I'm getting a lot of hits this month on a post from last year, "The amazing talking Neandertals". Don't know why....
There have been a couple of really informative papers in the last month about Neandertal genetics, I'll see if I can't get some information up about them soon.
On Edge, Svante Pääbo has a long and interesting narrative about Neandertal genetics, FoxP2 mice, his own biography, and everything else. Nothing new to be had, but much interesting background about old stuff.
How can I resist quoting this passage?
Probably the most likely thing was that this was introduced at 454 at the same time they were sequencing Jim Watson — I wouldn't be totally surprised if we tried to investigate this and there was some slight mixture of Jim Watson with the Neanderthal sequence there.
Poor Watson -- his DNA has been everywhere!
And why paleoanthropologists have such big arguments:
As an outsider to paleontologists, I'm often rather surprised about how much scientists fight in paleontology. And I am thinking about why that is the case. Why do we have less vicious fights in molecular biology, for example? I suppose the reason is that paleontology is a rather data-poor science. There are probably more paleontologists than there are important fossils in the world. To make a name for yourself is to find a new interpretation for those fossils that are extant. This always goes against some earlier person's interpretation, who will not like it very much.
Yes, I'm sure it's true. But you have to admit we have better taste in wine.
Fed up on hobbit news? Well, I'm going to do my best this week to scoop the science journalists, covering stories in paleoanthropology that ought to get some more attention but might be drowned out by otherwise hobbitrocious stories.
I'll start with a story in which I have a special interest -- a new paper by Jeff Wall, Kirk Lohmueller, and Vincent Plagnol, titled, "Detecting ancient admixture and estimating demographic parameters in multiple human populations."
A couple of years ago, Wall and Plagnol (2006) looked at a sample of genes in the "Environmental Genome Project. At that time, the sample consisted of 135 genes in 12 Yoruba and 22 CEPH individuals. It's not a large sample by today's 3.9-million genotype standards. But the EGP sample has one important thing going for it -- with resequencing data, we have access to a much larger number of mutational differences at very small map distances from each other. Tight linkage between sites means that we can use the genealogical properties of samples to examine much more ancient events. The HapMap gives us a vast number of genotypes from a large sample of individuals, but the density of loci is quite low -- an average of nearly 1000 base pairs between loci. The EGP doesn't sample as many loci, but it gives a denser representation of the variation at each locus. Only this kind of sample is sufficient to test for genetic ancestry of modern human populations in ancient populations of the Middle Pleistocene.
Plagnol and Wall applied a simple admixture model to these data, and found that the complete out-of-Africa replacement model did not adequately explain the variation in the European-derived sample. Instead, they found that a model with 5 percent admixture of some non-African Middle Pleistocene ancestral population was a much better fit for the current diversity of European gene trees. In other words, the low variation of recent humans cannot be explained by a small population in a single ancient population; instead, there must have been several populations, partly isolated from each other, one or more of which gave regionally-specific alleles to modern Europeans. Multiregional evolution fits those observations very well -- this is not one or two introgressive genes, and there is no specific evidence of selection on them (although selection may be responsible).
A number of people picked up on that study in the course of later work. Gregory Cochran and I discussed it in our own 2006 paper about genetic introgression. In late 2005, Dan Garrigan and colleagues had published their own analysis of a pseudogene region on the X chromosome, called RRM2P4. Garrigan reviewed this work together with Mike Hammer (2006) and again with Sarah Kingan (2007). Early last year, I also reviewed the evidence together with Cochran, Henry Harpending and Bruce Lahn (2008).
We and many other people are following up on this research, trying to discover the ancestry of human populations beyond the simple out-of-Africa replacement scenario. In the new study, Wall and colleagues extend their analysis to a more recent release of the EGP, including 222 genes, and adding 24 Chinese individuals to the 12 Yoruba and 22 CEPH individuals. It's a simple paper and relatively short. In a word, they find that their data reject the simple out-of-Africa replacement scenario, and that the genetic variation of coding genes in their sample must be explained in part by long-standing population structure.
It's not proof that the Neandertals, or any other particular group of ancient humans, survived and passed their genes on to more recent people. This is a study of the genes of recent human populations, and it merely concludes that their ancestors could not have lived in a single small population. Maybe every Neandertal became extinct, and present-day Europeans got this genetic variation from somewhere else. But it is logical to figure that non-Afircan populations may have been among the contributors to present non-African peoples -- particularly since the statistical test focuses on region-specific gene frequencies. The study also finds evidence that today's African population has a complex ancestry -- a kind of multiregional scenario playing out inside Africa (or potentially involving gene flow back into Africa from elsewhere).
Wall and colleagues reasoned that an allele coming in from an ancient, partially isolated human population would vary in a distinctive pattern. Because of the long history of partial isolation in an ancient subpopulation, they expected that such an allele would come in with multiple mutational differences from the non-introgressive allele. And if it came in from some non-African population, it ought to show relatively strong differences in frequency between populations. So they devised a statistic, mathematically combining FST and a linkage measure -- the idea being to detect alleles that differentiate populations and that are surrounded by large sets of tightly linked polymorphisms.
This kind of pattern might also occur under positive selection. But a new mutation under positive selection would start out weakly linked to nearby polymorphisms, each of which already exists at some substantial frequency in the population. An introgressive allele might be linked to several other unique mutations that happened during the long period of limited gene flow between ancient populations. And a new mutation would not tend to be surrounded by high FST polymorphisms, until it got to be very common in the population -- up above 50 percent. In contrast, an introgressive allele coming into the population with several nearby mutations would generate a cluster of relatively high FST polymorphisms even at low frequencies. It may not be a perfect test for any individual locus -- there's a lot of uncertainty. But applied to more than 200 loci, it should be possible to test the hypothesis that "archaic admixture" is zero.
Wall and colleagues do test that hypothesis, and they are able to refute it strongly for each of the three groups. Living European and Chinese samples refute the out-of-Africa replacement model with p<0.01. The Yoruba sample refutes the hypothesis of panmixia in ancient Africans at p<0.0000001.
The authors also provide a supplementary table with a list of genes that may be candidates for introgression. I didn't see any really obvious genes on the list, but each of them bears some examination. I expect that we will be able to use more detailed analytical techniques to look at the regions around these genes and see what is going on. Or at least, in the next couple of years more and more resequencing data will become available, allowing us to test the same hypotheses with larger samples.
It's worth pointing out that nothing in the approach of Wall and colleagues implies that any of the putative introgression occurred under natural selection. I've argued that introgression may have occurred under selection in ancient humans, but so far few other people have looked at the question with the idea of ancient selection in mind. No doubt we can improve a bit on the methods in the paper if we are willing to make some assumptions about the evolutionary dynamics involved in Late Pleistocene populations.
So what's not to like about this study? After all, here we have what appears to be strong evidence against an exclusive out-of-Africa replacement. It suggests that the ancestry of recent Europeans and Asians owes something to the Middle Pleistocene populations of those regions, and gives an estimate of that contribution consistent with what we know so far about the Neandertal genome.
