The telomeres of the australopiths
Speaking of old papers, I was just re-reading this one from Duncan Baird and colleagues (2000).
What got me started was this line from the recent paper by Garrigan and colleagues (2005:3):
Aided by a novel experimental design, we present the first genetic evidence that statistically rejects the null hypothesis that our species descends from a single, historically panmictic population.
Of course, that didn't sound right to me, because people have been talking about evidence for archaic genes in recent humans for several years. The Baird study wasn't cited in that paper, and I returned to it to see what the evidence looked like. Here's the last line of the abstract (Baird et al. 2000:235):
To explain the presence of a few diverged haplotypes adjacent to the Xp/Yp and 12q telomeres, we propose a model that involves the hybridization of two archaic hominoid [sic] lineages ultimately giving rise to modern Homo sapiens.
This more detailed consideration of the problem of divergent haplotypes comes from the discussion:
Two alternative explanations for the presence of divergent haplotypes adjacent to two telomeres can be envisaged. First, the divergent haplotypes arose independently at separate subterminal loci within an archaic hominoid [sic] genome. The high level of exchange between subterminal repeat sequences then resulted in the relocation of one of the subterminal sequences with a telomere to the end of the same chromosome, thus creating two highly diverged haplotypes at one locus. We think, however, that this explanation is unlikely, since there is no evidence that "donor" loci exist in the modern genome. The results of linkage analysis indicate that the only copies of the sequences that can be amplified by the 12qA, 12qB, and 12qArev primers are linked to the end of 12q. Also, although a related copy of the 12q telomere-adjacent sequence is present on some copies of chromosomes 7q, the sequence in this location does not show more similarity to one 12q telomere-adjacent haplotype than to the other. In addition, there is no evidence that a second locus with homology to the Xp/Yp telomere-adjacent sequence is present in the human or in other great-ape genomes. It would therefore be necessary to assume that the "donor" loci for the ends of both chromosomes were present in an ancestral genome but have been lost from the modern human genome. Another explanation is that the diverged haplotypes arose, in separate archaic hominoid lineages, from a common ancestral sequence. These lineages would have to have been isolated for sufficient time to allow divergent haplotypes to arise as a result of sequential mutations and of fixation in each lineage for one predominant haplotype. The degree of sequence divergence between the haplotypes would be dependent on the mutation rates of the loci examined. The high mutation rate in the telomere-adjacent sequences would have resulted in rapid divergence of these sequences in the different lineages. A subsequent hybridization of two hominoid lineages would bring the highly diverged haplotypes together. The continued existence of the diverged haplotypes after the hybridization event would depend on factors such as recombination, drift, and founder effect, and it could vary between loci. This model implies that Homo sapiens may have evolved from a hybridization event between two hominoid [sic] lineages (Baird et al. 2000:247-248).
There's that "hominoid" again. Why hominoid instead of hominid? It turns out these polymorphisms are pretty ancient. Not hominoid-ancient, but, well, read for yourself:
Since the timing of the proposed hybridization event is unknown, it is not possible to suggest which hominoid lineages may have been involved; however, the common ancestor to the lineages must have existed >2 million years ago, perhaps coinciding with one of the Australopithecine species. Additional analysis of the 12q telomere and its adjacent sequence in other human populations may distinguish between the explanations outlined above, but it is not unreasonable to suggest that hybridization between lineages separated by 1.9 million years could occur, because the orangutan subspecies Pongo pygmaeus abelii and Pongo pygmaeus pygmaeus are capable of producing fertile offspring, despite the existence of molecular data that suggests that the two subspecies diverged 1.5 -- 1.7 million years ago (Zhi et al. 1996). Of the two diverged haplotypes in the orangutan Xp/Yp telomere-adjacent sequence (discussed above), one haplotype (orang-lower) was detected in both the orangutan subspecies, but the second haplotype (orang-upper) was detected only in the Pongo pygmaeus abelii subspecies (2/18 alleles) (Baird and Royle 1997; Baird, unpublished data). Furthermore, the observation of homoplasy in skeletons of the Australopithecine species A. africanus and A. afarensis suggests that human evolution was more complex than is currently understood (McHenry and Berger 1998a; McHenry and Berger 1998b), and, recently, a skeleton with both human and Neanderthal characteristics was identified (Duarte et al. 1999) (Baird et al. 2000:248).
So, definitely hominid, but fairly ancient: they place the divergence of the haplotypes at at least 1.9 million years. The story here is not the time depth alone, but the lack of intermediate haplotypes between two extremes; which is the same story offered by Garrigan et al. (2005). Of course, it's not the "archaic" part that they claim is new, it's the "statistical test" part. They're starting to sound like paleoanthropologists!
References:
Baird DM, Coleman J, Rosser ZH, Royle NJ. 2000. High levels of sequence polymorphism and linkage disequilbrium at the telomere of 12q: implications for telomere biology and human evolution. Am J Hum Genet 66:235-250. Full text online
Garrigan D, Mobasher Z, Kingan SB, Wilder JA, Hammer MF. 2005. Deep haplotype divergence and long-range linkeage disequilibrium at Xp21.1 provide evidence that humans descend from a structured ancestral population. Genetics (online before print).
Has the dam broken on mtDNA selection?
The current Science has a paper by Eric Bazin and colleagues comparing mtDNA diversity with population size, history and ecology of 3000 animal species.
Here's the conclusion:
This study reveals that the mitochondrial diversity of a given animal species does not reflect its population size: No correlation between mtDNA polymorphism and species abundance could be detected, despite the large body of data analyzed. Nuclear data, in contrast, are fairly consistent with intuitive expectations. We conclude that natural selection acting on mtDNA contributes to homogenization of the average diversity among groups, in agreement with the genetic draft theory. mtDNA appears to be anything but a neutral marker and probably undergoes frequent adaptive evolution, e.g., direct selection on the respiratory machinery, nucleo-cytoplasmic coadaptation, two-level selection, or adaptive introgression, perhaps hitchhiking with a maternally transmitted parasite. mtDNA diversity is essentially unpredictable and will, in many instances, reflect the time since the last event of selective sweep, rather than population history and demography. Low-diversity mitochondrial lineages, typically disregarded as important from a conservation standpoint, might sometimes correspond to recently selected, well-adapted haplotypes to be preserved (Bazin et al. 2006:571-572, emphasis added).
This is a nice empirical comparison, and a very impressive exercise in data mining. To accumulate the dataset, they had to troll large data depositories for cases in which the same DNA segments had been sequenced in multiple individuals of single species, and then had to match those cases with ecological information about the species, as the accompanying perspective by Adam Eyre-Walker describes.
But, aside from the very persuasive presentation here, the fact has been obvious for years. I blogged about mtDNA selection last year. Finding such widespread mtDNA selection across taxa -- even into invertebrates -- is certainly strong support for the idea that it evolved adaptively in humans. And finding that the chance of adaptive evolution in mtDNA is proportional to population size enhances the likelihood of recent mtDNA selection in humans even more.
Eyre-Walker draws exactly the opposite conclusion than I do:
Interestingly, humans are an exception to the pattern seen by Bazin et al. If the authors are correct, then the effective population size estimated from mitochondrial DNA should be lower than that estimated from autosomal DNA. This is not what we see in humans; the effective population sizes estimated from autosomal DNA, Y-chromosome DNA, and mitochondrial DNA are all approximately 10,000. Does this mean that Bazin et al. are incorrect? Probably not. It may be that humans have such small effective population sizes that adaptive evolution in the mitochondrial genome is very rare; the neutrality index in human mitochondrial DNA, and perhaps nuclear DNA, certainly gives no indication of adaptive evolution. (Eyre-Walker 2006:538).
But of course, this is quite backward -- low mtDNA diversity cannot be evidence for neutrality; at best it can fail to refute a hypothesis of selection. With our long generation lengths, autosomal DNA would have to have coalescence dates in the Pliocene to make the low mtDNA diversity stand out statistically. It is not a question of them all being neutral, it is a question of packing most of human evolution into a space of 2 million years.
Supporting that is the observation that Eyre-Walker points out next:
Although nuclear diversity follows the expected pattern, with more diversity in organisms that are expected to have bigger population sizes, the differences are remarkably small; synonymous diversity varies by less than a factor of 10, and allozyme diversity by less than a factor of 4. This is striking given that the population sizes of marsupials and mussels, for example, must differ by many orders of magnitude, and one would expect diversity to be linearly related to population size. This observation is not new for allozyme data (4), but it is the first time this pattern has been so clearly illustrated for synonymous diversity in nuclear genes. The lack of a strong correlation between diversity and population size in nuclear DNA may also reflect the effects of genetic hitchhiking (ibid.).
In other words, selection has restricted mtDNA diversity, and it has also restricted nuclear DNA diversity -- just not as much. The "not as much" here is a function of recombination, which makes the nuclear genes true subjects of genetic draft.
This isn't news either. We've known about the restricted allozyme diversity since 1984. A few voices crying in the wilderness have been reminding us from time to time, like Gillespie.
I would note that some of their ecological substitutes for population sizes may themselves induce selective effects. For example, Bazin and colleagues note that marine molluscs have more allozyme variation than terrestrial molluscs, which they view as consistent with the greater dispersal of marine species. But greater dispersal might also involve the necessity to maintain diversity for dispersing into to different local environments, which would tend to drive frequency-dependent or balancing selection for traits responding to these local forces.
So there is more to be done on the nuclear DNA side of this equation, probably much more. But the mtDNA comparison is very important, and hopefully will drive some reevaluation of the use of mtDNA diversity as a proxy for genetic diversity in conservation and ecological studies.
