john hawks weblog

I covered this story earlier, here's a bit more (from Science Blog):

Researchers have found stronger evidence for a link between a parasite in cat faeces and undercooked meat and an increased risk of schizophrenia.

...

The researchers tested anti-psychotic and mood stabilising medications used for the treatment of schizophrenia on rats infected with T. gondii and found they were as, or more, effective at preventing behaviourial alterations as anti-T. gondii drugs. This led them to believe that T. gondii may have a role in the development of some cases of schizophrenia.

So (here's a reverse) they found that treating the neurological symptoms had the same effect as treating the infection. It reads like another iteration of the H. pylori-gastric ulcer connection, although they are careful to note that it can explain at best a fraction of cases of schizophrenia.

Hopefully the treatment will work on some people. The story says that clinical trials on humans have already begun.

I can't add much to this Guardian report:

Neanderthal man floated into Europe, say Spanish researchers

Spanish investigators believe they may have found proof that neanderthal [sic] man reached Europe from Africa not just via the Middle East but by sailing, swimming or floating across the Strait of Gibraltar.

Prehistoric remains of hunter-gatherer communities found at a site known as La Cabililla de Benzú, in the Spanish north African enclave of Ceuta, are remarkably similar to those found in southern Spain, investigators said. Stone tools at the site correspond to the middle palaeolithic period, when neanderthal man emerged, and resemble those found across Spain.

The paper is by José Ramos, but I haven't gotten a hold of it yet. The article discusses the fact that Iberia "has older examples of human remains" than other parts of Europe, so I assume the similarities are meant to indicate recurrent contact during the Middle Paleolithic. Hopefully we'll see.

There's a new paper in AJHG by Patin and colleagues, which is just chock full of interesting stuff. The genes studied are NAT1 and NAT2, called "N-acetyltransferase genes" (OMIM entry), and are involved in the metabolism of certain drugs and carcinogens.

For example, they detoxify some of the carcinogenic amines that result from grilling meat. Different alleles of the genes are involved in some harmful drug interactions, since they affect the rate of drug metabolism. In other words, these are the kinds of genes that people interested in "personalized medicine" are most interested in -- they help to determine the response to harmful environmental agents and outcomes to treatment.

Patin and colleagues (2006) studied the evolution of polymorphisms of the two genes. Here's a quick review of what they knew starting out:

Both genes carry functional polymorphisms whose effects on enzymatic activity have been well studied (Hein et al. 2000). Whereas the variants associated with reduced activity attain only low frequencies in NAT1, they constitute common polymorphisms in NAT2 (Upton et al. 2001). Two main classes of NAT2 phenotypes are therefore observed: the "fast-acetylation" phenotype, which refers to the wild-type acetylation activity, and the "slow-acetylation" phenotype, which results in reduced protein activity. In addition, NAT1 and NAT2 metabolize numerous common carcinogens, and variation in these genes can result in varying susceptibility to cancer (for a review, see the work of Hein [2002]). For example, the slow-acetylator NAT2 phenotype has been associated with side effects to the commonly used antitubercular isoniazid (Huang et al. 2002) and with higher risk for bladder cancer (Cartwright et al. 1982; Garcia-Closas et al. 2005). Nevertheless, most NAT2 mutations leading to the slow phenotype are found at high frequencies worldwide, calling into question the role of altered acetylation in human adaptation.

So, the polymorphism of NAT2 is a bit mysterious -- what advantage might the slow-acetylators have to keep them around?

They did the usual sampling on "geographically diverse samples" and a chimpanzee sequence to determine site polarities. A twist makes the study a bit more complicated than usual: the genes are physically close together, so an allele for NAT2 may be significantly correlated with an allele for NAT1, for example.

The paper finds good evidence for selection on NAT2 alleles. Different alleles in different populations appear to cause the slow-acetylator phenotype. One of these, mainly in Europeans (NAT2*5B) has a stronger phenotypic effect (i.e., slower-acetylation), and has the strongest signature of recent selection. They infer that this allele came under selection between 5800 and 7000 years ago.