But I have to approach this study as critically as I would any other piece of population genetics. In this case, there is a clear weakness to their model. The authors tested for significance of a single parameter, which they call "archaic admixture." Consider their Figure 1, a schematic of their population model:
Is "archaic admixture" significantly different than zero? Well, you can see that must depend on the values of no less than six other parameters. When did the European population start growing significantly -- was it after the Last Glacial Maximum? During the Neolithic? The Aurignacian? How about the African population? Was there really a long bottleneck in the ancestry of Europeans?
The reason why I'm so critical of population models used in genetics is simple. The authors of studies almost never try to make the simplest effort to justify these kinds of parameters against the archaeological or fossil record. Their conclusions -- in this case, the significant finding of ancient admixture -- depend on some range of values for these other parameters.
Now, Wall and colleagues take a fundamentally different approach than I would use. I would draw upon non-genetic sources of information about these parameters, to increase confidence about the others. In contrast, they performed a broader range of simulations, attempting to find maximum likelihood estimates for all the parameters simultaneously.
The problem with that approach is that it's hard to say that some other parameters may not have been more important. Consider recent positive selection. As I mentioned above, a recent positively selected mutation could in principle create a pattern like that described for an introgressive allele -- at least under the statistics used in this paper. The chances are low for any randomly chosen mutation under positive selection, because a new positively selected mutation isn't likely to be linked to other rare mutations -- it's much more likely to be linked to common polymorphisms. But if we actually have many hundreds, or even thousands, of recently selected alleles (as we do in humans), then there is a pretty good chance that some of them will look like introgression under the test used here. Another scenario that could mimic introgression under this statistical approach is long-standing balancing selection.
There are probably too many genes on these lists for all of them to reflect selective balances or recent positive selection -- there are a lot of recently selected genes, but few of them will have the specific kind of linkage that would show up as significant in this study. But I think the authors could do more to validate the demographic model against non-genetic evidence. Besides that, there is plenty of morphological evidence for gene flow among these ancient human populations. The authors would be well-served to work more directly with the morphological record of human evolution -- when they write that:
To our knowledge, the question of ancient admixture in other parts of the world has been relatively neglected by the evolutionary genetics community
it is both true and sad. There is abundant anatomical evidence addressing the issue of genetic continuity or gene flow in parts of the world other than Europe.
UPDATE (2009-05-08): Dienekes also looks at the paper, and suggests that finding evidence for ancient population structure in Europe and East Asia may be no big deal, because it may simply derive from population structure within Africa before the putative out-of-Africa migration. I'd have to review the data to be sure, but it seems to me there are two arguments against that explanation:
1. The East Asian and European comparisons come up with different genes showing evidence of putative introgression. There's not a lot of overlap between the sets. If this were merely ancient East African genes, we'd expect the populations outside Africa to have the same ones. And the numbers had actually been cut down by the serial founder effect scenario (Chinese having undergone more and larger bottlenecks), then we'd expect China to have a subset of the European introgressive genes. I wouldn't go out on a limb about this without looking at the actual frequencies of the supposed ancient alleles, but the pattern isn't consistent with Europe and China being drawn randomly from the same ancient African population.
2. The entire point of the out-of-Africa replacement idea is to draw humans from an unstructured ancient population. Humans have to be inbred to explain the low genetic variation today. A long bottleneck in Africa is one explanation for this inbreeding -- but the bottleneck has to have been severe, down to an effective size around 10,000, and it has to be very long. A long history of population structure within Africa works against that bottleneck -- population structure featuring several partially isolated populations would prevent the kind of inbreeding that a long bottleneck could create. If Wall and colleagues are correct, we would have to scrap the long bottleneck idea and come up with some other explanation for high inbreeding. There are some others, as I've pointed out before.
There are other arguments against exclusive continuity outside Africa, and in favor of some significant -- perhaps overwhelming -- gene flow from Africa into the rest of the world during the late Pleistocene. But no other argument is exclusive of some continuity outside Africa. And if we don't need the bottleneck anymore, accepting some continuity is the reasonable explanation for the facts that don't fit, including the observations in this paper and the morphological and archaeological evidence suggesting continuity.
Evans PD, Mekel-Bobrov N, Vallender EJ, Hudson RR, Lahn BT. 2006. Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage. Proc Nat Acad Sci doi:10.1073/pnas.0606966103
Garrigan D, Kingan SB. 2006. Archaic human admixture: A view from the genome. Curr Anthropol 48:895-902. doi:10.1086/523014
Garrigan, D., Mobasher, Z., Severson, T., Wilder, J. A., Hammer, M. F. 2005b. Evidence for archaic Asian ancestry on the human X chromosome. Mol. Biol. Evol. 22:189-192. doi:10.1093/molbev/msi013
Hardy, J., Pittman, A., Myers, A., Gwinn-Hardy, K., Fung, H. C., de Silva, R., Hutton, M. and Duckworth, J. 2005. Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens. Biochemical Society Transactions 33:582-585.
Hawks J, Cochran G. 2006. Dynamics of adaptive introgression from archaic to modern humans. PaleoAnthropology 2006:101-115. Open access
Hawks J, Cochran G, Harpending HC, Lahn BT. 2007. A genetic legacy from archaic Homo. Trends Genet doi:10.1016/j.tig.2007.10.003
Plagnol, V., Wall, J. D. 2006. Possible ancestral structure in human populations. PLoS Genet. 2:e105. doi:10.1371/journal.pgen.0020105
Wall JD, Lohmueller KE, Plagnol V. 2009. Detecting ancient admixture and estimating demographic parameters in multiple human populations. Mol Biol Evol (early online) doi:10.1093/molbev/msp096
Zietkiewicz, E., Yotova, V., Gehl, D., Wambach, T., Arrieta, I., Batzer, M., Cole, D. E., Hechtman, P., Kaplan, F., Modiano, D., Moisan, J. P., Michalski, R., Labuda, D. 2003. Haplotypes in the dystrophin DNA segment point to a mosaic origin of modern human diversity. Am. J. hum. Genet. 73:994-1015.
For most of their prehistory, humans were highly mobile hunter-gatherers. We can expect that Neandertals were also highly mobile, at least compared to sedentary post-agricultural human populations. Great apes are our closest living relatives, but they live in tropical forests -- a pretty different environment than the Neandertals. There are constraints on ape mobility, including difficulty of locomotion, habitat complexity, and extreme territoriality, that might not have constrained ancient humans, including Neandertals.
We might then consider the population structure of other highly mobile large mammals. Brown bears have been sympatric with humans in Europe since the Middle Pleistocene. Bear ecology has similarities and differences from Neandertals -- bears were omnivores accentuating meat consumption to a similar extent, but did not live in groups. Like Neandertals they may have exploited edges between habitat types, although brown bears are effective in open country as well.
