problem

To begin with, both hypotheses try to account for the evolution of today's humans from our Pleistocene ancestors. The difference between the hypotheses is in which Pleistocene people were our ancestors, and which were not.

Both hypotheses have to account for the same basic set of facts:

• Humans first left Africa and established populations in other parts of the world (first southern Asia, China, and Java, later Europe) by 1.8 million years ago.
• Humans today are quite different anatomically and behaviorally from archaic people (that is, most humans before 40,000 years ago) anywhere in the world. Recent people are called "modern" humans.
• Human populations today are genetically very similar to each other.
• African populations today are more genetically diverse than populations in other parts of the world.
• Recent humans in Europe and Asia share a few features with the ancient archaic people who lived in those places before 40,000 years ago.

Anthropologists consider many more detailed sources of evidence about human origins, but many sources of evidence fall into one or more of these basic categories. This combination of facts is a bit puzzling, and both hypotheses account for them a bit differently.

Out of Africa

Under the Out of Africa hypothesis, the first humans to leave Africa 1.8 million years ago divided into several different species during the Pleistocene. Species, of course, are defined by reproductive isolation, so the evolution of these several species of humans was separate. The fossil archaic humans that we find throughout the Old World belonged to these several species, but only one branch of this ancient family tree could give rise to today's humanity.

This branch was African. The origin of modern humans in Africa explains why today's Africans are more genetically variable than other populations --- they were the first human population to expand, and other populations (like those of Europe and Asia) were founded later. The recent origin explains why today's human populations are genetically similar -- they haven't had time to diverge very much.

The resemblances with archaic humans in some modern people are explained either as a result of parallel evolution --- the same selection in the same place leads to similar features --- or as a result of slight genetic contributions from archaic humans into today's populations.

Multiregional evolution

Under the Multiregional evolution hypothesis, the first humans to leave Africa 1.8 million years ago never divided into different species. Instead, these populations always exchanged genes with each other through recurrent gene flow. Today, we are part of this same species, which has evolved greatly over time to a very different morphology and behavior from the first humans.

The low genetic differences among human populations are a result of a history of gene flow between ancient populations. Our present morphology and behavior have greatly changed from archaic humans because of natural selection in a global human population. Resemblances between archaic and modern humans in some parts of the world are the result of ancestry.

The greater genetic variation within Africa is a consequence of larger African population size, greater ecological diversity and local selection, or both. These factors gave Africa a dominant role in the ancestry of today's human population.

Ray et al. (2005) (full text from Genome Research) compare two classes of models of modern human origins to observed data from human microsatellites. They first perform simulations to confirm that the data can distinguish the different models from each other ("multiregional evolution" vs. "unique origin" models). This they apparently should be able to do -- using only 20 markers, the simulations attained 99 percent classification accuracy.

On the other hand, none of the models explained the observed data very well. Out of the models, an origin in northern Africa fit the model best, but there was no significance test showing that the fit to their "unique" African origin was significantly better than their "multiregional" models.

The "models"

Why the scare quotes? Because these models are weird. Let's look at the clearest description of the "multiregional evolution" model (from the caption of figure 2):

(B) Multiregional evolution (ME) model. As in A, a small population went through a speciation event and instantaneously colonized the three continents 30,000 generations ago. For 26,000 generations the continents harbored relatively large populations and exchanged occasional migrants (see Table 1 for continent population sizes and migration rates under different scenarios). Then, 4000 generations ago, three range expansions were initiated from the three different origins shown in C.

Although the idea of populations connected by gene flow is consistent with multiregional evolution, this idea of geographic range expansion from three locations is batty. Who thinks that happened?

In practice, it appears that they used three separate range expansions because that is what they had the software for. And that raises another issue: these range expansions begin with an extreme bottleneck: a founding population of only 50 individuals.

Now if I ever write an article saying "Humans originated by multiregional evolution with small levels of gene flow, and in the Late Pleistocene there was a worldwide catastrophe limiting people to three far-flung populations of 50 people," I think people would call me crazy.