References:
Bazin E, Glémin S, Galtier N. 2006. Population size does not influence mitochondrial genetic diversity in animals. Science 312:570-572. DOI link
Eyre-Walker A. 2006. Size does not matter for mitochondrial DNA. Science 312:537-538. DOI link
Looking for more on the Genographic project?
Dienekes is all over the story, including a link to the video, news of some success stories, some details on the protocols from Spencer Wells, and details about the test kit.
Bertie Botts' genetic odyssey
I must admit, not many other clever thoughts came to mind about earwax. Nick Wade has an earwax genetics article telling you everything you probably wanted to know about it:
Earwax comes in two types, wet and dry. The wet form predominates in Africa and Europe, where 97 percent or more of the people have it, and the dry form among East Asians, while populations of Southern and Central Asia are roughly half and half. By comparing the DNA of Japanese with each type, the researchers were able to identify the gene that controls which type a person has, they report in the Monday issue of Nature Genetics.
They then found that the switch of a single DNA unit in the gene determines whether a person has wet or dry earwax. The gene's role seems to be to export substances out of the cells that secrete earwax. The single DNA change deactivates the gene and, without its contribution, a person has dry earwax.
There is some not-very-convincing hypothesizing about why dry earwax might have been selected in northern Asia:
They write that earwax type and armpit odor are correlated, since populations with dry earwax, such as those of East Asia, tend to sweat less and have little or no body odor, whereas the wet earwax populations of Africa and Europe sweat more and so may have greater body odor. Several Asian features, such as small nostrils and the fold of fat above the eyelid, are conjectured to be adaptations to the cold. Less sweating, the Japanese authors suggest, may be another adaptation to the cold climate in which the ancestors of East Asian peoples are thought to have lived.
Surely somebody can think of a better hypothesis than this. Although I must admit, one escapes me now.
In any event, I'm posting this because my genetics class has an assignment: write a 3-4 page paper about one human gene, and make it interesting. This article is a great example! It's one gene. There's something interesting about it. And it's unexpected. Great combination!
Modern human origins::X marks the spot?
Reference: Garrigan, Daniel, et al. 2005. "Evidence for archaic Asian ancestry on the human X chromosome. Molecular Biology and Evolution 22(2):189-192.
This is a short study of a single genetic locus, RRM2P4, an X chromosome pseudogene. The interesting thing about this locus is the relatively high diversity of the gene in Asia. This diversity is not only higher than within Africans, but it includes a basal lineage that is not present in Africa.
Most human genes have greater genetic diversity within living Africans, and where there is a difference among continents in the presence of basal lineages, such lineages are found in Africans moreso than elsewhere. The number of genes examined in this way is not presently large. For example, Takahata et al. (2001) included only a dozen or so genes when they considered the geographic origins of genetic variation. Thus, it remains a relative unknown what proportion of genes might still exist that reveal a greater degree of variation outside of Africa.
This genetic locus evidently was one with a long ancestry within Asia. The basal variant exists within some Asian populations at frequencies of over 50 percent, so it is far from evidence of a minimal survival of archaic Asians. At least in the current sample of 570 individuals it provides strong evidence that Africa was not the only source of genetic material that become common in living humans.
Some observations:
- Why was important piece of evidence not in a more prestigious journal, with news reports and so on? Well, the news reports may still come, since it is the February issue, but the fact is the locus doesn't tell us all that much we didn't already know. The current genetic evidence makes it quite clear that the replacement of all archaic people by African invaders could not have happened (Templeton 2002, Hawks et al. 2000). This locus doesn't revolutionize what we knew, it just adds.
- What does it add, then? Most importantly, it shows that some of the genetic material from ancient Asians not only survived into later populations, it became a central part of the diversity of living Asians. Genetic survival is one thing--for example, morphological evidence suggests that Neandertals in Europe contributed to later European populations, but that their genes became progressively less common over time. In Asia, this gene documents a contribution that may have retained its original frequency, or even increased it. In other words, it is genetic evidence for the adaptability of ancient human gene pools in the face of their contacts with other populations.
- What are the prospects for finding more genes like this? The answer to this really depends on the pattern of evolution from archaic morphology to modern human morphology (and possibly behavior). Considering that Africa probably always had more people than other regions, it is not all that surprising that most human genes appear to have a primarily African influence on their early diversification. But the populations in at least some other parts of the world clearly gave rise to local adaptations, so there is no logical reason why they should not also have gbiven rise to global adaptations. This locus is not one of them--it is a pseudogene--but it may be linked to an ancient globally selected gene that originated in Asia. I expect that many more will be found.
Eswaran's CA paper has been influential toward making people think about the introgression of African genes into the other continents. Ultimately, I think this influence has confused the issue rather than clarified it. Mostly, I think this because of its focus on a single event, modeled as a population dispersal from Africa into other continents.
There is no evidence for such a dispersal, genetic or otherwise. There is substantial evidence for gene flow from Africa to other parts of the world, but as shown by Templeton (2002), this gene flow happened on at least several different occasions at different times during the Pleistocene. There is no evidence that there were distinct "occasions" at all, in the sense of dispersals of people. Indeed, gene flow could have been completely uniform and still create the same pattern of variation.
More assimilation, genetic-style
Daniel Garrigan and colleagues (2005) have an article in press in Genetics, titled "Deep haplotype divergence and long-range linkage disequilibrium at Xp21.1 provide evidence that humans descend from a structured ancestral population." (via Dienekes). The research comes out of Mike Hammer's lab at the University of Arizona. The abstract includes the following:
Aided by a novel experimental design, we present the first genetic evidence that statistically rejects the null hypothesis that our species descends from a single, historically panmictic population. In a global sample of 42 X chromosomes, two African individuals carry a lineage of non-coding 17.5 kilobase sequence that has survived for over one million years without any clear traces of ongoing recombination with other lineages at this locus. These patterns of deep haplotype divergence and long-range linkage disequilibrium are best explained by a prolonged period of ancestral population subdivision followed by relatively recent interbreeding. This inference supports human evolution models that incorporate admixture between divergent African branches of the genus Homo.
So what's the story here? After all, Alan Templeton has been talking about evidence for a non-panmictic ancestral population for humans for a long time. And Templeton has worked with Hammer on earlier papers. So it clearly isn't true that this gene is the first evidence of non-panmixia.
Instead, what this gene might show is something even more extreme. Within the sample of X chromosomes in the study, there were two highly divergent haplotypes, separated by 10 mutational steps. One of these haplotypes is very common, found in most of the individuals globally. The other appears to be rare, founded only two Mbuti pygmy individuals. The interesting thing about these haplotypes is that there appeared to have been almost no recombination events between them -- despite the fact that the gene lies in a region of relatively high recombination, and there are many recombination events among different variants of the common haplotype. Garrigan and colleagues (2005) shows that this result is highly unexpected if the population ancestral to all of the sampled individuals was panmictic. But the very low likelihood of observing this result under panmixia indicates that it is likely that parts of the ancestral population were out of genetic contact for some period of time. The paper illustrates this by showing an impermeable bar, representing reproductive isolation, separating the two haplotypes in the ancestral population. The clear inference is that the persistence of two highly divergent lineages in this instance without recombination is indicative of some substantial period of reproductive isolation in the past.
Unfortunately, the paper actually doesn't statistically test this hypothesis. It focuses instead on testing the null hypothesis of panmixia. It may well be that some kind of population structure including isolation by distance, instead of complete isolation, is consistent with the observations.
In my view, this is an instance of people being less than careful about their assumptions. The chart in the paper clearly shows a hypothesis of reproductive isolation. But isolation is not tested in the paper. This kind of isolation is a prediction of the "assimilation model" of modern human origins. After all, without the isolation there would be nothing to assimilate -- instead, archaic humans would of been part of one regionally dispersed population. Garrigan and colleagues (2005:7) go so far as to formally call the model the "Isolation-and-Admixture (IAA) model," following Jeff Wall (2000) in the assumption that archaic humans may have represented divergent lineages with little (or at the boundary condition, no) interbreeding between them.
Indeed, the findings of this paper might actually be consistent with the Out of Africa replacement model, in that they show evidence for a single dispersed population within Africa. This kind of regionally differentiated African population has long been a prediction of some proponents of a recent African origin, sometimes called the "weak Garden of Eden model". Insofar as strong regional isolation is not demonstrated by the study itself, such a model remains credible as an explanation for this gene. The strength of refutation of the out of Africa model still depends on the combination of many different genes, which together are not consistent with a single recent origin in a small African population. What remains to be demonstrated is the extent to which archaic-modern human contacts occurred.
In that context, it is interesting that this paper raises the issue of archaic-modern contacts within Africa itself. Africa was a highly diverse population in the past, it retains a strong degree of genetic diversity today, and there is every reason to expect that past African differentiation might have left traces in the present distribution of African genes. Garrigan and colleagues (2005:14-15) discuss the issue as follows:
An interesting feature of our inference is that the putative isolation and admixture event likely occurred between ancient African subpopulations. The question of hominin admixture has typically focused on events either between AMH [anatomically modern humans] and Neanderthals in Europe or AMH and Homo erectus in Asia. Given recent fossil evidence, Africa may have provided the greatest opportunity for admixture between archaic subpopulations of Homo, simply because Africa harbored the highest levels of hominin taxonomic diversity (Wood 2002; Tattersall 2003). If the IAA [isolation and admixture] model is correct, it implies that subpopulations of archaic Homo existed in allopatry within Africa for much of the Pleistocene. Regardless, the Xp21.1 data re-iterate the key role of African hominin diversity in the evolution of our species (Jolly 2001).