For bears, like other European mammals, one of the most important questions is what happened to their population during the Last Glacial Maximum (LGM). The LGM was only around 18,000 years ago, so it's not an issue for Neandertals who were long gone by that time. But because the LGM is relatively recent, we have a relatively large representation of bear mitochondrial genetics spanning that time interval. So it gives us a chance to look at the relationship of population structure and genetic diversity in a large, mobile, European mammal. The bear comparison also lets us consider the effects of a smaller sample on our conclusions about ancient population structure and dynamics.
Brown bears are very common in archaeological and subfossil paleontological faunal lists. During the LGM, brown bears are known from northern Spain and Moldova. Evidence from today's bears suggests the occupation of at least four refugia (Sommer and Benecke 2005) -- basically Iberia, Italy, the Balkans and the Carpathians. These four areas can be expected to have housed substantial diversity during the LGM. The subsequent recolonization of northern Europe may be the largest factor organizing the present pattern of genetic variability, with the differential expansion of lineages through space.
Taberlet and colleagues (1998) collated phylogeographic evidence from 10 European species, ranging from plants to large mammals and including brown bears, to trace the likely pathways of postglacial recolonization of Europe. They found evidence for the importance of three refugia -- basically Iberia, Italy, and the Balkans. But most interesting, they found that each of their 10 species showed different patterns of postglacial expansion dynamics.
It seems that each taxon has responded independently to Quaternary cold periods, and therefore is largely a unique case with its own history. For example, if we compare lineages present in Italy and in the Iberic peninsula, they are closely related in Ursus (less than 1% of sequence divergence in the cytochrome b gene) but much more distantly related in Crocidura (6.4%), in Arvicola (7.6%) and in Triturus (8.5%), while the Sorex species considered here exhibit two lineages in each of these two refugia. Populations occurring in France come either from a refugium in the Iberic peninsula (e.g., Arvicola sapidus, Triturus marmoratus), or from a refugium in the Balkans (e.g., Chorthippus parallelus, Fagus sylvaticus).
...[T]he results obtained in Europe and North America (Zink 1996) suggest that congruence is the exception at the continental scale. The consequence of an independent history for each taxon is that assemblages of plants and animals comprising particular communities are not stable over time, an observation consistent with previous findings based mainly on fossil pollen data (Bennett 1990) (Taberlet et al. 1998:459).
Before going on to cite their conclusion, I want to note one possibility that they don't consider -- namely, that the species have similar dynamics of range constriction and expansion but that the mtDNA evidence represents these dynamics with substantial variance.
One aspects of that study stands out as interesting as applied to the Neandertals. Although the species did not share any single pattern of expansion from refugia, one aspect was shared: species did not expand from Italy. The authors speculated that the Alps are an effective barrier to rapid recolonization of northern Europe from Italian refugia, and indeed most northern species were recolonized either from Iberia or from the Balkans, or both. Thus Italy today contains many endemic lineages that were stuck in Italy during the LGM or other contractions, and never left. The possibility of an Italian-Croatian population of Neandertals was raised by Fabre and colleagues (2009). Was recolonization from this population possible during warmer phases of the Pleniglacial? If not, this population of Neandertals may have been exceptionally variable -- containing many long-standing endemic variants compared to other Neandertal populations. It may also have been substantially divergent from those other populations. Since Vindija is the most important source of the Neandertal genome, it's an important aspect of biogeography to try to understand.
So much for the general pattern of recolonization. Now back to brown bears.
Sommer and Benecke (2005:161) considered further the present population of European brown bears and likely refugia in southern Europe. They returned to the genetic data developed in earlier studies by Taberlet and colleagues to conclude:
It is possible to detect three different glacial refugia from their data: (i) the Iberian Peninsula (Spain), (ii) the Italian Peninsula and (iii) the Balkans (Bulgaria/Greece). Furthermore, the investigation into the mitochondrial DNA of brown bears in Europe (Taberlet & Bouvet, 1994) shows four main points:
1. The individuals of southern Scandinavia originated from the Iberian Peninsula are closely related to the individuals from the Balkans and the Italian Peninsula, and form a 'western lineage'.
2. The bears of northern and eastern Scandinavia, from the Baltic States, from north-western Russia and the Carpathians differ with a sequence divergence of 7.13% from those individuals in the western lineage (Fig. 5).
3. Based on their genetic similarity, the brown bears from northern and eastern Scandinavia, the Baltic States, and north-western Russia are designated as 'eastern lineage' and a glacial refuge in eastern Europe is assumed to be the origin of this genotype (Hewitt, 1999).
4. Within the mitochondrial DNA of brown bears from the Carpathians, three different genotypes can be identified, whereas the genotype of bears from north of the Carpathians (Slovakia) is distributed throughout bears from Norway, Finland, the Baltic States and north-western Russia (Fig. 5).
They used these observations to argue for a refuge in the Carpathians during the LGM, which seems eminently reasonable based on their observations.
They did not point out (but I will add) that the expansion from an Iberian refugium toward Scandinavia mirrors the pattern of expansion of Magdalenian assemblages after the LGM. The recent literature has described this as a slow and tentative process of expansion (e.g., Jochim et al. 1999), but it was nonetheless as fast or faster than accomplished by small mammals, and may have mirrored the movements of the Magdalenians' large mammal prey animals. That human movement may also explain the distribution of mtDNA haplogroup H in Europe, which Pereira and colleagues (2005) attributed to a post-glacial recolonization from Iberia northeastward. This is not a new idea; Cavalli-Sforza wrote about this direction of postglacial migration some 30 years ago.
Later, Sommer and Nadachowski (2006) extended the map of refugia to take in more species, using faunal records from LGM archaeological sites. The map below helps to put these observations into context:
Figure 2 from Sommer and Nadachowski 2006. The position of Last Glacial Maximum archaeological sites is noted. The faunal lists from these sites provided the data underlying the inference of LGM refugia. I would point out that it seems not unlikely that a large mammal species like a bear might move in significant numbers across this entire range.
The possible ranges of human occupation and mammal refugia seem very extensive across southern Europe but are not necessarily contiguous. For example, the Alps form a partial barrier around the northern part of Italy, and the Pannonian Basin might partially cut off from Italy/Dalmatia as well. But it's not hard to imagine a large mammal like a bear (or a human) traversing the distances between such refugia, or walking along corridors between them such as the coasts.
We have to remember that the interpretation of semi-isolated refugia has been based on the pattern of genetic variation in living species in Europe. But geographic differentiation need not only have occurred because populations were once fragmented during glacials. Differentiation may also be a product of range expansion, selection, or later interaction with other species, including humans. Today's differentiation is not necessarily a trace of refugia in the past.
So it becomes important to test the hypothesis of semi-isolated refugia, by looking at the variation of ancient DNA sequences. Last year, a study by Valdiosera and colleagues did exactly that -- looking at new sequence data from a larger set of brown bear subfossil remains from Iberia.