The weirdness of the model is confirmed by their results. Here's how the paper describes its "multiregional" model results:

Among the ME scenarios, it is worth noting that the best fit to the data is found for scenarios 26 and 29, which corresponds to cases in which the Pleistocene migration rates between continents are very limited (Nm = 0.1, or one migrant gene exchanged every 10 generations). This very limited amount of gene flow between continents makes it difficult to understand how humans could have evolved simultaneously toward modernity, as advocated by the supporters of the multiregional evolution hypothesis (Hawks et al. 2000; Wolpoff et al. 2000). It is also interesting to note that the best supported ME scenario (no. 26) assumes equal continental sizes, whereas previous studies (Takahata et al. 2001; Satta and Takahata 2004) had found a better support for ME scenarios in which the African continent would have had a much larger population size than other continents. It supports the view that the pattern of genetic differentiation between human populations is more affected by the geography (migration corridors, contours) of the continents than by their population densities.

This is beyond weird. The paper is saying that unlike all other data, their microsatellite distances support the idea that human populations were strongly isolated in the past, and that Africa had no more people than any other region. I say it is beyond weird because the data even more strongly support their "unique origin" model, in which the ancestral population was panmictic. Which is it? Panmictic or highly structured?

Now look at the description of a "unique origin" (i.e. replacement) model:

(A) Unique origin (UO) model. In this model, 30,000 generations ago, a small population (N = 100 genes) went through a demographic expansion after a first speciation event. Then, 4000 generations ago, a range expansion followed a bottleneck of 10 generations to mimic a second speciation event. The large population preceding the speciation and range expansion can be considered to be a large subdivided population.

OK, so we have one large subdivided population, which undergoes a short bottleneck and then expands around the world. Here's the problem: if this earlier population actually were subdivided, then this model would be multiregional evolution (!). But the model doesn't have a "large subdivided population", it actually has a single small panmictic population.

And again, there's the strange bottleneck. I just don't understand why they include it, unless it's an artifact of their simulation method. They don't report any reason for the bottleneck, other than that it "simulates a speciation". But it doesn't look like any speciation I ever heard of.

And what about Zhivotovsky et al. (2003)? That paper used exactly the same set of microsatellite data to infer the demographic history of humans. It concluded that different continental populations of humans underwent a population expansion from an initial size of between 1000 and 3000 individuals at times ranging from 4000 to 36000 years ago. These values bear little relationship to the values used by Ray et al. (2005) --- expansion from an initial size of 20000 (with a short bottleneck of 100) some 120,000 years ago. Should we believe the demographic model? Or should we believe the geographic model? Ray et al. (2005) don't cite Zhivotovsky et al. (2003), so maybe they didn't consider that the two estimates should, maybe, match?

What's going on here?

Here is my completely uninformed line of speculation about these results. It begins from these premises:

1. The test statistic is a goodness-of-fit between the observed matrix of distances between populations (R_ST) and the simulated matrix.

2. None of the simulated matrices fits the observed data very well; simulated data fit their predictions much better.

3. This means that the simulated scenarios are not generating data that look like the observed pattern of genetic distances between populations.

4. But the observed pattern of genetic distances between populations is a very good fit to isolation-by-distance! This shouldn't be a hard distribution for a simulation to match.

5. Hence, there is something very weird about the models.

Now, what explains the weird results? Here are some ideas:

6. Consider the "multiregional" model here: three initially divergent populations in the corners of the Old World begin to expand. As they expand, their allele frequencies drift in random directions. At some point, these geographic expansions meet, but mix only slightly before the simulation ends. Result: strong differences in allele frequencies along very narrow geographic corridors where the populations met -- a distribution that looks nothing like the observed pattern. Bad fit from a bad model.

7. Under this scenario, the "unique" origin models ought to do better. But here the puzzle is different: why do the South Asian and Southern African "unique" origins do so much worse? Neither of these regions is all that far from the North African locations that do so well. An origin in either location seems like it ought to be more likely than an Australian origin. Considering the obvious problems with the "multiregional" models, they ought to outperform them as well. But they don't.