If the AMH genome contains any degree of dual ancestry (i.e., archaic and modern), the ÒRecent African ReplacementÓ model in its strictest definition (i.e., that of complete replacement) must be rejected. While the majority of the AMH genome may descend from a single African population, if further studies corroborate the inferences made from the Xp21.1 data, it would imply that the evolutionary lineage leading to AMH did not evolve reproductive isolation from other archaic hominin subpopulations and, thus, cannot be considered a distinct biological species.
The possibility of archaic-modern human interaction within Africa is often neglected, mainly because there is little African fossil evidence that could substantiate it. But there are substantial regional differences within Africa in MSA traditions, possibly marking ancient population boundaries. Moreover, some ancient populations within Africa may not yet be represented by fossil or archaeological evidence, including the ancestors of the pygmies considered in this study. Genetics may have much to say in the next several years about the population variation within Africa in the past and the way that it may have contributed to the formation of the modern human phenotype.
References:
Garrigan D, Mobasher Z, Kingan SB, Wilder JA, Hammer MF. 2005. Deep haplotype divergence and long-range linkeage disequilibrium at Xp21.1 provide evidence that humans descend from a structured ancestral population. Genetics (online before print). Abstract
Genetics and multiregional evolution, meetings 2005
Several papers at the AAPA meetings presented evidence for deep Asian-specific lineages in the present human gene pool. For example, from Mike Hammer's abstract:
Preliminary data from two loci that show evidence of ancient admixture will be discussed. A gene tree constructed from sequence data at the first locus roots in East Asia and has a most recent common ancestor ~2 million YBP. The pattern of nucleotide variation at the second locus reveals two major lineages that have not undergone recombination for over 2 million years, and statistically rejects the null hypothesis of panmixia during the early ancestry of modern humans (Hammer et al. 2005:115).
And from Shimada and Hey (2005:195):
Most sequences [from a 10.1 kb region of the X] are quite similar to one another, however three sequences differed from the others at an average of 28.6 substitutions. Assuming a molecular clock, and a human/chimpanzee divergence time of 6 million years, the estimated age of the base of the human sequences is 1.1 million years ago, whereas the estimated base of the tree excluding these divergent human sequences is 290,000 years ago. These divergent sequences were found in samples from the Middle East (Druze and Bedouin populations) and North Africa (Mozabite population). The pattern is suggestive of admixture between non-African archaic humans and Modern Humans [sic].
There were also more analytical papers by Hey and separately by Alan Rogers and colleagues (2005:182):
The "ancestral allele" at a given locus is the allele thought to have been carried by the last common ancestor (LCA) of all humans. These are only estimates, of course, but they are often relatively good ones. Thus, it is interesting that human ancestral alleles are usually most common in Africa. Some claim that the ancestral allele should be most common in Africa, because it is the ancestral population. We argue otherwise. In the absence of selection or ascertainment bias, the expected frequency of the ancestral allele is the same in each modern population, regardless of the history of population size, subdivision, or gene flow. The observed tendency of ancestral alleles to cluster in Africa argues either for some form of ascertainment bias or for some form of selection.
We attribute the pattern to two forms of ascertainment bias, which affect different sorts of locus. These biases, together with a history of expansion out of Africa, are capable of producing the observed pattern. The only loci that are certainly free of bias are those that sequence arbitrary stretches of DNA far from known genes. In these bias-free systems, there is no tendency for ancestral alleles to be most common in Africa.
Out of these papers I found the last to be the most interesting. What the paper essentially said was that earlier work that had found the "ancestral allele" of most genes to lie in Africa was entirely irrelevant to the issue of modern human origins. This is because there is no reason to expect this ancestral allele should preferentially appear in any population, regardless of their demographic history. Rogers reported in the presentation that the last paragraph of the abstract was wrong: they now have good reason to believe that ascertainment bias is not responsible for the observed pattern. That would leave natural selection as apparently the only explanation, although what pattern of selection would create the excess of ancestral alleles in Africa is up for grabs. I have an idea, but I'm not sharing it just yet.
The study is a powerful blow against the case for a recent, exclusively African origin of modern humans. It doesn't demolish the case, since the arguments for a recent African origin extend to other aspects of the genetic record, but it is damaging and suggests that a lot of work should be reevaluated.
But if work supporting Out-of-Africa should be reevaluated, the study suggests that work refuting it should be reconsidered also. The genes examined by Hammer and colleagues and by Shimada and Hey both rely upon the finding of ancient genetic variation outside of Africa -- in essence, placing the "ancestral allele" for these genes in Eurasia. Rogers' and colleagues' analysis shows this logic to be misleading.
The key is, that as we look at an increasing proportion of the genome, we are more likely to see a complex set of relationships. From my standpoint, that indicates that the pattern of human relationships was also likely complex, and that multiple forces (especially selection) were important in generating the current pattern of diversity. But for someone supporting a pure Out-of-Africa model, it means a retrenchment to a "consistency"-based argument: if you can't show the data are inconsistent with (i.e. absolutely falsify) a recent African origin, then you're just whistling in the wind. Despite the complete sequence of the human genome and a growing sample of individuals for many genomic regions, we can't seem to settle on whether the boundary case (no archaic input into human populations) has been falsified.
Hammer and Jeff Wall are working on the problem; looking for analytical methods to definitively falsify an exclusive Out-of-Africa model. In short, they're looking for smoking gun evidence of archaic genes in the recent human gene pool, and they think they have two. One of these was described in Garrigan et al. (2005), discussed in an earlier post. Another shows a similar pattern of diversity outside of Africa. Together with the work by Shimada and Hey, and the earlier work of Alan Templeton (2002), these loci would appear to show very strong evidence of ancient genetic exchanges among human populations, beyond the timeframe predicted by the Out-of-Africa model.
In my opinion, much of this logic is misleading. Many people studying the problem have a tendency to think that "archaic" genes should be hugely divergent from the genes of most living people. The search pattern to find them is to look for something very rare and different outside of Africa, or to place the root of the genealogy unambiguously in Asia or Europe. This is the premise behind Wall's 2000 study for example:
To model archaic admixture, I use an infinite-sites coalescent model with recombination. I assume there is no selection and a constant rate of recombination per base pair per generation. Consider a panmictic population with diploid effective population size N. Going backward in time, suppose that at time T0 the remaining ancestors are placed randomly into one of two subpopulations with probabilities c and 1 - c. From time T0 to time T1, these subpopulations are assumed to be completely isolated from each other and panmictic with diploid effective population sizes of cN and N, respectively. Then, at time T1, all remaining lineages are placed into a single panmictic population with diploid effective size N (Wall 2000:1272-1273).
To translate a bit; the study assumed that archaic humans were arranged into completely isolated populations for a long period of time. This long period of isolation (described as a "deviation from panmixia") resulted in genetic sequences that were artificially elevated in their divergence from the mainstream of modern human origins, and these might be recognized by examining the genetic variation in living Eurasians. In Hammer and colleagues' abstract, the concept of "statistically rejects the null hypothesis of panmixia during the early ancestry of modern humans" comes straight from this sort of logic.
But the hypothesis that archaic humans were completely (or even largely) isolated from each other is artificially extreme. It is a Pleistocene version of polygenism, except with a recent frenzy of interbreeding in the Upper Paleolithic. I don't believe it, and I don't know anybody who seriously would.
Far more likely is the idea that archaic humans were always connected to each other by some level of gene flow. I would take as a null hypothesis that the level was consistent with the current FST of 0.1 to 0.15, which would mean an average of around two individuals moving between each pair of continents per generation. At this level, selected alleles can move relatively quickly across the human range. With the small effective size estimated for human populations, no ancient human group should have been very genetically divergent from another. This means that we shouldn't expect to find "archaic" alleles that are very different from most living people. And if we could have sequenced their DNA when they were alive, we would find that archaic people weren't very different from each other, either.
DNA sequences from Neandertals confirm this expectation. The most recent common ancestor of the Neandertal mtDNA sequences and living humans may have lived as recently as 250,000 years ago. The initial estimate was around 600,000 years, which is elevated because of the anomolously high divergence of the Feldhofer 1 sequence. But even at this high date, the MRCA is significantly more recent than the earliest habitation of Europe, and far more recent than the initial dispersal of people from Africa. In other words, these archaic populations were connected to each other, and were exchanging genes. If there was any isolation of later Middle Pleistocene populations, such as the Neandertals, it was short compared to their shared ancestry. Their genes weren't very different from ours, and they were probably cycling toward greater similarity with us.
If this is true, then we shouldn't expect to find many genes that indicate a strikingly divergent pattern for non-Africans. We should expect most genes to be more or less the same, although many will show greater African diversity for ecological and demographic reasons. Only those genes with exceptional histories of local adaptation will show highly divergent alleles in one place or another. These genes might well be interesting because some of them will be related to the morphological features of archaic humans. But they will probably be exceptionally rare.
So maybe that's why we are only now beginning to find them.
References:
Garrigan D, Mobasher Z, Severson T, Wilder JA, and Hammer MF. 2005. Evidence for archaic Asian ancestry on the human X chromosome. Mol Biol Evol 22:189-192.
Hammer MF, Garrigan D, Wilder JA, Mobasher Z, Severson T, and Kingan SB. 2005. Sequence data from the autosomes and X chromosome: evidence for ancient admixture in the history of H. sapiens? (abstract). Am J Phys Anthropol suppl 40:115.
Shimada MK, and Hey J. 2005. History of modern human population structure inferred from the worldwide survey on Xp11.22 sequences. Am J Phys Anthropol suppl 40:195.
Templeton AR. 2002. Out of Africa again and again. Nature 416:45-51.
Wall JD. 2000. Detecting ancient admixture in humans using sequence polymorphism data. Genetics 154:1271-1279.