Here's a paragraph from the discussion of that paper:
Under traditional glacial refugia hypotheses (4, 17), the extant brown bear phylogeographic structure derives from ancestral glacial refugia: the western lineage originating from Iberia, Italy, and the Balkans, and the eastern lineage possibly derived from a Carpathian refugium (14, 16). In contrast to such a strict refugial model, but in concordance with a continuous European prehistoric population, we have identified a sequence from a Pleistocene Iberian brown bear from Arlanpe site (the Basque country) that belongs to the eastern clade. In our analyses, such a phylogenetic assignment is supported by maximal posterior probabilities (Fig. 1 A). This pattern is further supported by three Pleistocene brown bear sequences from Valdegoba (northern Spain), which cluster with a previously published sequence from Atapuerca (northern Spain) and with several sequences from modern Italian and Balkan bears. Furthermore, AMOVAs suggest little geographic substructure among Spanish and European Pleistocene populations. These new data confirm the lack of phylogeographic discontinuity in European brown bears before the LGM (23). Although Spanish and European Holocene populations appear geographically differentiated in our AMOVAs, a recent study has suggested that gene flow could have continued from the Pleistocene to the Holocene (20). An Iberian brown bear, dated to the time of the LGM from the site of Atapuerca in Burgos in the north of Spain, was more closely related to Italian/Balkan bears than to the Iberian ones. Moreover, during the Holocene in Mont Ventoux (southern France) three mitochondrial groups are found between 1,570 to 6,525 years B.P.: one belonging to the Iberian group, another one to the Italian/Balkan one, and yet a third one not associated with any of the three main glacial refugia (20). Note, however, that support for the Spanish and the Italian/Balkan clades are low in our tree. In this study, we have found three different individuals from Valdegoba, a Late Pleistocene site also in Burgos, that group together with the sample from Atapuerca (Valdiosera et al. 2008: emphasis added).
I think this study is so interesting because of the way it shows the influence of sample size on the phylogeographic interpretation. Consider how the conclusions of the study would have been different if the sample had been smaller. The authors found one Iberian Pleistocene bear that belonged to a clade otherwise comprising bears from Austria, Germany and Russia. This one bear is their clearest indication of ancient movement between plausible refugia. Had they not found a sequence in this bear, the evidence favoring two distinct refugia would have been much stronger.
Likewise, their sample includes three bears from Pleistocene France that belong to a clade of their own. This diversity no longer exists among today's bears -- at least, not the ones sampled up to now. If this region of France happened not to have produced bear remains, we would not have any evidence of this divergent clade at all. Again, the record would suggest that present bears derived from two largely isolated refugia. As it is, either another French refugium existed or the Pleistocene Iberian population harbored more diversity than present bears of Iberia.
That last element, a reduction of diversity over time, is also suggested by the pattern of variation between Pleistocene and Holocene bear remains. It has a lesson for the interpretation of human variation -- some human mtDNA haplogroups have reduced in frequency in recent Europeans, others have apparently increased. In the case of humans, we may be looking at selection. Brown bears have had a smaller effective size than humans during the last 10,000 years, so we might be looking at an actual reduction in numbers or geographic range.
In any event, with the bears every additional sample carries information about ancient population structure. We can expect that the addition of more Neandertal mtDNA samples will likewise add information about Neandertal population structure. The addition of samples is more likely to confuse a simple story than to confirm it, although either is possible.
Valdiosera and colleagues conclude that brown bears were actually highly mobile during the LGM, moving easily across a range that, although limited compared to earlier and later time periods, extended from east to west across southern Europe. It's hard to believe that Neandertals weren't capable of similar movement. On the other hand, chimpanzees are likely capable of long-distance movement but still have substantial population differentiation. This may be because intervening groups prevent individuals from moving long distances. So the dispersal character of Neandertal populations may have depended upon their social dynamics, an aspect of behavior that we are poorly situated to test.
Pereira L and 12 others. 2005. High-resolution mtDNA evidence for the resettlement of Europe from an Iberian refugium. Genome Res 15:19-24. doi:10.1101/gr.3182305
Sommer RS, Benecke N. 2005. The recolonization of Europe by brown bears Ursus arctos Linnaeus, 1758 after the Last Glacial Maximum. Mammal Rev 35:156-164. doi:10.1111/j.1365-2907.2005.00063.x
Sommer RS, Nadachowski A. 2006. Glacial refugia of mammals in Europe: evidence from fossil records. Mammal Rev 36:251-265. doi:10.1111/j.1365-2907.2006.00093.x
Taberlet P, Fumagalli L, Wust-Saucy A-G, Cosson J-F. 1998. Comparative phylogeography and postglacial colonization routes in Europe. Mol Ecol 7:453-464. doi:10.1046/j.1365-294x.1998.00289.x
Valdiosera CE and 10 others. 2008. Surprising migration and population size dynamics in ancient Iberian brown bears (Ursus arctos). Proc Nat Acad Sci USA 105:5123-5128. doi:10.1073/pnas.0712223105
There's a new paper in PLoS ONE by Virginie Fabre, Silvana Condemi and Anna Degioanni, titled "Genetic evidence of geographical groups among Neanderthals." I think this is an ambitious paper -- it uses 12 mtDNA sequences recovered from Neandertal fossils to compare different phylogeographic scenarios for Neandertal populations.
The authors applied several different models to the data, attempting to find a population history that matches the geographic distribution of mtDNA diversity in Neandertals. They found that a model in which Neandertals had been part of three long-standing geographic populations was a better fit than others. Here's the relevant part of the abstract:
In this paper we used a new methodology derived from different bioinformatic models based on data from genetics, demography and paleoanthropology. The adequacy of each model was measured by comparisons between simulated results (obtained by BayesianSSC software) and those estimated from nucleotide sequences (obtained by DNAsp4 software). The conclusions of this study are consistent with existing paleoanthropological research and show that Neanderthals can be divided into at least three groups: one in western Europe, a second in the Southern area and a third in western Asia. Moreover, it seems from our results that the size of the Neanderthal population was not constant and that some migration occurred among the demes.
I like the study, and I have no strong objections to the conclusion. It has always seemed sort of likely on morphological grounds that Neandertals may have had modest geographic differentiation. Amud 1 doesn't look like a French Neandertal; nor does Teshik Tash. So I'm inclined to think the results are not too surprising.
Still, the data have some big weaknesses. Phylogeography is a tall order when we only have 12 sequences.
Many have pointed out, going back to McCown and Keith (1939), that time is another possible cause of morphological differentiation of Neandertals. The mtDNA sequences cover a wide range of times -- the Scladina sequence comes from roughly 100,000 years ago, the others cover the span from 50,000 down to 29,000 years ago. Why not test temporal groups instead of geographic groups? Temporal clusters might reflect interglacial colonizations, differential gene flow, or natural selection. There is a good precedent -- last year a report of complete mtDNA sequences from woolly mammoths found evidence for geographic structure among mtDNA lineages, one of which apparently replaced the other (Gilbert et al. 2008).
Time is just one example of an alternative model for variation. But I think it helps to clarify the basic problem of the a priori models -- you have to draw boundaries between the specimens somewhere. In the current paper, Fabre and colleagues divided the samples into one, two, or three groups. The one-group model amounts to a simulation of panmixia. The other models are a little like the setup of a Bayesian STRUCTURE analysis -- how well does the sample fit a model in which the the latter as the more likely null hypothesis.