The footprints of natural selection identified in western/central Eurasians raise the question of which event(s) may have provoked fluctuations in the spectrum of xenobiotics inactivated/activated by NAT2 (e.g., NAT2 activates heterocyclic carcinogens found in well-cooked meat [Hein et al. 2000; Hein 2002]) in these populations. In this context, given the geographic distribution of the slow-acetylator phenotype and the estimated expansion time of the slowest-encoding 341TC mutation (5,797Ð7,005 years ago in western/central Eurasians), it is tempting to hypothesize that the emergence of agriculture in western Eurasia could be at the basis of such environmental changes. Indeed, there is accumulating evidence that this major transition resulted in a profound modification of human diets and lifestyles (Cordain et al. 2005) and, consequently, in the exposure of humans to chemical environments (Ferguson 2002). Moreover, the highest frequencies of slow acetylators are observed in the Middle East (fig. 5), one of the first regions where agriculture originated 10,000 years ago, and these frequencies decrease toward western Europe, North Africa, and India, three regions where agriculture was subsequently diffused from the Fertile Crescent (Harris 1996). However, the hypothesis that the transition to agriculture influenced both the human exposure to xenobiotic environments and, consequently, the selective pressures at NAT2 remains tentative and requires a better characterization of the naturally occurring substrates of the NAT2 enzyme.

The story for NAT1 is even more interesting. The coding region as a whole is much less variable than NAT2. But there is a divergent haplotype, separated by 17 SNPs from the rest of the alleles, and found in only three individuals (in France, India, and Thailand). Patin and colleagues propose that the haplotype may represent ancient population structure, similar to the earlier study from last year by Garrigan et al. (2005). Here's the relevant section of the paper:

Purifying selection may not be the only evolutionary force that has influenced NAT1 diversity. Indeed, one of the most salient observations of this study is the highly divergent tree topology and high TMRCA (2.01 ± 0.29 MYA) of this locus (fig. 2). This binary pattern is translated into significant departures from neutrality in populations presenting the divergent haplotype NAT1*11A (see table 7 and results of the HKA test). The probability of finding such a high TMRCA under a Wright-Fisher model was found to be low (P = .029). Different hypotheses can be proposed to explain such long basal branches in the NAT1 gene tree. First, long-term balancing selection can result in divergent haplotype clusters, by maintaining two or more alleles over time, provided that they result in functional differences. Nevertheless, our data do not support this hypothesis, since the two nonsynonymous mutations separating the two clusters (fig. 2) have been shown to have no significant effects on the in vivo protein activity in human cells (Hein 2002) or on the stability and activity of the recombinant protein in yeast (Hughes et al. 1998). Any kind of selection due to a hitchhiking effect with neighbor genes is equally unlikely, because the two closest genes (ASAH1 located 5 and NAT2 located 3) behave as independent haplotype blocks (this study and the HapMap database). Furthermore, our sequence data from the NAT1 coding region are consistent with the action of purifying selection rather than balancing selection, with the first selective regime having a minor influence on tree topologies (Williamson and Orive 2002). Second, gene conversion could also lead to such divergent haplotype patterns by the replacement of a segment of NAT1 with a tract from its nearby paralogs (NAT2 and/or NATP). This alternative is unlikely, however, since the 17 SNPs separating the two divergent NAT1 lineages are not physically clustered (fig. 2) as one would expect after gene conversion between duplicated loci (Innan 2003). Thus, if gene conversion formed the basis of such a haplotype pattern, multiple conversion events must be invoked, with some tracts of lengths