The Genographic Project
Information about the project from the Waitt Family Foundation
National Geographic Genographic Project site
As reported in the news stories above, the Genographic Project is a collaborative research undertaking by the National Geographic Society, the Waitt Family Foundation, IBM, and a number of independent research labs around the world. The goal of the project is to sample over 100,000 individuals from diverse global populations in order to achieve a fine-grained understanding of migrations recent in human prehistory.
MSNBC is reporting that the project is funded to the tune of 40 million dollars. For some perspective, this would fund all the research projects under the Physical Anthropology section of NSF for roughly 15 years.
The project leader is Spencer Wells. Wells is best known for his documentary program, "Journey of Man," in which he trekked around the world to illustrate the evidence for human migrations from the Y chromosome. The most memorable scene is one in which he corners a bewildered man in a Kazakh village to tell him he has a sequence inferred to be ancestral to a billion Asians. The poor man thought that Wells had come to tell him he was going to die. In a nutshell, this is the effect that anthropological genetic work has come to have on indigenous peoples around the world.
The current project is audacious in its scope. It bears clear echoes of an earlier proposed project, called the Human Genome Diversity Project, but with even more extensive sample sizes. If it met all of its goals, the Genographic Project would clarify the course of human movements and population growth since the development of agriculture 10,000 years ago, and possibly even earlier.
Who will do the work?
Here's what Wells says in the FAQ at the Waitt Foundation site:
We assembled a team of top human population geneticists from around the world - 10 principal investigators focusing on indigenous peoples around the world, plus one focusing on ancient DNA, from the USA, Brazil, UK, France, Lebanon, South Africa, Russia, India, China and Australia. They are all experts in their respective fields, very thoughtful scientists, and passionate about the work they do. I'm lucky to be collaborating with them - it's like having the "dream team" of human population genetics.
It is fairly unclear to me just what IBM is going to contribute aside from bioinformatics. I don't know, for example, if they have someone who can model population movement to generate simulated samples to test migration hypotheses against. I think it is unlikely that they have anyone who is modeling natural selection, which is the force most likely to affect the geographic distribution of many human genes, the Y chromosome included.
Should you send in your DNA?
You may be thinking, "It sounds great; I just wish I could participate myself!" Well, if you want to, you can! For only $99.95, you can purchase a Genographic Participation Kit from the National Geographic Store:
With a simple and painless cheek swab you can sample your own DNA. You'll submit the sample through our secure, private, and completely anonymous system, then log on to the project Web site to track your personal results online.
This is not a genealogy test and you won't learn about your great grandparents. You will learn, however, of your deep ancestry, the ancient genetic journeys and physical travels of your distant relatives.
But is it safe? Won't they take your DNA to make tiny clones of you and fetal pig implant organs to support them?
Here is what National Geographic says in their FAQ about the DNA sequences sent in by people who purchase their "kits":
We will keep your cheek scraping sample only for the Genographic Project. Your sample will not be used for any other purpose without your written permission. The genetic tests we will perform are designed only to research early human origins and movements. The tests do not tell us anything about your health, or about any health problems you (or your family) may have. This is an anthropological study only. Unless you instruct us otherwise, your cells will be destroyed at the conclusion of the Project....During the project, you will have the opportunity to contact Family Tree DNA, the company licensed to perform testing for Genographic Project participants, to request follow up testing if you choose. Unless you do so before the conclusion of our project, your cells will be destroyed and will not be available for follow up testing.
Sounds like a great marketing opportunity. Which isn't, I think, exactly what anthropologists ought to be promoting.
My advice is, don't send in a swab. Not to say I don't trust the National Geographic Society; in fact I think that this part of the project is pretty innocuous. My main concern is that $100 is a lot to pay for something that is very likely to tell you what you already know: "Gee, I come from Europe, and my ancestors got there 15,000 years ago from the Near East." Or something that is very likely to be patently false: "Gee, I have a sequence found in Greece and also found in one village in northwestern Pakistan. My ancestors must have ridden with Alexander the Great!" Please don't waste your money. It is much more useful to learn about your grandparents.
Of course, the kit does come with the video featuring Spencer Wells. If you're into that kind of thing. He does have a high Q-rating.
If anyone does order these, let me know. I would really like to be able to report on the contents, and especially the kind of results that they send. I am imagining this is only a step removed from those genealogy companies that send you your "family crest" and a story to accompany it, but I would be happy to be proved wrong.
Is this the Human Genome Diversity Project?
The short answer is, "Not exactly, but it comes from some of the same people who brought us that one."
Three things set the project apart, as I understand it. One is the apparent lack of public funding sources. This is in part a function of increased efficiency of genetic research: this can be done much more cheaply today than would have been possible in 1995. Also, the National Geographic Society has done very well for itself recently by pushing projects that generate publicity like this one. In a way, it is a perfect match, since it is literally "geographic" and since it involves the possibility of direct public participation. Of course the lack of public funding means that the project is not subject to public oversight, which places it beyond some of the critics of the HGDP. To me, this is a matter of some concern. The advisory board of the project is chaired by Luca Cavalli-Sforza (Stanford University) who was the main figure behind the HGDP.
Second, there is no guarantee of complete coverage of indigenous peoples. With the HGDP, there was the ostensible goal of sampling intensively among language families and other ways of determining "ancient" groups that were worth sampling. Merritt Ruhlen (Stanford University) was one of the principal linguists advocating this approach for the HGDP; he is on the advisory board of this project, so there may be some attempt to do a similar thing. The New Scientist story says, "Collecting genetic information from relatively isolated populations will be a priority because this will provide the clearest picture of humankind's evolutionary past." Of course it was this kind of logic that got the HGDP in trouble in the first place. At this point, the project does not explicitly describe how such sampling will be done, so I assume that its sample of indigenous people will include mainly those groups who have participated in such research before.
Third, there is the ostensible limit of data acquisition to Y chromosome and mtDNA markers related to migration history. This may also be a consequence of technological change since the mid-1990's. Today, researchers can design "gene chips" to very rapidly type an individual's genome for particular markers of interest, without going through the effort of obtaining an entire sequence. This is very efficient and low in cost, and I would expect that this is the technology they are using on most of the samples, including all those from the DNA kits.
On the other hand, this methodology throws away much of the interesting data on diversity. Going without complete sequencing introduces an ascertainment bias that can make it difficult to determine interesting demographic characteristics about the population. This may make it more challenging to determine whether the population expanded at particular times in the past, for example. These biases may partially be overcome by sequencing thousands of individuals, so there is clearly a strategy at work here. But I would be very surprised if a large subset of the individuals -- the ones for which a larger tissue sample is available, or for whom a cell line has been produced -- were not subjected to sequencing of long genomic regions. I expect there will be microsatellite and SNP data coming out of these samples from other genomic regions in addition to the Y and mtDNA analyses.
With these caveats, the Genographic Project clearly carries on the legacy of the HGDP. This means that we should consider the criticisms of the HGDP to see if they apply to this project. The most important criticism was the human rights issue, and in particular the opinion that the human subjects had not been sufficiently protected. In large part this was because informed consent from members of indigenous groups might never have been possible without undergoing specialized training in genetics and medicine, and because the project therefore depended upon approval from "tribal elders" or other individuals chosen to speak for their groups. This procedure was viewed by many critics as fundamentally outside the normal protections of liberal democracies, and such criticisms were never satisfactorily answered.
But this was far from the only criticism of the HGDP, and there were a number of scientific issues that questioned the fundamental worth of the project. One criticism was the sampling strategy. The idea of capturing DNA from small tribes and linguistic groups that are dwindling in numbers doesn't seem like such a bad one at first glance. But the fact is that the changes in process in such groups are not biological ones, they are cultural ones. For the most part, although there are exceptions, the people are not becoming extinct, nor are their genes. They are just adopting new lifestyles and joining new groups.
This cultural change certainly complicates the attempt to find patterns of ancient history and migrations. But sampling the dwindling small groups speaking languages that are nearly gone probably won't help. These groups themselves were the product of similar movements and group losses in the past. To be sure, some of these movements are precisely those that the Genographic Project is attempting to recover. But sampling groups rather than locations confounds the effects of cultural and geographic factors leading to human variation. A better sampling strategy would be designed around geographic coordinates instead of linguistic ones.
The issue of sampling strategy is related to the separate issue of analytical method. There was never a clear methodology that satisfied critics that the results would be valid. The sampling strategy that promoted groups or language families as fundamental elements of analysis invites a cluster or dendrographic-based analytical method. Since human populations do not fit a tree well, this statistical method is guaranteed to mislead about relationships. But geography-based methods, such as Cavalli-Sforza's famous PC plots of genetic variation over space, also yield misleading results.
Today, most analyses of Y chromosome and mtDNA variation use "founder analysis," which is an attempt to delinate the earliest movement of people to a region based on the most recent common genetic ancestors found in both the region and its presumed source. This kind of analysis is also limited in the information that it can generate, and its results are also subject to challenges. Especially, the method is sensitive to the age and distribution of discrete markers (the very markers that this research is designed to look for), which really cannot be aged very precisely, and which may have different distributions today than at the relevant time in the past.
And of course, there is the overarching assumption of no selection, which for the Y chromosome and mtDNA has become increasingly problematic.
Will companies be profiting from this research?
Apparently for the public kits, there will be no research other than the Y chromosome and mtDNA markers useful for a narrow study of migration history.
For the larger samples acquired as part of the "diversity sampling," no such guarantees have been given. Nor should we expect to see any such guarantees, because these samples include thousands of tissue samples from people that have already been taken with no conditions attached.