8. Here's my guess: migration. The geographic model appears to include migration among all populated demes -- even the ones that have been populated a long time. That is a good thing about the model; it is markedly more realistic than models that assume no migration. But it creates a problem, since their test statistic is Fst. If the only factor creating differences among demes is a founder effect at their establishment, and migration is constantly making them more similar, then it follows that the demes closest to the origin should be the least different from each other. (Populations far from the origin may also be very similar to each other, because very little variation gets to them at all, but that's a separate point.)

9. Ooops...that's a problem. The empirical data have fairly large interpopulation differences in Africa.

10. Southern Africa therefore won't work as an origin with this model. The simulations control the rate of migration though the assumption of a parameter called "friction", which is supposed to represent the difficulty of moving to a particular kind of environment. It is easy to move to a nice place, and hard to move to a bad place. The paper doesn't report the "friction" parameters (there are over 9000 of them, after all), but Southern Africa ought to be relatively nice, and the demes have few neighbors so they should mix easily. In the model, a Southern Africa origin would make those populations too much like each other.

11. Northern Africa evades this problem, because it is a desert. If the authors recognized this by assigning high "friction" to these demes, then these demes would sustain more genetic differences. These would be more similar to the observed data (although still not very much like it in many respects).

So I don't think the article advances the issue of modern human origins.

Parameters

The problem is not that the models are unrealistic. A simple but unrealistic model can still advance the problem by suggesting ways that it is deficient. New studies can build on a failed simple model by adding parameters to better approximate observed data.

But this paper doesn't have any simple models. The models here each have more than 18000 parameters. The models are drowning in complexity.

Let me point out that it is possible to completely fit an Rst matrix with a migration matrix that has the same number of cells (effectively one fewer, since all the others can be expressed in terms of one of them). This model would simply be a multiregional model, in which the migration between each pair of demes was the only cause of their present level of difference. Here, the number of parameters is always equal to the number of degrees of freedom, which both depend on the number of populations being compared.

Now, if you have a simple model that fits the data perfectly, why would you want to go to a more complicated model? Why in particular would you go to a model with over 18000 extra parameters?

This is not to say that the simple migration matrix is the true model; it is just an observation that adding more parameters should not result in a lower fit to the data. The data should be overfit 18000 ways. If your fit to the data gets worse then you should definitely abandon your model!

I have some thoughts on this, but I'm holding on to them for a bit. They are shaping up to be a nice paper.

In the meantime let me say: if you intend to add 18000 extra parameters, please try to make sure that any case you test is at least reducible to the perfect-fit model. In this case, we know that we can construct a multiregional model that fits the observed Rst matrix. Why should we pay attention to the weird models that fit the data worse?

References:

Ray N, Currat M, Berthier P, Excoffier L. 2005. Recovering the geographic origin of early modern humans by realistic and spatially explicit simulations. Genome Res 15:1161-1167. Full text (free)

Zhivotovsky LA, Rosenberg NA, Feldman MW. 2003. Features of evolution and expansion of modern humans, inferred from genomewide microsatellite markers. Am J Hum Genet 72:1171-1186.

I've been trying to think of the best way to approach last week's "serial founder effects" paper by Ramachandran and colleagues (abstract). The paper has been publicized as a support for the out-of-Africa theory.

I always find the science-by-press-release a bit irritating, because it is impossible to examine the claims to see if the data support them. I guess I should adjust my expectations: if there is a press release and no paper yet, I should just assume the data are weak.

The short answer is, the paper doesn't prove out-of-Africa. It doesn't even present any new data that support out-of-Africa. It presents some new simulations of how an out-of-Africa dispersal might work, but it doesn't test those simulations by comparing them to data that might differentiate their preferred model ("serial founder effect") from other hypotheses that might explain the same observations.

In the end, I really don't have a problem with the paper. You see, it doesn't actually mention the words "out-of-Africa". It doesn't claim to support out-of-Africa. All it does is show a correlation between their simulation results and some genetic data. Personally, I wouldn't have written the paper without testing the hypothesis with data that might refute it, but that's just me.

Of course I'm very interested in modern human origins and genetic information about the subject, so I'll try to give a record of my thought process. I include some discussion of isolation-by-distance as a model for genetic variation, different scenarios that would produce the pattern, and the kind of data that would test those scenarios.