In this view, an alternative and most likely scenario to explain our data is a demographic event such as ancient population structure. A number of studies have recently reported gene genealogies that present not only unexpectedly old coalescent times (2 MYA) but also long basal branches (Harris and Hey 1999; Webster et al. 2003; Barreiro et al. 2005; Garrigan et al. 2005; Hayakawa et al. 2005). Our observations at NAT1, together with these studies, further support the view that some diversity in the genome of modern humans may have persisted from a structured ancestral population (Harding and McVean 2004). In addition, NAT1*11A appears to be absent in sub-Saharan Africa, since it was not detected in either our genotyping panel of 144 sub-Saharan Africans from distinct geographic locations or 600 African American individuals reported elsewhere (Upton et al. 2001). Therefore, the observation that the NAT1 gene tree is rooted in Eurasia questions the geographic location of such a structured ancestral population (Takahata et al. 2001). The origins of NAT1*11A could thus be placed either in sub-Saharan Africa, from where it must have subsequently disappeared, or in Eurasia. Should the latter be the case, the NAT1 gene tree is at odds with the commonly accepted replacement hypothesis (Lewin 1987) and is more parsimoniously explained by the occurrence of partial hybridization between modern humans expanding from Africa and preexisting hominids in Eurasia, as recently sustained by the RRM2P4 locus (Garrigan et al. 2005). However, such inferences require further support from the analyses of multiple independent loci in increased numbers of samples and human populations.

And all this from some cooked meat genes.

References:

Patin E et al. 2006. Deciphering the Ancient and Complex Evolutionary History of Human Arylamine {N}-Acetyltransferase Genes. Am J Hum Genet (online early) Full text

Not much to do but link to this and wait for the paper to appear:

[Jean-Pierre] Bocquet-Appel and anthropology graduate student Stephan Naji analyzed skeletal remains in 62 prehistoric North American cemeteries.

They found that the number of immature skeletons increased by 37 percent over a 600-to-800 year period that coincides with the adoption of farming in North America about 2,500 years ago.

...

The baby-boom pattern has been observed in African and European cemeteries dating about 5,000 to 7,000 years earlier, according to Bocquet-Appel. This period also coincides with the shift in those regions from foraging to agriculture at the end of the Stone Age.

The current (February 2006) issue of AJPA carries an article by Craig Stanford describing the context of bipedal posture for chimpanzees in the Bwindi Impenetrable National Park. When considering how bipedal locomotion evolved in early hominids, it is an essential comparison how chimpanzees (or other hominoids) use bipedal postures. Stanford writes:

As Hunt (1994, 1996) pointed out, hypotheses for the advent of bipedalism that involve behaviors in which prehominids may have frequently engaged offer the most plausible explanations for the adaptive shift from quadrupedal to bipedal posture (Stanford 2006:225).

Stanford was able to observe a large number of episodes of bipedal posture in the study group -- 179 cases in 247 observation hours. I find the context to be the most interesting result:

All 179 instances of bipedalism were recorded while chimpanzees were foraging in large trees. All but one instance occurred as postural rather than locomotor bipedalism, and 96% of all instances occurred in a feeding context....Chimpanzees appeared to forage bipedally most often when feeding in the upper portion of the crown, reaching up to branches emergent in the sunlight, and perhaps containing harder-to-reach ripe fruit. (Stanford 2006:227).

Studies of bipedal posture in wild chimpanzees have been rare, as Stanford reviews, but have typically found fewer instances of bipedality and have included some terrestrial cases. The key finding of all studies appears to be that foraging for fruit is the main reason why chimpanzees occasionally stand.

What do the chimpanzees tell us about early hominids? Here is the suggestion:

The behavior of wild chimpanzees suggests that several aspects of the positional behavior of earliest hominids may have been given less attention that they merit. First, arboreal bipedal posture is not dichotomous with arboreal quadrupedal posture. Bwindi chimpanzees moved fluidly between four-legged, three-legged, and two-legged postures while feeding in tree crowns. Their use of three-dimensional space in tree tops incorporated elements of positional behavior most often seen as binary states. This fluid quadrupedal-bipedal shifting may have occurred in the earliest hominids as well. Arguments about whether early hominids were fully adapted to bipedal walking, or facultatively arboreal, have been carried on for at least three decades (Susman et al., 1984; Lovejoy, 1988). Recent evidence suggests that knuckle-walking may have been employed by the immediate ancestors of the australopithecines (Richmond and Strait, 2000). Chimpanzee bipedal behavior suggests that early hominids likely engaged in a fluid variety of positional behaviors and postures, but provides little evidence for the adaptive advantage of terrestrial knuckle-walking in the last common ancestor of apes and humans (Stanford 2006:230).