The news stories about the Genographic Project say that commercialization is not the goal. For example, New Scientist reports:
In the 1990s, Luca Cavalli-Sforza at Stanford University in California, US, attempted to set up an even more ambitious project called the Human Genome Diversity Project, to map genetic diversity around the world. But it foundered after opposition from groups representing indigenous peoples, who saw it as an attempt by western companies to profit from their genes.
IBM says the Genographic Project is different as no medical studies will be done, and none of the data will be commercialised. An independent advisory board, including indigenous advocate Tammy Williams of Cape York, Australia, will oversee sampling and research.
I think this is very misleading. For the research to be minimally useful, it must include markers beyond those on the Y chromosome and mtDNA. Although it has usually been argued otherwise, the fact is that single loci cannot give good information about migration. The evolution of any single locus is stochastic, so that the overwhelming majority of information that it might hold about migration depends on how it compares to other genetic loci. But even excluding the obvious necessity to look at other areas of the genome, both the Y chromosome and mtDNA are of increasing biomedical interest. Several recent research articles have examined the possibility that normal geographic variants of the mtDNA are associated with increased disease risk. So regardless of the intentions of the project, any public information resulting from the project will be applied in biomedical contexts.
The question really is whether anyone will profit from it. For this, a purely private research enterprise can offer nothing but its word, and that of its advisory board. I don't have any reason to think that these people have any motives to profit directly from biomedical information, but I would rather have some very solid guarantees about the way information will be used. Again, I do not doubt their good intentions, but I would be cautious. At this stage, after the project has just been announced, that information has not yet been provided to the public. The participant with the most to lose is the National Geographic Society, which risks squandering much of the goodwill it has in developing nations if it fails to make explicit how research subjects will be protected.
What unforeseen consequences will this research have?
Of course if I can foresee them, then they are by definition foreseen rather than unforeseen! Nevertheless, there are some consequences that you are not going to hear anyone talking about.
Here's something that won't be reported anywhere but seems fairly obvious. If National Geographic and IBM are working with around ten research centers on a project involving 100,000 genetic samples, then the scale of anthropological genetics has irreversibly changed. Labs that are not now capable of dealing with samples of thousands of individuals fairly quickly are in danger of being shut out of empirical research entirely.
That is not to say that smaller projects are irrelevant. Ancient DNA research will never involve more than a few individuals at a time, and the study of genetic structure within small-scale human societies and primate groups will never involve thousands of samples. But the point is coming, if we have not already reached it, when these small projects will be tackled more easily by graduate students at a large lab than by independent scientists with a small lab. It makes little sense to maintain small labs when the economy of scale on DNA sequencing makes it much cheaper to obtain more data from larger setups. And as DNA data becomes cheaper, more reviewers will expect that things are verified by resequencing; so that most small labs may end up sending things out for this reason anyway. Only if technology ultimately provides small, portable solutions to yield sequences in the field will the balance shift to smaller setups. But then one hardly needs to be a molecular specialist to get DNA data, especially if one is using the same computer programs for analysis anyway.
What we will see with the project is probably not greatly different than we would have seen without it. The findings of the project will appear to confirm some arbitrary number of interesting historical population movements. We have already seen this with the Phoenician research project led by Wells, Brian Sykes' research on early Europeans, the "Genghis Khan" sequence, the Cohanim and Lemba connection, and any number of others. Together, they will create an impressive perception of progress toward understanding human history. Individually, each of them will be a flimsy case based on weak evidence.
But they will make for some interesting National Geographic specials.
The science of Helicobacter pylori
There is an article in the February 2005 Scientific American with the intriguing title "An endangered species in the stomach." The article fairly well covers the current science of H. pylori, especially focusing on its role in the ecosystem of the stomach. For a little background, H. pylori exists in the stomachs of a large proportion of people in the world, and because of its tolerance of the acid environment of the stomach it is the only bacterium that can regularly survive there.
The frequency of H. pylori infection is high in most areas of the world. However in the developed world, the frequency of infection has been decreasing, mainly due to routine administrations of antibiotics for other infections. Evidently a short course of antibiotics is all that's necessary to wipe out H. pylori from the stomachs of most individuals.
This decline in H. pylori frequency in Western populations has said several effects, which the article points out are both good and bad. Unmistakably good is the decline in stomach cancer-which has a much higher incidence in people with H. pylori infection. The article points out that in 1900, stomach cancer was the most common form of cancer with the highest rate of mortality. Today it is much less severe as a cause of mortality with a much lower incidence-lower than the incidence of many other kinds of cancers.
The article describes the bad effects of H. pylori disappearance as surrounding an increase in the incidence of acid reflux disease. Acid reflux disease is a painful condition in its own right, but later in life it can lead to more serious complications including adinocarcinoma of the esophagus. In the article, Blaser explores the ecosystem of different strains of H. pylori in order to explain why acid reflux disease has increased.
Different strains of H. pylori express different genes and some of these genes have more or less damaging effects on the tissues of the host. Blaser finds that this diversity of genes actually has a function in feedback communication between host and the parasite. For example, one gene that is particularly damaging in attacking stomach tissues can actually cause the body to reduce the level of acidity in the stomach. This reduction leads to a reduction in the irritation that leads to acid reflux.
Blaser is clearly very interested in the negative feedbacks between H. pylori and the host, and suggests that the understanding of this system may lead to advances in medical treatment. He suggests that the use of probiotic treatments (applying live bacteria to the body instead of applying antibiotic agents) might become common if scientists could properly evaluate the best microbial environment for each individual. This is an interesting perspective, but considering the complexity of drug interactions were only one substance is involved, it seems unlikely that scientists will be able to unravel the highly complex interactions of organisms any time soon. Even so, the possibility does point to the necessity of the FDA or some other kind of oversight body considering what kind of regulations may be necessary on probiotic treatments. Since live bacteria are clearly not drugs, it's not obvious that the regulations that currently apply to drugs and other medical substances will apply to this form of treatment.
====Parasites tracing human history
The article also mentions attempts to use the distribution of variation in the H. pylori around the world to trace the history of human migrations. This general concept is not new-it has been applied to other human parasites before with varying levels of success. The main benefit of using pathogens and other microorganisms as proxies for human variability is that there markedly more variable in their DNA sequences than are individual humans. This means that the microorganisms more accurately trace events over relatively short time spans, like those involved with recent human migrations to different parts of the world.
On the other hand, there are disadvantages. Microbes are not people, and they're not inherited a in the same manner as human genes. Some microorganisms have relatively vertical forms of transmission-meaning that there typically inherited by individuals from one of their parents or another closely-related individual. JC virus is an example of relatively vertical transmission, being inherited early in life predominantly from close relatives. H. pylori is also inherited early in life, although it is not clear to what extent the microbial population may change over the course of a lifetime.
The other important difference between microbial evolution and human evolution is the intensity and form of selection. With their rapid generation times, microbes are under relatively intense selection, especially if they have some kind of effect on the host. The interactions between pathogens in the host's immune system are very complex, and most genetic changes in microbes can be expected to be adaptive in one way or another. In some pathogens, like JC virus, the effects on the host are absent or negligible, and in such cases we may argue that the evolution of their genes is-or at least might be-relatively neutral. Other pathogens, like human papillomavirus, exert a greater effect on their host, including the possibility of mortality. These microbes can not be considered to have evolved neutrally.
It seems clear from the consideration of the effects of H. pylori on human health then it does have potentially major effects on its host. If the microbial ecology of the stomach is actually affected by these kinds of interactions, then clearly the explanation for the diversity of these organisms around the world is more likely in the realm of natural selection then in the realm of neutrality. This means that H. pylori probably is useless in yielding new information about human migrations. Instead, it should be considered to give valuable information about the history of human gut adaptations.
Nevertheless, the mention in the Scientific American article prompted me to look back at the original work on H. pylori variation in Science, in a 2003 paper by Falush and colleagues. Like other examples, this paper tries to match the variation found in different populations around the world with a model of human dispersals. Like other articles, it uses the same model of dispersals-a model in which humans began in Africa and then dispersed to Asia and Europe and much later dispersed to the New World and the Pacific islands.
As with other papers along the same lines, the question is whether the new data in the paper (in this case H. pylori variation) actually adds anything new to what we think we know about ancient migrations. It helps to have some understanding of what form the new data takes. In this study, the authors sequenced small parts of eight genes. Each of these genes is functional, meaning that the alleles carried by each of the microbes for these eight genes probably affect their survival and dispersal capacities. After sequencing, the researchers plugged the data into a computer program with a one guiding assumption: that originally all of these H. pylori variants came from a small number of discrete populations. In other words, the study assumes a humans once belong to a small number of pure races, each carrying a single H. pylori variant. It is a mixture among these ancient traces that is assumed to have led to the current variation of human genes, as well as the variation of the H. pylori genes.
This is an extraordinary assumption, but unfortunately not a rare one. it is certainly possible to write a computer program to reconstruct putative ancestors under this assumption. Most researchers who apply an assumption like this do it because of the ease of such application, not because they believe the assumption is valid. But in this case, as in most other cases, the problems with the assumption are ignored once the result is in hand. Humans did not once belonged to five pure races, the number concluded by this instance of computer analysis. H. pylori did not descend from five ancient strains. It is very likely that there was as much diversity 50,000 years ago in H. pylori as there is today, and that that diversity was equally scrambled as we now observe. What has happened in the interim is a small number of major human migrations-such as the migration of people to the New World-and a high level of natural selection in H. pylori distributions. It is probably impossible to say exactly what pattern of natural selection would lead to the observed distribution, but to assume that that selection was absent, or that it had only minor effects on the current pattern of variation, is clearly wrong.