But unlike STRUCTURE, in this case, each specimen had to be assigned deliberately to one group or another. That's why the authors generated three different versions of their three-group model -- in each version, the boundaries between groups were drawn in slightly different places.
That's not a criticism of the paper; it's just an inherent property of the method. There's no better way to come up with boundaries of the groups, and I've done similar things in earlier work. It's rational to have the groups contiguous with respect to geography, but without clear isolating barriers, no special reason why the groups should be bounded along any particular line.
In this case, one of the three-group models provided a substantially better fit between simulated data and the observed mtDNA sequences. So the paper concludes that three groups are supported.
Thinking about it, I would probably use the data to test a slightly different set of hypotheses.
I would start with an analytical approach, explicitly testing the hypothesis of panmixia; then explicitly testing isolation-by-distance. Panmixia should be easy to refute -- if you don't then phylogeography is a non-starter. I see isolation-by-distance as the appropriate null hypothesis, and while the time-dispersion of the samples makes life a little more complicated, a simple test of IBD would be straightforward. I don't expect you need simulations for either of these tests, although you could use simulations to explicitly include the ages of the specimens in the test.
One reason to start with IBD is that the specimens are heterogeneously distributed through space. Since there are some large gaps in the geographic distribution, the observed sequences may tend to clump into groups even if no real boundaries between groups existed. The best-supported model in the paper divides the sample with a clump of Italian and Croatian specimens, a large gap between Ukraine and Uzbekistan, and most of the specimens in one large group. That looks like a pattern that might be consistent with IBD, complicated by the actual ages of the specimens.
At any rate, the conclusion in the paper should make one set of people nervous: those who think that Paleolithic archaeological industries reflect populations. I can't see any obvious alignment between these three "groups" of Neandertals and well-known cultural units at any time interval. There are some localized and relatively long-lasting industries or variants within the boundaries of some groups, and there are others that span the boundaries.
Now, if these groups really reflect long-standing population boundaries -- spanning some 100,000 years in the model -- then we might expect it would have been hard to exchange information across them.
The same should have been true of Africa, which I've mentioned shows evidence for population differentiation going far back into the Late Pleistocene if not earlier. In Africa, the MSA shows both long-standing variations in different regions and relatively rapid temporal fluctuations within regions. The same general picture holds for the Mousterian, although one may argue whether the correspondence is exact. In any event, the African regional variants show no obvious correspondence to the genetic differentiation of African populations today. Maybe that's because of subsequent changes in the African population -- today's differences don't necessarily reflect those of MSA populations.
But suppose we take the Neandertal model seriously. Information transfer in living people occurs on a much more rapid timescale than genetic exchange. That cannot always have been true in human evolution -- it isn't generally true of other primates, where long-distance information transfer basically depends on the transfer of individuals from their natal groups. What should an intermediate stage look like, in which the amount of information transfer may be less than in recent human groups (with writing, accounting and vastly more people), but the pace of transfer may have been comparable? I doubt they would correspond well to genetic populations over much longer timescales, although they may be limited by them to some extent.
I raised the question in my class today. If these really are groups of Neandertals, occupying different geographic ranges for a hundred thousand years, what do we call them? I thought it was a good lead-in to talk about species concepts in paleoanthropology, and of course it is.
If these aren't species, why aren't they? Presumably because we think that genetic exchanges across this range would have been likely. You can test the hypothesis by comparison with living humans and other primates. Mitochondrial phylogeography of human populations includes some long-standing population structure going back more than 60,000 years. Within great apes, there are long-standing subspecies that go back much further, hundreds of thousands of years. In humans, we tend to call the resulting groups races or populations. Among great apes, we tend to call them subspecies.
So are these subspecies of Neandertals? Races? Geographic populations? I wouldn't interpret further without really determining the nature of the boundaries here. As I mentioned earlier, I think the null hypothesis is isolation-by-distance. It's conceivable that the Neandertal population was patterned in a similar way to recent humans -- although considering our rapid recent evolution, I wouldn't be quick to assume that human differentiation is a good model.
One other thing. Let's assume that the Neandertals really were differentiated from each other, and that the groups proposed by Fabre and colleagues are generally right. In that case, the Neandertal Genome Project has been concentrating on an individual from the Southern subpopulation, a subpopulation otherwise very far the population interface between Neandertals and other humans before 45,000 years ago. Hence, that sequence may be a bad place to look for evidence of interactions between Neandertals and modern humans. Genetic exchanges are more likely to have happened across long-standing areas of contact -- which in Fabre and colleagues' best model, would likely involve the Western or Eastern subpopulations.
That's entirely speculative on my part, but it does seem to be one implication of the model.
Fabre V, Condemi S, Degioanni A. 2009. Genetic evidence of geographic groups among Neanderthals. PLoS ONE 4:e5151. doi:10.1371/journal.pone.0005151
Gilbert MTP and 32 others. 2008. Intraspecific phylogenetic analysis of Siberian woolly mammoths using complete mitochondrial sequences. Proc Nat Acad Sci USA 105:8327-8332. doi:10.1073/pnas.0802315105
I want to point people interested in recent human evolution to a new book, The 10,000 Year Explosion: How Civilization Accelerated Human Evolution.
The authors, Gregory Cochran and Henry Harpending, are good friends of mine, and I have worked with them on some of the material covered in their book. So, you can hardly expect me to give an unbiased review!
However, I have now heard from a number of people not connected to the authors, who have read the book and enjoyed it. So it's not just me.
T. J. Kelleher reviewed the book in SEED, bringing out several interesting points:
Cochran and Harpending also find value in such work [as the Genographic Project], but they argue for a fuller appreciation of the geographic distributions of genes, and in doing so, they herald a new era not only in biological anthropology, but also for history. They do not stop with what information about human history can be found in the genes, precisely because many gene variants are not neutral. Where the usual geographical analysis treats the distribution of genes as an effect of history, in Cochran and Harpending's view, the genes themselves are a cause: Two variants in the same gene do not necessarily have the same effect, and the relative selective advantages and disadvantages of them will — not surprisingly, to anyone versed in evolutionary biology — influence the movements of genes through populations over both space and time.
That's a very ambitious agenda. On the way there, the book covers several topics of great interest to me. Naturally recent evolution by natural selection, particularly in post-agricultural populations, comes to the fore. The possible introgression of genes from Neandertals, as another source of possible adaptive variation in recent human evolution, also gets a chapter.
With this background in place, Cochran and Harpending explore some hypotheses that may link the distinctive histories of human groups to recent genetic changes and exchanges. One is the expansion and dispersal of Indo-European languages, a series of events that anthropologists have tried to connect to a jumble of different factors, ranging from conquering hordes of steppe nomads to conquering hordes of Anatolian farmers. Cochran and Harpending suggest that pastoralism and the resulting population growth connected to milk consumption was the prime mover.