Now, humans are fully adapted to bipedal walking, and we are facultatively arboreal (that is, we can climb trees), so there is no reason to think that early hominids were less facultatively arboreal than we are, and I would venture that they were probably a good deal more so.

The fundamental question about early hominids is why they abandoned the ability to be facultative quadrupeds. That is something that chimpanzee positional behavior isn't going to tell us -- after all, chimpanzees take on bipedal posture in ways that don't compromise their quadrupedal abilities.

The chief importance of the chimpanzee comparison is to illustrate the kinds of ways that locomotor diversity occur in hominoids. After a brief discussion of locomotor flexibility in gorillas, Stanford concludes with this:

Rose (1984) argued that there is no reason to view the origin of bipedalism as a progression from "poor biped" to "good biped." Instead, there was likely a diversity of forms of bipedalism in the earliest hominids. One such hominoid example may be Oreopithecus bambolii, a sup-
posed bipedal ape (Kohler and Moya-Sola, 1997). The bipedal evidence from Bwindi, Mahale, and Gombe supports this view of early hominid evolution. Instead of viewing the earliest bipedal adaptation as the lowest
rung on a posture/locomotion evolutionary ladder, it may be that early hominid species evolved a variety of forms of bipedalism in particular ecological contexts (Stanford 2006:230).

I guess that is one possibility to explain evidence of vertical posture in early hominids in the absence of good evidence of bipedality (from postcranial evidence).

The "diversity of forms" argument really suggests a stage during early hominid evolution when the ability to be effective quadrupeds had not yet been lost. Perhaps we will find these quadrupedal hominids. Perhaps we already have. On the other hand, this idea opposes the hypothesis that locomotor evolution may have either caused the origin of the hominid lineage or very closely followed it.

It seems to me that the level of species diversity of early hominids and this locomotor problem may be strongly linked. But I think they might be linked in the opposite direction than one might assume.

Suppose, for instance, that the hominid lineage arose as an adaptive radiation resulting from a significant new adaptation for bipedality. The "adaptive radiation" would be the origin of many new bipedal species spreading and adapting to different ecologies. Early hominid species diversity would be a consequence of their novel locomotor adaptation.

In contrast, if hominids originated as one among many quadrupedal apes in the Late Miocene, they might well have adapted over a long time as quadrupeds within a single ecology to which they remained limited. Perhaps the attainment effective bipedality would have spurred an adaptive radiation, but this event would have followed long after the origin of the hominids. Hominid species diversity might have always been low, or might have remained low until the Late Pliocene.

Now I don't think any of these arguments can be taken very far. It is always possible that bipedality arose early without any consequent adaptive radiation, or that there were multiple bipedal ape lineages other than hominids, or almost any other combination of events. There just isn't fossil evidence that could delimit hypotheses about hominid origins.

But I can't think about diversity without considering the mechanisms for it to have arisen. And while it is possible that many hominoid lineages were experimenting with bipedal posture and locomotion in diverse ways, I can't think of what would have caused the diversification of a large array of hominid species in the absence of bipedality.

References:

Stanford CB. 2006. Arboreal bipedalism in wild chimpanzees: Implications for the evolution of hominid posture and locomotion. Am J Phys Anthropol 129:225-231. Abstract

In 2003, Mead and colleagues (Full text) suggested that the prion protein gene (PRNP -- OMIM) in humans had been under long-term balancing selection in humans worldwide.