This is not to say that the current pattern of variation is without structure, or that human geography is irrelevant to H. pylori variation. In fact human variation and dispersal is probably the main contributor to H. pylori variability over short time spans. However, over spans of hundreds or thousands of generations, the effect of selection substantially outweighs the effects of population history. Even over short time spans, changes in H. pylori variation may reflect forces other than human population movements, or mechanisms other than human movement. The researchers find a high frequency of European haplotypes around the world, and attribute this to recent movements of European peoples, especially since the Age of Exploration. But it is not just European people that have moved since that time, it is also European livestock. How much of the spread of this H. pylori variation stems from the movement of people, and how much stems from their cultural and technological baggage? For H. pylori, as for most microbes, these questions are not merely unanswered, they're usually unasked.
I wonder if over the past 50,000 years, we're at the point in time where many kinds of genetic evidence retained just enough neutrality to partly match geographic movements, but not completely so. Not everything has been under selection recently in humans, and human populations have been partially isolated over time. But as we consider earlier in earlier times, it is much more likely that selection will have occurred for any particular gene, and it is much more likely that dispersal between regions will have allowed the exchange of advantageous variation. Is there a critical time before which we will tell nothing about ancient history from genetic variation? I doubt that there is any single time comprising an impenetrable barrier to our vision into the past. But clearly as we move further and further into the past our vision must become foggier. So echoes of our current geographic distribution may be stretched into the past for a longer period than might actually be justifiable. And over long periods of time, tens of thousands of years in length, the geographic distribution of people does exert constraints on the evolution of their genes.
In this study as in so many others, the new data actually add nothing new to our understanding of human movements. The researchers find that they are consistent with their understanding of human movements from other sources. "Consistent with" means "Provide no independent test of". And that's the bottom line, in a very real sense. Humans are geographically variable. This variation is structured by distance. Under an assumption that we had a single origin, this geographic structure is consistent with sequential migrations over time. And some large-scale migrations have happened. Taking these facts as a baseline, is it surprising that any human gene-or any human-associated microbe-should have a pattern of variation consistent with this?
"New" information would be obtained if we had an independent estimate of the date of such movement, or an independent estimate of the order of dispersals, or an independent estimate of the population sizes of the different regions in the past. So far, H. pylori has given us none of those. Nor has any other microbe. And only too rarely have human genes been interpreted in this way. Until we begin to consider whether different genes actually match each other's patterns of variation will we be testing hypotheses about human prehistory. Until then, we're just playing consistency games.
References
@article{Blaser:2005,
author = {Martin J. Blaser},
year = {2005},
title = {An endangered species in the stomach},
journal = sciam,
volume = {292},
number = {2},
pages = {38--45} }
@article{Falush:2003,
author = {Daniel Falush and Thierry Wirth and Bodo Linz and
Jonathan K. Prichard and Matthew Stephens and Mark Kidd
and Martin J. Blaser and David Y. Graham and Sylvie Vacher
and Guillermo I. Perez-Perez and Yoshio Yamaoka and
Francis M\'egraud and Kristina Otto and Ulrike Reichard and
Elena Katzowitsch and Xiaoyan Wang and Mark Achtman and
Sebastian Suerbaum},
year = {2003},
title = {Traces of human migrations in \emph{Helicobacter pylori}
populations},
journal = {Science},
volume = {299},
pages = {1582--1585} }
Continents of continuity
Harding and McVean (2005) present a review of current genetic evidence addressing the origin of modern humans. Unlike other recent reviews, they do not present a litany of evidence in favor of a recent African origin. Instead they step away from the past to look at the prospects for more complex metapopulation models to explain all of the genetic data, rather than merely one part of it. Their basic theme is that contradictions between evidence that suggest a recent single origin and contrary evidence that suggests regional continuity may be resolved by considering a fuller range of demographic models. Such models encompass geographic structure in the ancestral population leading to modern humans.
Harding and McVean never make explicit the difference between effective population size (Ne) and census population size. Ne describes the apparent rate of inbreeding in the ancient human population, while census population size describes the actual number of people that existed at any one time in the past. These values are widely divergent for most living animal species, including most mammals. This means that for most mammal populations, inbreeding is not merely a consequence of small population size, but also other evolutionary forces--chiefly natural selection. I think that Harding and McVean do not mean to confuse Ne with census size, and indeed they do not make the equation between the two that has led to so many errors in other papers. But their failure to note the difference between them leads to some conceptual mistakes. Consider:
The search for an ancestral history that can satisfactorily explain the genetic architecture of modern human phenotypies will require models that include positive selection within a structured population. Compelling genetic evidence has been found for geographically local adaptation from analysis of FST values [citing Akey et al. 2002]. However, the relatively small Ne values for humans and other primates, compared with Drosophila or rodents, implies weakened purifying selection and an expectation for some level of polymorphism among slightly deleterious variants. It will be easy to misinterpret the latter as evidence for positive selection in the form of local adaptation (671).
This quote brings up a really interesting idea--that human populations may appear to be locally adapted because their demography has exposed them more or less to a single global pattern of selection. But demography is not the only influence on Ne. Although humans certainly are on a different scale from Drosophila or mice in terms of genetic drift, nevertheless, the most important influence on genetic diversity in all these species has probably been purifying selection and hitchhiking.
Likewise, Harding and McVean (2005) confuse the issue of Ne when referring to the demographic implications of particular gene genealogies:
It has become easy to accept the recent age for mitochondrial Eve, and also to justify the many older TMRCA estimates for autosomal gene geneaologies, by assumng that Ne has not been reduced from 10 000, but an NRY TMRCA estimate of 60 000 years, which is so much younger than mitochondrial Eve, has produced a quiet sense of unease (669).
They ignore the easiest explanation for these problems with young genealogies, which is positive selection. This again was necessitated by their focus on Ne as a meaningful demographic parameter. In effect, they argue that the recent coalescence dates of NRY and mtDNA challenge the idea that there was a panmictic population before 100,000 years ago, because in such a population there should have been less heterogeneity of gene genealogies.
To be honest, I can't follow this argument (on page 669) that the NRY somehow shows that:
African populations must have been more strongly subdivided and isolated from each other than non-African populations, and that some African populations were not a direct source for the range expansions out of Africa (669).
This idea seems completely in opposition to the Y chromosome evidence, taken at face value. A low variability for any genetic locus should be evidence for a recent origin in a small population that had no subdivision, except in the case where the gene was subject to positive selection.
But of course if the Y chromosome, mtDNA, and other genes with recent coalescence dates were actually under selection, there would be no reason at all to oppose Harding and McVean's other scenario:
An additional and more contentious possibility is that not all modern human diversity presently found outside of Africa evolved from recent African ancestry. The greater time-depth of autosomal and X chromosome loci, compared with mtDNA and Y chromosomes, allows subdivision in the ancestral population to date to a time when modern human morphology was evolving from an archaic form. Patterns in these genetic data do suggest admixture between the Late Pleistocene humans, whose range expansions are visible in mtDNA and Y chromosome data, and populations established earlier. Probably, most of this gene flow took place within sub-Saharan Africa, but we cannot rule out admixture elsewhere in the world (669).
The last part of this is not supported by the data; Templeton (2002), Garrigan et al. (2005) and others have shown evidence for ancient genetic contributions from Middle Pleistocene non-Africans. As far as I can tell, the idea that this contribution mysteriously occurred by the translocation of ancient Asians to sub-Saharan Africa is a fiction. Nor is the major issue time depth, since a deep time depth for autosomal DNA would easily be consistent with a purely African origin. The issue is geographic distribution, and the same observations that make a single panmictic population unlikely within a purely African context certainly cannot rule out a wider geographic context. And as Templeton (2002) points out, an origin limited exclusively to Africa may already be falsified by the genetic data.
Is there any point to examining metapopulation models for human evolution? I speak as a believer in the idea that humans were a geographically structured metapopulation. But Harding and McVean (2005) do little but raise a few intriguing scenarios for past human metapopulations. They do not draw attention to the problems of metapopulation models. The most critical problem is deciding which parameters will be allowed to vary and which will be constant. It may be true that a more complex demographic scenario fits the pattern of data better than panmixia and constant population size.
But it is probably true that multiple models provide a better fit. Certainly the best of all possible fits would be if natural selection was considered to act in a unique and independent way on every genetic locus. In this way, every gene would be maximally explained. But that hypothesis, we would object, is overparameterized -- in other words, it isn't parsimonious. The question is which of the potential parameters should we consider first to maximize both parsimony and explanatory power? The answer to this question is of course that we should test many, and include those that test out as potentially important.
Moving to a metapopulation concept of ancient humans is undoubtedly a good idea, since ancient humans must have been a metapopulation. But I think that including selection as a parameter can explain more that we currently consider to be problematic with the panmixia model. This would include the recent coalescence dates of mtDNA, NRY, FoxP2, and other low-variation genes. It might also include the estimate of Ne at 10,000. On the other hand, there are metapopulation models that can also explain human Ne, and these may be part of the story. I tend to reject them because they would require that many other species also have distinctive metapopulation structures like ancient humans, and that seems less parsimonious than the idea that genomic selection in animal species is more common and powerful than usually thought.
On the other hand, considering the distinctiveness of some fossil human populations, I think a metapopulation model makes a lot of sense. In particular, I am working on explaining many aspects of Neandertal evolution by reference to the idea that Pleistocene Europe was a population sink. This metapopulation concept is potentially very explanatory, and does have consequences for the interpretation of ancient DNA evidence and modern human variation. So metapopulation models must be considered as part of the overall explanation of human evolution. The question that we all face is which kinds of models we should turn to when the panmictic model is shown to be wrong.
References:
Harding RM and McVean G. 2005. A structured ancestral population for the evolution of modern humans. Curr Op Genet Devel 14:667-674.