The press

What I could find out last week at this time came from the press, much of which can be traced to the October 18 University of Michigan press release:

Small groups of settlers expanding outward from Africa are the most likely progenitors of the modern human population worldwide, according to a new study by researchers at the University of Michigan and Stanford University.

This led to a National Geographic News article on the same date, which says this:

"When we searched over 4,000 points around the world, we found that no point outside of Africa had as high a fit as any point inside of Africa," [University of Michigan geneticist Noah] Rosenberg said. "So this seems to support an 'Out of Africa' historical model for human evolution."

Genetic diversity is highest, and thus oldest, in Africa. This fact has led many geneticists to point to the continent as the birthplace of humankind.

A Discovery Channel news brief picked up the story October 21, starting like this:

Modern humans left Africa in waves and colonized the Mideast first and then Europe, according to a new study that traced early human migration patterns through variations in DNA.

The study, which supports the "Out of Africa" theory that humans first emerged in Africa before migrating to other parts of the world, determined that South America was the last settled region.

But these were the only two news sources to bite, apparently. That itself is usually a bad sign -- "supports out-of-Africa" tends to gather more press attention.

The paper

The paper itself appeared in PNAS Early Edition on October 21, three days after the press release. A text search shows no mention of "out of Africa". Or "recent African origin". Or anything of the sort.

Hmmm.... I'm confused.

The dataset in the paper includes 783 microsatellites sampled in 1027 individuals from different source populations. Like many other genetic samples from humans, this sample has two notable characteristics: overall variation is higher within Africa than elsewhere, and geographically distant populations are more genetically different than geographically close populations. This correlation of geographic distance and genetic difference is often related to the model of "isolation-by-distance", in which the movement of individuals between populations is a function of distance.

Isolation-by-distance

Isolation-by-distance makes perfect sense for human populations. Historically, people have tended to mate with other people close to them, and the chance that they will move a long distance to mate is much less than the chance they will move only a short distance. But isolation-by-distance is no support for any kind of recent mass migration, out of Africa or anywhere else. People could have always lived where they are now, and the genes would still show isolation-by-distance.

There is a long story here that is increasingly only of historical interest. During the early 1990's, a series of comparisons of genetic variation in Africa versus variation in Europe and Asia made a really bad assumption -- they assumed that people in these regions never interbred with each other. If this were true, and if none of the differences between these populations were the result of natural selection, then you could figure out how long ago these "separate" populations must have shared a common ancestry. These studies were among the earliest supports for the idea that modern humans had a recent African ancestry -- owing to the fact that the "date" of population divergence between Africans and non-Africans was between 50,000 and 100,000 years ago or so. By the late 1990's, there were studies that tried to trace the population history within China, or Europe, or Africa using the same methods. Assume the populations never interbred, work out the dates, and presto! There's your population history.

Of course, the assumptions behind these estimates were basically bunkum. A global correlation of geographic distance and genetic difference is compatible with lots of hypotheses of population history -- from long-term isolation-by-distance to "demic diffusion" to recent mass migrations. But what it is not consistent with is a complete lack of interbreeding among human groups. And when you examine the "fit" between these "tree" models of population history (the no-interbreeding models) and real genetic data, you find that they just don't fit very well (Templeton 1998 reviews this issue).

So what about those "dates" of population divergences? Turns out they aren't necessarily divergence dates at all. In fact, if you just assume that the populations never diverged but always interbred, the genetic distances can be explained by different rates of migration (Relethford 1995).

This entire controversy consumed a lot of ink (and now pixels), all based on a single faulty assumption.

Subsets of diversity

A better strain of argument was first proposed by Tishkoff et al. (1996). By this time, it was known that many genes were more variable in Africa than elsewhere, and that Native Americans lacked much of the variation present in Eurasia. But in an analysis of linkage disequibrium around the CD4 gene, Tishkoff et al. (1996) showed that diversity itself formed a gradient, or cline, in which some African populations at or near linkage equilibrium, and populations geographically more distant from Africa showed stronger disequilibrium. This mirrored the pattern of variation of mtDNA, and appeared to indicate a contrast: variation was continuous across space, but discontinuous across time. The greater disequilibrium in populations farther from Africa could be explained as a consequence of recent genetic movement (at least of CD4 genes) into those populations from more variable populations.