A mutant form of the prion protein is the agent the causes Mad Cow disease, Kuru, and other spongiform encephalopathies. Kuru is a disease that can be transmitted by cannibalism -- if you eat a person's flesh who has the disease, you can contract it yourself. Mead et al. (2003) give a good short review:

Kuru came to the attention of Western medicine in the 1950s as the affected area of the Eastern Highlands of Papua New Guinea came under Australian administrative control. The Fore and neighboring linguistic groups occupied a remote highland area that had had no direct contact with the outside world before this. It was the practice in these communities for kinship groups to consume deceased relatives at mortuary feasts. From the evidence of local oral history, this practice was not ancient among the Fore and is thought to have started around the end of the 19th century. The first remembered case of kuru was around 1920, and the disease rapidly increased in incidence. Adult women and children of both sexes were primarily affected, reflecting their selective exposure -- adult males participated little at feasts. At its peak, kuru killed around 1% of the population annually, and some villages were almost devoid of young adult women. Kuru was the first human prion disease shown to be transmissible, by inoculation of chimpanzees with autopsy-derived brain tissue (2). It is hypothesized that kuru originated from consumption of an individual with sporadic CJD (3), a disease with a remarkably uniform worldwide incidence of around 1 per million and a lifetime risk of around 1 in 50,000. The ban on cannibalism imposed by the Australian authorities in the mid-1950s led to a decline in kuru incidence, and although rare cases still occur, these are all in older individuals and reflect the long incubation periods possible in human prion disease -- kuru has not been recorded in any individual born after the late 1950s (4) (Mead et al. 2003:640).

A major polymorphism in humans at one nucleotide site of PRNP appears to give heterozygotes an advantage in resisting kuru, and homozygotes of one allele are the only people who have contracted "Mad Cow", or variant Creutzfeld-Jakob disease (CJD). So the hypothesis of balancing selection suggested that humans may have had a long history of Kuru or other diseases transmitted by prions. PRNP heterozygote cannibals would have been less susceptible to bad prions.

Kreitman and Di Rienzo (2004) noted a problem with the study: ascertainment bias. This article in The Scientist does a really good job of explaining the ascertainment bias problem.

However, in July 2004, [Martin] Kreitman and Anna Di Rienzo, also of the University of Chicago, published a criticism of the Mead et al. paper in Trends in Genetics, citing an ascertainment bias in haplotype sampling. Mead and colleagues sequenced the full PRNP gene in a few people of European ancestry, and then used the single nucleotide polymorphisms (SNPs) they discovered to genotype a larger, global population. But without resequencing every individual included in the final study, the authors likely biased their results toward common polymorphisms, the signature of balancing selection, Kreitman told The Scientist. "They had in fact excluded the low-frequency variants and only looked at the common ones -- and then came to the conclusion that there are too many common ones," Kreitman said.

Soldevila et al. (2006) sequenced a large sample to settle the issue of blancing selection:

Our analyses reveal the worldwide pattern of variation at the PRNP gene to be inconsistent with neutral expectations, indicating instead an excess of low-frequency variants, a footprint of the action of either positive or purifying selection. A comparison of neutrality test statistics for PRNP with other human genes indicates that the signal of positive selection on PRNP is stronger than expected from a possible confounding genome-wide background signal of population expansion. Two main conclusions arise from our analysis. First, the existence of an ancient, stable, balanced polymorphism that has been claimed in a previous study and related to cannibalism can be rejected and is shown to be due to ascertainment bias. Second, our results are consistent with a complex history of selection including mainly positive selection, even if short local periods of balancing selection (Kuru-like episodes), or even a weak purifying selection model, are consistent with our data (Soldevila et al. 2006:1).

OK, so no long-term balancing selection. The origin of the key coding variant (site 129) is inferred to have happened within the last 100,000 -- 200,000 years or so. There is not great resolution to the genealogy: there are two major variants (differentiated by site 129) and lots of minor ones branching off these two.

My hypothesis would be that both the major alleles came under positive selection at their origins. The first of these was variant S1, which is distinguished from the chimpanzee allele by an A at site 171. Two African haplotypes (S18 and S28) also have the G at 171, but coupled with the derived G at 129 -- this means that the presence of the presumably ancestral nucleotide must either be a recurrent mutation or a recombinant with an older haplotype not present in the sample. The selective sweep of this allele is complete. As S1 increased, it kicked off a few minor alleles, each of which differs from it at a single site.