Resetting the molecular clock
A commentary in Nature by molecular biologist David Penny discusses a recent paper in Molecular Biology and Evolution by Simon Ho and colleagues (2005). The subject of the paper is the observation that recent species divergences seem to have higher apparent mutation rates.
If mutations are completely neutral, then the rate of substitutions within species lineages should be the same as the rate of mutations. Of course, not all mutations are neutral: many of them are deleterious, a few are advantageous.
Ho and colleagues focus on purifying selection on deleterious mutations as the most likely reason for the apparent acceleration in rates for recent divergences. The idea is that slightly deleterious mutations remain in the population for a period of time inversely proportional to the strength of selection against them. Very weakly selected mutations can remain for a long time; strongly selected ones will disappear quickly. But none of these are likely to become fixed in a population. Therefore, natural populations harbor a number of slightly deleterious variants that, if observed, tend to inflate the apparent rate of mutations. This inflation is more severe for recent divergences, because these deleterious mutations make up a higher proportion of the total mutational difference between the species considered.
The data were consistent with purifying selection, because the proportion of nonsynonymous mutations (the ones that can have a phenotypic effect) is higher within species than among species, and higher between closely related species than between distantly related ones.
Ho and colleagues (2005:1565-1566) provide new estimates for human and Neandertal divergences based on their correction:
Using an alignment of d-loop sequences from four Neandertals and four humans (African, Caucasian, Chinese, and Indian) (alignment available as Supplementary Material online), we recalculated the ages of the last common ancestors of Neandertals, humans, and of Neandertals and humans. The new date estimates were computed by solving equation (7) numerically with the parameter values estimated from the primate d-loop data (eq. 6) and with HKY85-corrected distances estimated from the alignment using the program baseml (Yang 1997). Ages of last common ancestors were as follows: Neandertals and humans 354 ka (222--705 ka), Neandertals 108 ka (70--156 ka), and humans 76 ka (47--110 ka). These date estimates are intermediate between the values obtained when either the lowest or highest rates of change from figure 1c are used for divergence date estimation.
The three new date estimates were considerably younger than those estimated in previous studies, which gave ranges of 365--853 ka (Ovchinnikov et al. 2000), 550--690 ka (Krings et al. 1997), and 317--741 ka (Krings et al. 1999) for the Neandertal-human divergence; 151--352 ka (Ovchinnikov et al. 2000) for the last common ancestor of Neandertals; and 106--246 ka (Ovchinnikov et al. 2000), 120--150 ka (Krings et al. 1997), and 111--260 ka (Krings et al. 1999) for the last common ancestor of humans (fig. 5). This discrepancy arises because high, short-term rates of change were taken into account by our approach.
Notice here, the largest effect of overestimation occurs for the most recent, within-species comparisons. This observation is consistent with earlier disagreements about the mutation rate of mtDNA -- some studies found that recent humans apparently were mutating at ten times the rate expected from interspecific comparisons.
Notice also, that the TMRCA of human mtDNA on this estimate is between 47,000 and 110,000 years ago. This date is more recent than early modern humans in Africa. The bulk of the confidence interval is later than the first emergence of "modern" humans from Africa. If the TMRCA for humans is really this recent, there is next to no chance that this origin of human mitochondrial variation actually is a signature of the origins of all modern humans. It may be a signature of the movement of some modern populations, but that is a different issue, and one that must ultimately be sorted out from the pattern of selection on mtDNA.
Does the finding have any importance for the way we study variation within humans? Well, there is this:
For some reason, the continuum between population heterozygosity and long-term evolution has not been adequately studied. Although it is a continuum, the techniques required may change as the timescale decreases. For example, some concepts from long-term evolution (binary evolutionary trees with sequences studied only at the tips) have been extended into populations where trees are no longer binary, and ancestral sequences (at internal nodes) are still present in the population. There are hints that a formal multiscale study is necessary, because even though the same underlying process is occurring, different features of trees are observed as the timescale changes (Penny 2005:184).
Just a note that it is a mistake to look at genetic variation within a species and treat it the same way as long-term neutral variation as measured between species over long spans of time. Human variation dates to anywhere between 50,000 years old and over 3 million years old for different genetic loci. The more recent and more ancient parts of this time interval may not be explained by the same pattern of evolution.
And wouldn't it be boring if they were?
References:
Ho SYW, Phillips MJ, Cooper A, Drummond AJ. 2005. Time dependency of molecular rate estimates and systematic overestimation of recent divergence times. Mol Biol Evol 22:1561-1568. Full text online
Penny D. 2005. Evolutionary biology: relativity for molecular clocks. Nature 436:183-184. Full text (by subscription)
The Journey of Mankind!
It is really not worth looking at, but I couldn't stop laughing, so I have to point it out. The Journey of Mankind site is an animated map and timeline of people originating in a suburb of Nairobi 150,000 years ago, and then spreading through the world. You can follow the trip with a moving arrow, like in Raiders of the Lost Ark.
Of course the whole thing is silly, but the fun really begins when the initial foray into the Levant fails ("A global freeze-up turned this area and north Africa into extreme desert"), and Cavalli-Sforza's "beachcomber" hypothesis kicks in.
The part that had me rolling was when the red arrow of beachcombers wanders aimlessly around Borneo:
From Sri Lanka they continued along the Indian Ocean coast to western Indonesia, then a landmass attached to Asia. Still following the coast they moved around Borneo to South China.
Yeah, that would be the way I would choose, too.
Then Mt. Toba erupts! The world is plunged into volcanic winter, and the arrow is cut off in South Asia. You see, the volcanic ash covered it up. Without a trace. I can't make this stuff up.
When I clicked on it I assumed it was connected with Spencer Wells' work (Journey of Man), but actually it was compiled by Stephen Oppenheimer. He's the author of Out of Eden, upon which the BBC based its documentary "The Real Eve." He also proposes that the sinking of the Sunda continent eradicated the origin of rice agriculture and led to a cultural exodus that became or stimulated the Polynesians, Harappans, Chinese, and others.
This is what we get when there is not enough critical science of human dispersals. We're not seeing history here, we're making it up.
And selling books.
Kreitman on human mtDNA selection
This is an old paper that I ran across today, a review of tests of selection with application to humans. Martin Kreitman is well known as a specialist in the population genetics of selection. The abstract says this:
Attempts to understand the nonequilibrium configuration of silent polymorphism in human mitochondrial DNA illustrate the difficulty of distinguishing between selection and alternative demographic hypotheses. The range of plausible alternatives to selection will become better defined, however, as additional population genetic data sets become available, allowing better null models to be constructed.
And the conclusion says this:
An instructive example of this problem lies in the interpretation of human mitochondrial nucleotide polymorphism. In a very insightful paper, Di Rienzo and Wilson reported that the genealogy of mitochondrial sequences in non-Africans was more starlike in shape than might be expected under neutrality and that the distribution of pairwise differences was Poisson shaped (20; also see 74). Di Rienzo interpreted this apparent departure from neutrality as an indication of recent population expansion. Theoretical treatment of the problem provided additional support for the expansion hypothesis (90), but a bottleneck at ~50,000 -- 100,000 years ago, possibly caused by the selective sweep of a favorable allele, could not be rejected.
Mitochondrial DNA has been assumed to be nonrecombining (but for evidence of recombination, see 4, 24); the sweep of a favorable mutation anywhere in the mitochondrial genome will cause the fixation of a single haplotype. Support for the selection hypothesis has come from the analysis of nuclear encoded genes. The nuclear genome shows little evidence for a skew towards rare alleles (18, 37, 38, 42, 83, 106), and thus towards a negative Tajima's D, as predicted under the population expansion hypothesis.
Theoretical investigation of bottlenecks and subsequent expansions (25) shows, however, that Tajima's D can be negative or positive depending on the size of the bottleneck and the timing and magnitude of an expansion. Given that the mitochondrial genome has a smaller effective population size (being maternally inherited and effectively haploid) than the nuclear genome, the conflicting portraits of polymorphism in the two genomes may be consistent with a population bottleneck (25). The exciting possibility of a selective sweep in the modern mitochondrial genome remains, unfortunately, an unresolved issue (Kreitman 2000:553).
I was happy to run across this reference that I previously missed, and so I'm posting it for others. It's good to read a review that appreciates the difficulties of detecting selection and distinguishing it from demography. The final paragraphs are sobering:
The only current safeguard against gross misinterpretation of test results vis-a-vis selection vs historical demography is to have an a priori hypothesis about the type and direction of selection that are expected for the locus under investigation. The previously described work on Duffy provides a good example of this approach (37). There are two reasons to hope, however, that the situation for analyzing human polymorphism data sets will improve. First, as additional data sets accumulate, a reduction in the number of plausible historical demographic scenarios will be possible. The specific range of parameter values, for example, allowing mitochondrial genes but not nuclear genes to differ in the observed frequency spectrum of mutations may be shown to be unrealistic. Second, population history, whether it involves ancient bottlenecks, recent expansions, or specific population movements, affects the polymorphism of all nuclear genes equally. From a practical perspective, this means that the common signatures of human history on genetic variation should yield to the avalanche of data expected in future polymorphism studies. Better data mining techniques and sharper theoretical predictions are needed, however, to make this a reality (Kreitman 2000:553-554).
It should be possible, in principle, to construct a realistic neutral model of human variation that takes into account major features of human history. Such a model would then serve as a null hypothesis, a selectively neutral backdrop, against which to look for evidence of natural selection in individual genes. In no other organism is this possibility likely to be achieved at the high level of resolution possible for humans. Our species, despite its low levels of nucleotide polymorphism, issues in ethical sampling of native populations, and the inability to control matings, may thus replace Drosophila species as the poster child for molecular population genetics.