Another hypothesis connects the psychometric literature on Ashkenazi Jewish people to some of the distinctive genetic disorders common in that population, such as Tay-Sachs disease, Gaucher disease, torsion dystonia and others. In a nutshell, Cochran and Harpending suggest that natural selection for general intelligence has occurred during Ashkenazi history, resulting in a distribution of IQ between 0.5 and 1 standard deviation above the European mean.
I can just imagine many readers twisting in their chairs when reading this chapter. And they should: relying upon both documentary evidence and whole-genome surveys of variation Cochran and Harpending puncture several myths about Jewish history, psychometrics, and admixture of populations. In the past, human geneticists have been all-too-willing to believe completely bogus scenarios of population history. The idea that Ashkenazim underwent a severe and prolonged population bottleneck, completely isolated from the surrounding European population, is one of the most pernicious of these scenarios. Cochran and Harpending's hypothesis, that alleles causing sphingolipid storage disorders were positively selected in Ashkenazi populations of the last 1500 years, is plausible and certainly testable. Plausibly, these alleles may have been selected for their roles in some other function, although none suggest themselves. The bottleneck theory, on the other hand, is not plausible, refuted by both the historical record and the genomic variation of living people of Ashkenazi descent.
I found the book to have a good combination of humor, interesting anecdotes, and description of new science. I've read most of the recent popular books about human evolution or genetics. To me, this one stands above the others. Maybe that's because I'm already thinking hard about the central proposition -- indeed the subtitle -- that "civilization accelerated human evolution." Like I said, I'm hardly unbiased.
But I think it's mostly more fun than most other genetics books. Some science writers cover their tentative approach to genetics by using dark, brooding prose. This book doesn't suffer from ponderosity, and its organization helps -- divided into dozens of little stories with odd historical facts, it's the kind of book you can stash in your bag for bus rides.
UPDATE (2009-02-19): I wanted to mention that Cochran gave a wide-ranging interview about the book to 2blowhards.
I had fun reading the interview because Cochran's suffer-no-fools attitude toward purely speculative ideas about recent evolution. He's looking for testable ideas, not mere generalizations. My favorite quote, with reference to an idea about behavior and mythological characters:
I think this line of analysis is about as sound and solid as Citibank.
Harpending also makes an appearance worth quoting, referring to the question of how much of the book is scientifically established and how much is speculative:
The basics are secure -- population genetics, demography, history, etc. But there are certainly a number of hypotheses we have that are not solidly established. But that is the way science works. If something were rock solid it would be widely known and would be too boring to talk about in the book. We don't spend a whole lot of time for example on malaria defense polymorphisms.
We really hope to see our hypotheses tested, maybe modified, maybe falsified, or not. We don't believe them in any strong sense. Whenever you read a scientist who is deeply committed to his or her ideas, hang on to your wallet!
I was out of town last week when the Max-Planck Institute made its announcement about the completion of 1x coverage of the Neandertal genome. It was an exciting day for me. Already, I had scheduled a number of radio shows and a public lecture to commemorate Darwin Day. Several press interviews regarding the news of the Neandertal sequencing project added to the hectic nature of the day, so I didn't get a chance at the time to sit down and write my reactions.
So, nearly a week later, I've finally caught up. I've answered many questions about the Neandertal genome before, so I'm focusing these on the current announcement.
For answers to other kinds of questions, try these posts:
And now, some new questions arising this week:
No. This announcement is a milestone, not an endpoint.
Much remains to put together an entire genome sequence. The ongoing work represents a massive technical achievement, and is well worth celebrating. But we are not yet at the point where we can talk about structural variants in the Neandertal genome compared to humans, length polymorphisms, or a number of other things. Plus, as noted below, only 63 percent of the nucleotides have been sequenced once -- leaving a lot of basic sequencing left to get even a single pass over the whole genome.
Some stories have used the term "decoded" -- that also would be a misstatement. We don't know the import of the variations that might so far have been found. That is, we cannot yet convert the information that Neandertal sequences provide to us about their genome into information about their phenotypes. Keeping that in mind, "decoding" the human genome is an ongoing process. With the Neandertals, we have barely begun.
They set up an announcement when they knew they would be past sequencing 3 billion bases. And in fact they've reached 3.7 billion.
That would be more than the whole genome, if they could pick out exactly which parts they are sequencing. But the shotgun sequencing approach they are using means that some parts of the genome are represented several times in their 3.7 billion bases, while others are not represented all.
It's sort of like painting your house. You could calculate how many gallons it would take for "full coverage" with a paintbrush, but if you shoot that many gallons out of a paint gun there are going to be a lot of gaps that didn't get painted.
For the Neandertal sequence right now, the gaps add up to around 36 percent of the whole genome. Which is an awful lot of missing data.
So why make an announcement now? I dunno. Darwin's birthday makes a good occasion? They could easily have published last year or the year before on many different genes, just as they published the whole mtDNA last year. It seems likely to me that they've been holding off announcing or publishing until they were sure they had worked out a solution to the contamination problems they were having.
I think they deserve to pop some champagne bottles and celebrate. When there is a public data release, we can all celebrate!
If you've been around a while, you'll remember that I thought the initial report of contamination was a bit overblown. Nevertheless, the possibility of substantial contamination, documented by comparisons between sequencing methods, stopped almost all work on the publicly available data. It was a serious problem, and the research groups responded seriously to the presence of contamination in the samples. Few details of this response were made public, but clearly there was a concern that the longer fragments coming out of the 454 machine didn't originate in the Neandertal sample.
According to the Max-Planck press release, they've taken a number of steps to eliminate contamination. I'll quote the relevant sections:
One essential element developed by Pääbo’s group was the production of sequencing libraries under “clean-room” conditions to avoid contamination of experiments by human DNA. They also designed DNA sequence tags that carry unique identifiers and are attached to the ancient DNA molecules in the clean room. This makes it possible to avoid contamination from other sources of DNA during the sequencing procedure, which was a problem in the initial proof-of-principle experiments in 2006. They also used minute amounts of radioactively labeled DNA to identify and modify those steps in the sequencing procedure where losses occur. Together with other advances implemented during the project, these innovations drastically reduced the need for precious fossil material so that less than half a gram of bone was used to produce the draft sequence of 3 billion base pairs.
In order to reliably compare the Neandertal DNA sequences to those of humans and chimpanzees, the Leipzig group has performed detailed studies of where chemical damage tends to occur in the ancient DNA and how it causes errors in the DNA sequences. The researchers found that such errors occur most frequently towards the ends of molecules and that the vast majority of them are due to a particular modification of one of the bases in the DNA that occurs over time in fossil remains. They then applied this knowledge to identify which of the DNA fragments from the fossils come from the Neandertal genome and which from microorganisms that have colonized the bones during the thousands of years they lay buried in the caves. They have also developed novel and more sensitive computer algorithms to put the Neandertal DNA fragments in order and compare them to the human genome.
