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

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

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

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