On a positive note, I think he's right that humans have become the best model for considering the molecular correlates of microevolution. We clearly know much more about ourselves than we do about other species, and it is hard to ignore evidence for long-term regional or local selective pressures.
I wonder whether we are at a tipping point now, in 2005, compared to 2000. Have we reached the point where no single demographic hypothesis can explain both mtDNA and other genetic variation? Certainly we are, but there is more than that. Many autosomal genetic loci are inconsistent with each other in their pattern of variation. Selection has affected most areas of the genome in different ways. And some of those changes have been very recent.
On the one hand, there is nothing surprising about this, since we know that humans have been evolving and still are. On the other hand, the universality of selection is not necessarily something anybody expected to find. We may need to ask ourselves, is there anything that doesn't bear the mark of selection on some linked site?
References:
Kreitman M. 2000. Methods to detect selection in populations with applications to the human. Annu Rev Genom Hum Genet 1:539-559. Full text online
Playing games with dates
Two papers in the in the current (May 13, 2005) Science and an accompanying commentary focus on the mtDNA evidence relating to human dispersals into South and Southeast Asia. One paper, by Vincent Macaulay (University of Glasgow) and colleagues provides mtDNA sequences from aboriginal populations of the Malay peninsula.
Here's the abstract:
A recent dispersal of modern humans out of Africa is now widely accepted, but the routes taken across Eurasia are still disputed. We show that mitochondrial DNA variation in isolated "relict" populations in southeast Asia supports the view that there was only a single dispersal from Africa, most likely via a southern coastal route, through India and onward into southeast Asia and Australasia. There was an early offshoot, leading ultimately to the settlement of the Near East and Europe, but the main dispersal from India to Australia 65,000 years ago was rapid, most likely taking only a few thousand years (Macaulay et al. 2005:1034).
The second paper, by Kumarasamy Thangaraj and colleagues, covers the mtDNA variation of Andaman Islanders. The abstract is less informative; here's the conclusion:
Our data indicate that two ancient maternal lineages, M31 and M32 in the Onge and the Great Andamanese, have evolved in the Andaman Islands independently from other South and Southeast Asian populations. These lineages have likely been isolated since the initial penetration of the northern coastal areas of the Indian Ocean by anatomically modern humans, in their out-of-Africa migration 50 to 70 thousand years ago. In contrast, the Nicobarese show a close genetic relation with populations in Southeast Asia, suggesting their recent arrival from the east during the past 18 thousand years (Thangaraj et al. 2005:996).
Nicholas Wade has an article about the paper in the New York Times. Here's a great exchange:
There is no evidence of modern humans outside Africa earlier than 50,000 years ago, said Dr. Richard Klein, an archaeologist at Stanford. Also, if something happened 65,000 years ago to allow people to leave Africa, as Dr. Macaulay's team suggests, there should surely be some record of that in the archaeological record in Africa, Dr. Klein said. Yet signs of modern human behavior do not appear in Africa until 50,000 years ago, the transition between the Middle and Later Stone Ages, he said.
"If they want to push such an idea, find me a 65,000-year-old site with evidence of human occupation outside of Africa," Dr. Klein said.
Of course, there is no chance whatsoever that a 65,000 year genetic date is significantly different from 50,000 years. Both the current papers follow a long and dishonorable tradition of not providing any confidence interval for their date estimates. Both papers do provide standard errors -- without explanation, they report different standard errors for the same clades -- but standard errors do not say anything about the real uncertainty in the age estimates. It is not all that easy to figure out what the full range of uncertainty in the estimates may be, since it owes not only to the distribution of uncertainty in coalescence times (which is assymmetrical and skewed toward the high end) but also in uncertainty coming from assumptions like the human-chimpanzee divergence time and adequacy of the sampling scheme. Based on the standard errors alone (ranging around 7,000 years for the clade ages related to the "dispersal"), the 63,000 year date is not significantly different from 50,000 years. The true range of uncertainty is probably far greater.
Now, why wouldn't a reader of the papers know anything about this range of uncertainty? Not only do the papers not report confidence intervals in the text, but also the entire presentation of the data is relegated to the supplementary information online, which for both papers is substantally longer than the text. These are not just data tables, but relatively full literature reviews (as full as they get for these papers) and methods sections. This is a disturbing new trend for Science: reporting only results in the journal, and putting the information necessary to evaluate the results into a secondary source. What if you are asked by a reporter to comment on an article, and they send you an embargoed draft? You don't know enough about the paper even from the full text to evaluate it.
I've been thinking today about "media packaging" of research results, and this strikes me as a pretty stark example. Two papers on a single theme, packaged together with a commentary. Both of the papers make relatively cautious (although not cautious enough in my estimation) interpretations; the commentary is more daring. Media reports focus on the issue raised in the commentary, quoting other scientists who haven't seen enough of the research to be informedly critical. Good science reporters know enough to be skeptical; look where the preceding exchange goes:
Geneticists counter that many of the coastline sites occupied by the first emigrants would now lie under water, because the sea level has risen more than 200 feet since the last Ice Age. Dr. Klein expressed reservations about that argument, noting that people would not wait for the slowly rising sea levels to overwhelm them but would build new sites farther inland.
Dr. Macaulay said genetic dates had improved in recent years, now that it is affordable to decode the whole ring of mitochondrial DNA, and not just a small segment.
But he said he agreed "that archaeological dates are much firmer than the genetic ones" and that it was possible his 65,000-year date for the African exodus was too old.
So in other words, there's no result here. But this only applies to the young end of the range of dates for possible "Out of Africa" migrations -- the end that Richard Klein has been so active in examining. There is no word at all about the older end of the time range in any of the articles, commentaries, or press reports. But just as there is no chance these dates aren't significantly different from 50,000 years, there is likewise no chance they are significantly different from 80,000 years, or probably even 100,000 years. Let's cover the scenario for the initial Out-of-Africa colonization:
The very similar ages of haplogroups M, N, and R indicate that they were part of the same colonization process [see (23)]. This most likely involved the exodus of a founding group of several hundred individuals (27) from East Africa, some time after the appearance of haplogroup L3 85,000 years ago, followed by a period of mutation and drift during which haplogroups M, N, and R evolved and the ancestral L3 was lost. Although the details of this period remain to be elucidated, the next stage is much clearer. The presence in each region of the same three founder haplogroups, but differentiated into distinct subhaplogroups, indicates that there was a rapid coastal dispersal from 65,000 years ago around the Indian Ocean littoral and on to Australasia (Macaulay et al. 2005:1036).
Thus, the initial timing of this putative migration is bounded on the lower end by the 65,000 year dates, and on the upper end by the 85,000 year estimate for haplogroup L3. The standard error on this estimate as reported in the supplementary information is 8,400 years, which means that this date could easily be 20,000 or more years higher than it is. So an ancestry by Skhul and Qafzeh is not excluded by these analyses, either. But the paper does not even raise this issue. More strikingly, the commentary puts the two facts in adjacent sentences without adding them together:
Early humans even ventured out of Africa briefly, as indicated by the 90,000-year-old Skhul and Qafzeh fossils [HN9] found in Israel. The next event clearly visible in the mitochondrial evolutionary tree is an expansion signature of so-called L2 and L3 mtDNA types in Africa about 85,000 years ago, which now represent more than two-thirds of female lineages throughout most of Africa. The reason for this remarkable expansion is unclear, but it led directly to the only successful migration out of Africa, and is genetically dated by mtDNA to have occurred some time between 55,000 and 85,000 years ago (Forster and Matsumura 2005:965).
Ignoring this one, the paper leaves us with these options:
Three possible hypotheses can be distinguished using these data. If modern non-Africans are descendants of populations that dispersed along both northern and southern routes, then mtDNA lineages belonging to relict populations (including Orang Asli, Papuans, and Aboriginal Australians) should diverge from founder types that are distinct from those leading to the main continental Eurasian groups. If there were just a single dispersal, then all non-African populations should diverge from the same set of founders, which would coalesce to 45,000 to 50,000 years ago if the Levantine corridor model were correct, or 60,000 to 75,000 years ago if they were all the result of the proposed earlier single southern route (4). At this time, a northern passage was most likely blocked by desert and semi-desert (26) (Macaulay et al. 2005:1035, citations therein).
Okay, hmm...let me get this straight: modern humans had uber-technology to float across the Red Sea, kill mammoths, and outcompete every archaic human in every ecology they had occupied for a half million years or more, but they couldn't manage to move in 10,000 years across a semi-desert? And let's not forget the "modern" humans that get thrown under the bus in this scenario -- Skhul, Qafzeh, Liujiang -- either they don't qualify as "really" modern, or they've been misdated. Oh, and, there is the slight problem that no other locus provides any evidence of this pattern of population movement -- even the Y chromosome -- and many are not consistent with it.
There is a strategy to deal with these evidentiary problems:
Firm archaeological age estimates are more recent [more ancient dates are simply disregarded in this paper] -- 50,000 years for Australia and ~45,000 years for southeast Asia -- but early evidence may have been lost to sea level rises. Moreover, human populations may then have diffused from the coast into the continental interiors more gradually, leaving a greater archaeological signature on the landscape as they grew in size (Macaulay et al. 2005:1036).
This is always possible, but it can't be a good sign when your hypothesis depends on the same logic as the aquatic ape theory.
A short word about the bottleneck
From the commentary:
One intriguing question is the number of women who originally emigrated out of Africa. Only one is required, theoretically. Such a single female founder would have had to carry the African L3 mtDNA type, and her descendants would have carried those mtDNA types (M, N, and R) that populate Eurasia today. Macaulay et al. use population modeling to obtain a rough upper estimate of the