I'm satisfied that they've done everything possible to eliminate contaminants. The examination of the chain of events from extraction to the final sequence is especially important. In many ancient bones, the steps taken to sterilize and extract from deep within the bone somehow still don't eliminate contamination in the final sequence data. Most of that contamination must arise during the processing and sequencing steps, despite the oft-quoted "clean room" conditions in ancient DNA labs. So the methodological advances toward understanding the sources of contamination are very scientifically significant.
There's a hint in some of the earlier press coverage that the pace of sequencing has vastly sped up in the last few months. For example, in December, Ewen Callaway reported that the genome was halfway done:
Half the Neanderthal genome has been decoded and the rest should be sequenced by year's end, a scientist involved in the project told a human evolution conference last week.
Researchers will roll out a rough draft of the Neanderthal nuclear genome after their sequencers have read every letter in the genome on average once - "1x coverage" in genomics speak.
Callaway is a careful reporter, but we should keep in mind that the comments in the story might not quite have conveyed the full situation. Still, if we take that assessment at face value, we can speculate that the process of working out the contamination issue took a long time during which sequencing was relatively slow or paused. If they actually had only sequenced half the 3 billion bases by December, that's pretty fast work since then (a perception that was echoed in some press reports prior to the announcement).
The switch to the Illumina platform seems like an underreported aspect of the story. The press release claims that a billion reads were done on the Solexa, compared to only 100 million from 454 -- that also suggests a switch later in the process, since we know that they were using 454 initially and through early 2008. The press release doesn't explain why they moved from the 454 machine to Illumina. Maybe it's just efficiency of the current platform, but there must be a story there.
I was talking to a reporter on Tuesday before the press conference, and I said,
"They're no doubt going to give us a list of some genes, with well-known variations in living people, that they've genotyped in Neandertals. And, aside from FoxP2, which we already know about, and microcephalin, I don't know what those will be. I think it would be the most boring possible outcome if they told us that the lactase persistence allele wasn't there. Because there's no news there.
Well, I gave a big belly laugh when I saw the press release. Gee, Neandertals didn't have lactase persistence. Big surprise there! What did they think, they were secretly milking goats?
OK, I admit, that's overly snarky. I mean, what if they'd found the opposite? It would be contamination, of course. So finding the wild-type lactase allele is worth something.
But it's sort of like if your friend was looking through a telescope on Christmas Eve and caught the first-known glimpse of Santa and his reindeer. And you asked her, "What does he look like?" And she says, "He's wearing a red coat!"
It's like being trapped in a Laurel and Hardy routine. And I'm Hardy.
Experts on Neandertal bone morphology can readily distinguish them from later Europeans, assuming that the correct parts of the skeleton have survived. So from that perspective, Neandertals were clearly a "distinct" population. They had a morphological configuration no longer found anywhere in the world, and not found in the Europeans who immediately followed them in Europe.
On the other hand, the bones of early Upper Paleolithic Europeans share some interesting similarities with the Neandertals. You wouldn't call the Oase 1 cranium a Neandertal. It lacks nearly all of the features that set Neandertals apart. But it has a mandibular foramen shaped like a small horizontal oval -- like a bit over half of Neandertals, and nearly a quarter of early Upper Paleolithic mandibles. This is a very rare morphology today, and it is rare elsewhere in the human fossil record, although it has been found in the very early Homo erectus sample from Dmanisi. There are two hypotheses for why this feature and others should be most common in two populations living in the same place in adjacent time periods: descent or parallel evolution.
Looking only at the morphology, we have only our personal limit of credulity to argue one way or the other. How many features does it take to be convinced that descent must explain some of the similarities? Sadly, the answer to this question is different for different researchers.
I think that the most reasonable explanation for the morphology is gene flow between Neandertal and other populations. But I have to say that others disagree.
Genetic evidence may be most useful because we are much more likely to agree on the score. A unique gene sequence is unlikely to arise twice in parallel, and in any event the probability of such parallelism can be calculated in real numbers, not shopworn guesses. With 3 billion base pairs to compare between our populations, we have a good chance of finding and quantifying even low levels of genetic exchanges.
However, these conclusions still depend on assumptions and models that not all anthropologists agree about. At the moment, the state of the science is such that the meaningful distinction is not whether Neandertals and humans may have interbred, but instead whether such interbreeding was common enough to be evolutionarily important, or to establish Neandertals as a "distinct" population. Since "important" and "distinct" do not have quantifiable meanings in evolutionary theory, you can see that we have a long way to go before paleoanthropology agrees on testable models of Neandertal population history.
I think the science will be lively for the next few years, as the focus goes away from details of morphological characters and toward details of evolutionary models. The morphology will still remain important -- particularly as the observable evidence of variation within ancient populations. It will take many years before we have a good picture of genetic variability within these samples. But questions of "distinctness," which depend on shared characters and levels of interbreeding, must be answered at the level of models, not features.
According to the press conference, the human-derived allele of MCPH1 was not found in the Vindija sequence. Bruce Lahn and colleagues had suggested that this allele might have come into the recent human population from Neandertals, based on its present pattern of variability. This allele is quite divergent from the rest of human variation at the locus, it is common outside of Africa but rare inside of Africa, and it appears to have been under positive natural selection for around 30,000 years. I have an FAQ on MCPH1 and introgression, and I've published on the topic. If the human-derived allele is not in the Neandertal genome, that obviously weakens the argument for introgression of this gene from Neandertals.
We have interpreted this gene cautiously from the beginning. Neandertals are one likely source for such introgression, but not the only one. In my FAQ, I wrote this:
Well, the D haplogroup [of MCPH1] is common in many areas outside of Africa in addition to Europe. So it isn't possible to really specify in what archaic population it may have originated. There is some chance that it may be found in the Neandertal genome sequence, when that becomes available. In fact, that would be the ultimate test for many candidate introgressive alleles.
But there is a good chance that it won't be found in the Neandertal sequence. After all, Neandertals were probably pretty thin on the ground -- especially in Europe. A sampling of their genes would be sort of unlikely to yield a high proportion of archaic alleles that may have survived to the present day. So there is hope that we will find and document such alleles, but the best evidence for many of them may remain their current pattern of variation in living people.
I think those points are important. There were not many Neandertals, and it may be much more likely for present-day humans to have genetic variation that originated in South or West Asia, or even multiple regions of Africa (a hypothesis suggested for some other gene loci).
But I still think it very likely that out of the 20,000 genes in the human genome, some will have derived variants that were also present in the Neandertal genome. Human evolution over the last 50,000 or more years was driven by new variation, and multiple human populations would have been one of the largest potential reservoirs of adaptive variation for selection to work upon.
Paleoanthropology is a science that generates huge public interest. But it gives very few chances for public participation. Those of us who are close to paleoanthropology know how much our science is driven by good ideas from many other fields. The pathways by which those insights enter our science tend to be highly constrained -- radiocarbon dating, scanning electron microscopy, isotopic analysis of enamel, and now genetics have all been brought into paleoanthropology by extremely skilled scientists from outside the field. I think that the Neandertal genome has the potential of breaking new ground.
One year from now, there will be high school students working with sequences from the Neandertal genome. Who knows what they will discover?