Why do I think that S1 was not the ancestral haplotype? Mainly because it looks -- if anything -- more selected than the newer haplotype S2. The absence of any clear tree structure to the haplotypes with 129A just emphasizes that the allele hasn't been around that long. So if it was not ancestral, it was a substitution. This older allele is more common in the samples from Europe and East Asia, less so in Africa, West Asia, and America.

One of the variants kicked off of S1 was haplotype S2, with a G variant at site 129. This also came under positive selection upon its origin. It happened long enough ago to spread into all these populations, including America. It might be in selective balance, but that balance isn't very old -- it is recent enough that what we see is the increase in frequency of a new allele. That means that the variant might also be a simple positively selected allele with no balance or heterozygote advantage, at least in most populations.

The question is, what were these two variants selected for?

Phylogenetic comparisons show that PRNP is conserved in primates, with no excess of coding substitutions in humans. The comparison with the chimpanzee sequence emphasizes that: if the S1 haplotype was derived from a more ancient haplotype in humans, that would most parsimoniously be the chimpanzee haplotype itself, meaning that chimpanzees had no substitutions at all, and humans had none before the selection on S1.

So for a gene that had no coding changes in humans or chimpanzees, why would there recently have been two successive selected changes in humans?

For a highly conserved brain-expressed gene, why would there recently have been two successive selected changes in humans?

Hmmm....

References:

Kreitman M, Di Rienzo A. 2004. Balancing claims for balancing selection. Trends Genet. 20:300-304.

Mead S et al. 2003. Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science 300:640-643. Full text (subscription)

Soldevila M et al. 2006. The prion protein gene in humans revisited: Lessons from a worldwide resequencing study. Genome Res epub. Abstract

I mentioned last month that the January issue of Discover had a list of the top 100 science stories of 2005 along with a short writeup about each. Now the magazine has put all the archaeology-related stories online for free.

They include the Mexican footprints (are they or aren't they?), the use of multispectral imaging to read faded papyri, the attempts to decode Incan khipus (knot patterns), the discovery of ancient Thracian goldwork, an artifact-looting bust, and of course the continuing Homo floresiensis carnival.

The Boston Globe has a story about geneticist George Church and his quest to bring whole-genome sequencing below $1000.

Church knew that a key to making gene sequencing fast and affordable lay in miniaturizing the process. He coats a slide with millions of microscopic beads, each impregnated with chemicals that light up when exposed to DNA base pairs. A digital camera fitted to a microscope photographs the pattern, and software decodes the results. His process is more than 250 times faster than conventional technology. In short, rather than take seven years to sequence the human genome, Church's machines can theoretically do it in less than a week. He says "theoretically" because he and his students have only decoded the DNA of E. coli, which is 1/1000th the size of the human genome. Based on his current costs, he thinks he could decode a human genome for about $2.2 million.

I wrote about this technology last year, but the Globe article is pretty informative about the work behind it.

And it has this hint:

Meanwhile, at least half a dozen well-funded labs across the country are shooting for that $1,000 target. One, a Connecticut firm called 454 Life Sciences that runs a somewhat different microscopic technology, rivals Church's so closely that no one can predict who will reach the goal first.

My question is, why are they shooting for $1000? It seems to me that if you can go from $2.2 million to $1000, it won't take very much longer to go to $100, or even less. The materials cost and computational resources certainly won't cost that much in volume.

They are framing the cost in terms of the cost of a personal computer, but it wasn't so long ago that the "accepted" cost of a PC was over $3000, and now most buyers spend a lot less than $1000. So that's arbitrary too.

My guess is that the magic $1000 figure that keeps getting quoted is an attempt to prime insurers to expect that billing amount when the process becomes common. The question is not how much you would pay for a genome, but how much an insurance company would pay on your behalf. A lot of diagnostic procedures approach that billing amount, so it is a convenient pricing hook.

If I'm right, then you can place the $1000 genome in the same category as MRI scans and X-rays, neither of which is priced at what it is worth in materials or energy, but in terms of amortization of equipment and expert interpretation.