Several other genes were later found to show similar patterns: variation was high in Africa, and became systematically lower in populations further from Africa. Sometimes this pattern was characterized as "subsets of diversity", in which Eurasian populations contained only a "subset" of the alleles present in Africa. "Subset" was a misnomer for the actual pattern (at least in every case I looked at), since it implied that no uniquely Eurasian variants occur. The actual pattern is generally more complex, with a smaller number of uniquely Eurasian variants (so-called "private" alleles) than African variants, and a greater average age for African variants than for Eurasian variants.

One hypothesis to account for this pattern of diversity is a "serial founder effect". The idea is that a small group left Africa to found a population in West Asia. Then a small group from that population left to found a population in, say, India. Then a small group from India left to found a new population in Thailand. And so on, until the entire world was populated.

Under this hypothesis, a substantial number of African alleles would be left behind in Africa. Even more of these alleles would be left behind in West Asia. More would be left behind in India. In the end, the diversity of populations would reflect the series of founding events that trace their ancestors' movement out of Africa and into the rest of the world. A serial founder effect from Africa across the globe could account for the decline in genetic variation in populations further and further from Africa.

But there is a problem: notice that the serial founder effect, once again, assumes no interbreeding between human groups. If Africans could move out of Africa into West Asia not only 100,000 years ago but every date after that as well, then their alleles ought to be a lot less likely to have been left behind.

Now this problem is not so pronounced as for the model with a small number of branches. With enough steps (i.e. individual founder effects), it is much easier to make a serial founder effect consistent with human variation, which is clinal.

Even better, if you actually channel comparisons of geographic and genetic distances through a small set of "waypoints", you can get the two to match really well. These "waypoints" represent chokepoints of human movement -- that is, you can't get from Asia to Africa without passing near Cairo; you can't get from Asia to Europe without crossing the Bosporus, etc.

Except, well, you can get from Asia to Europe without crossing the Bosporus, if you can go north of the Black Sea. And you can get from Asia to Africa without going near Cairo if, like the Austronesians, you take a boat by way of Madagascar.

All this is just to say, that if you make your model of founder effects complicated enough -- say, by including a huge number of steps -- then you can come close to matching the overall pattern of human genetic variation. But building a complicated model along one set of assumptions (in this case, the idea that all genetic variation can be explained by drift and founder effects) doesn't confirm the hypothesis that this scenario really happened.

Nor does it test other possible hypotheses for human genetic variation.

Other hypotheses

The data that the paper attempts to explain are (1) the correlation of genetic distance and geographic distance among human populations, and (2) the decrease in genetic diversity in populations farther from Africa. We may ask, what other hypotheses would explain the same data? And what kind of evidence could test these hypotheses, instead of just asserting that they "match" the pattern of evidence.

One scenario that matches the evidence is multiregional evolution with a recent African dispersal of some adaptive genes. This is the hypothesis presented by Eswaran (2002). The idea is that human populations interacted for a long time in Africa and Eurasia, and that during the Late Pleistocene, adaptive changes within Africa allowed those populations to spread alleles into existing populations in Eurasia. The strength of the "founder effect" in this scenario depends on the genetic structure and selective advantage of the new African adaptive complex. Ramachandran et al (2005) actually cite Eswaran (2002) as an example of a serial founder effect. So the idea that there was widespread genetic movement out of Africa does not necessarily imply an out-of-Africa population replacement. The data do not require a replacement, and some -- even many -- of the genetic variants outside of Africa may have nothing to do with recent genetic movement out of Africa.

A second hypothesis is presented by Templeton (2002), who proposed that several founder effects happened at different times in the Pleistocene, each carrying one or more genetic variants out of Africa. The pattern of genetic variation appears to indicate that some genes left Africa during the Lower or Middle Pleistocene, while others dispersed later, during the Late Pleistocene. For Templeton (2002), this pattern indicates multiple dispersals, none of which was sufficient to wipe out the genetic contribution of earlier dispersals. This scenario also would lead to a pattern of correlation of genetic and geographic distanc