I just think that is tremendously exciting. For the first time, the primary data of paleoanthropology will be available to everyone.
Friday morning, I got back to teaching after my trip this week. So I filled my students in a bit about the Neandertal genome. One of them had been reading the news, and noticed several stories seemed to obsess over the chance that Neandertals would someday be cloned.
So she asked, "Is that something that you anthropologists sit around talking about?"
Well, naturally I couldn't give away any professional secrets....but in this case I can honestly say I've never sat at the meetings, even after several beers, and discussed cloning Neandertals with other anthropologists.
Not unexpectedly, this led to a short but animated class discussion about the ethics of Neandertal resurrection. I pointed out that some people are morally opposed to mammoth cloning, on the logic that we have to provide a full habitat for them, rewilding the American prairie. And even more think it unethical to bring a Neandertal baby into the world -- even disregarding the current inefficiencies of cloning. But some students found that thoroughly unconvincing.
One who was unconcerned by the plight of the Neandertal baby nevertheless thought that the necessary mixture of Neandertal genes and human (or chimpanzee) oocytes was an ethical problem.
Meanwhile, apparently just at the time I was discussing this little ethical conundrum in class, John Tierney was posting about it (Why Not Bring a Neanderthal to Life?). Well, why not indeed?
But I’m afraid I can’t see the problem. If we discovered a small band of Neanderthals hidden somewhere, we’d do everything to keep them alive, just as we try to keep alive so many other endangered populations of humans and animals — including man-biting mosquitoes and man-eating polar bears. We’ve also spent lots of money reintroducing animals into ecosystems from which they had vanished. Shouldn’t be at least as solicitous to our fellow hominids?
... If our species disappeared and a smarter species took over the planet, I’d take the offer to be resurrected just on the theory that being alive beats being dead.
Naturally, that drew a whole lot of comments -- many inane, but some give an interesting cross-section of peoples' base assumptions about Neandertals. In response to Tierney's last question, the first commenter wrote:
Sure, I would too. But would you choose to have this smarter species create a virtual great-grandchild, who you would never meet or interact with, who you would have no opportunity to pass on any knowledge or wisdom or kinship to, who would live a life essentially as lab animal and historical exhibit? I would not.
One was more sanguine:
Yet, the hunger gatherer culture [sic] of the humans we label Neanderthal is truly dead –not hidden in genes. We will find out once we bring them back that Neanderthal will fully enjoy sitcoms, buy T shirts, and go shopping. In fact, with their bigger musculature and bigger brains, they are sure to find many a willing partner in match.com.
From one who doubts that Neandertals are internet dating material:
Mr. Tierney, if you knew with 100-percent certainty — before conception — that a pregnancy would lead to a severely mentally challenged human, would you think it “nifty” and a “gift” to bring to life such a hypothetical child? I see no difference between your proposal and giving a deliberate lobotomy to a newborn.
I won't carry this on any further, but I find the exercise revealing. Some respondents want to bring them back to be lab animals for pharmaceutical testing, others think they will have as-yet-unknown powers. A few suggest that Neandertals are walking around us now; others think that we'd better be ready for female Neandertals that go into heat.
My favorite, spinning off the "Dame Edna" high-pitched Neandertal voice idea, suggests that we may find a new Steve Perry.
Tierney and others have given the price of Neandertal cloning as $30 million. As far as I can tell, that's just a wild-ass guess. But since I happen to be looking at a Geico ad right now, I would say that the price has to drop before there's likely to be a corporate sponsor. How about $6 million?
I will say one thing, in all seriousness. Someday not too far from now, we will have the technology to add genes to chromosomes in human embryos, or to generate human embryos with artificially constructed chromosomes. On that day, the Neandertal genome will already be published and freely available. And there will be nothing to stop someone from generating an embryo with as high a fraction of Neandertal genes as desired.
I can easily imagine the Abraham Lincoln genome, or the Mozart genome, or the Einstein being published. Once they are published, what would stop potential mothers from birthing baby Einsteins, or baby Lincolns?
Is it really such a stretch from a baby Lincoln to a Neanderbaby?
Rex Dalton reports that Svante Pääbo's presentation at the AAAS meetings next week will have a little surprise:
Project leader Svante Pääbo will announce the results of the preliminary genomic analysis at the American Association for the Advancement of Science annual meeting in Chicago, Illinois, which starts on 12 February.
"We are working like crazy at the moment," says Pääbo, adding that his Max Planck colleague, computational biologist Richard Green, is coordinating the analysis of the genome's 3 billion base pairs.
...
Pääbo says that his group will publish a first draft of the entire Neanderthal genome later this year, as a single read of all base pairs. However, some published human genomes had all their base pairs read eight to ten times before publication. The team says that its single-read of the Neanderthal genome is sufficient for publication because the technique used does not rely on the same DNA reassembly process used in conventional 'shotgun' sequencing.
Three billion base pairs. Perhaps 4000 amino acid substitutions between them and us, and an unknown number of regulatory changes. There are likely to be some surprising similarities, as well as many surprising differences.
We're going to have plenty of work.
Anyway, the story doesn't specify what will be new about next week's announcement. I'm sure there will be some surprises.
If your goal is to make cross-species hybrids, there is this problem to contend with:
NEW YORK (AP) — It may be futile to try producing stem cells by putting human DNA into cow or rabbit eggs and making hybrid cloned embryos, a strategy that triggered controversy recently in Britain, a new study says. The animal eggs don't reprogram human DNA in the right way to generate stem cells, researchers report.
"Instead of turning on the right genes, it turns out the animal eggs actually turn them off," said senior study author Dr. Robert Lanza of Advanced Cell Technology in Worcester, Mass.
Cows and rabbits are pretty far off -- 140 million years or so of evolutionary separation might well have changed gene regulation in early embryogenesis so that the chemical signals in a donor egg wouldn't work with a human genome. Other hominoids would be less likely to generate problems. Of course, egg cells from rabbits are easier to come by than egg cells from gorillas.
I'm more interested in the far-off possibility of cloning an extinct hominid. Would a Neandertal genome in a human egg lead to similar incompatibilities?
There are a few lines of argument against it. For one thing, the combination of paternal and maternal genetic material in fertilized eggs doesn't tend to generate such incompatibilities between closely related mammals. The very fact that we see interspecific hybrids is a clue that the mechanisms of early embryogenesis are conservative, with few changes that would interrupt development.
A complementary argument is that different groups of people living today are distantly related enough to have seen some such incompatibilities, if they were likely to happen. People in the world today are, on average, more alike than any living human and a Neandertal. But the total range of mutational variation today exceeds the average human-Neandertal difference for any given gene.
On the other hand, there are reproductive incompatibilities today between some individuals within populations. And we don't know whether interfertility is identical between every pair of populations. We often assume this, but who has carried out the experiment?
In any event, some kinds of genetic transfer will not work without being able to design custom cells. An egg cell that is not just taken out of a donor species, but is built to contain a specific array of signals, might avoid the problems with regulatory incompatibilities. Or it would give entirely new opportunities for epigenetic modification of genetic information.