Except for genome sequences, the fixed investment may be a whole lot less than for any radiographic equipment. After all, with an MRI machine, you have to have it on site (in the basement, since no floor can hold it!), and you can only run people through at a slow rate. More patients per hour and you need more machines.

With genomes, you can always send material away to a central lab -- it doesn't have to be on site, and with enough miniaturization and automation there may be no hard limit on the speed of sequencing.

What we are not seeing is much in the way of justifying the value of the genome sequences in terms of medical cost savings. So far, the benefits are purely hypothetical -- if you know your alleles, you can take measures to prevent disease early, or you can avoid harmful drug interactions, etc.

So far, "personalized medicine" is a race where the only competitors want to add drugs (or other patented compounds) to the normal regimen of people we now consider healthy. The promise is that this addition will evade problems later in life.

But what would be really nice (and quite possibly necessary given the explosion in health costs) is for genomes to decrease the cost of medical care. Know your genome, and avoid expensive problems. Or other unnecessary tests.

Maybe a long life of taking cheap prophylactic drugs will save many expensive hospital stays in the long run. Maybe enough harmful drug interactions will be avoided to create net savings.

But I'd like to see the other competitors in the race, if there are any.

(Via Gene Expression)

In Nature a couple of weeks ago, Robin Dennell and Wil Roebroeks had a provocative paper exploring the possibility that early humans (i.e. Homo erectus) originated in Asia rather than Africa.

The paper is all speculation of course; there is no evidence of any earlier hominid in Asia.

But it is the good kind of speculation. Although maybe not quite this big:

Most probably, we are on the threshold of a profound transformation of our understanding of early hominin evolution that might prove as far-reaching as the demise of the notion of Man the Hunter in the early 1960s (Dennell and Roebroeks 2005:1103).

Here's the abstract:

The past decade has seen the Pliocene and Pleistocene fossil hominin record enriched by the addition of at least ten new taxa, including the Early Pleistocene, small-brained hominins from Dmanisi, Georgia, and the diminutive Late Pleistocene Homo floresiensis from Flores, Indonesia. At the same time, Asia's earliest hominin presence has been extended up to 1.8 Myr ago, hundreds of thousands of years earlier than previously envisaged. Nevertheless, the preferred explanation for the first appearance of hominins outside Africa has remained virtually unchanged. We show here that it is time to develop alternatives to one of palaeoanthropology's most basic paradigms: 'Out of Africa 1' (Dennell and Roebroeks 2005:1099).

It is worth reviewing exactly what "Out of Africa 1" is supposed to be. The paradigm is that emergence of hominids from Africa required increases in brain size and/or body size, coincident with the emergence of hominids like KNM-ER 3733, KNM-WT 15000, and others. The motivation for this hypothesis is simple: australopithecines have not been found outside of Africa. Nor has anything like Homo habilis, which is australopithecine-sized but has larger brains.

Of course, it is questionable just how basic this paradigm is. Consider what I (and my colleagues) were able to write only seven years ago:

The problem is that significant range expansion out of Africa occurred a half million years or more later than the first H. sapiens [corresponding to others' H. erectus or H. ergaster]. Population size before then may have remained small, and this is not an inconsequential time span, being one quarter of the time H. sapiens has existed. An important date in behavioral evolution is 1.5 MYA because it is marked by the earliest appearance of the Acheulean, the ubiquitous hand-axe industry of the Early and Middle Pleistocene.... Before this time, humanity was limited to Africa and immediately adjacent sections of Asia such as the Levant (Hawks et al. 2000:7).

Evidence for large body size in Late Pliocene humans (notably KNM-WT 15000 but also many others) made it very plausible that larger bodies were necessary for dispersal from Africa. But without good evidence for such dispersal before around 1.4 million years ago (and arguably not before 1 million years), larger bodies could not be assumed to be a sufficient condition for dispersal. Writing about the origin of humans, we had to consider all these alternatives -- at a time when the Dmanisi sample consisted of a single uncertainly dated mandible and the Mojokerto date stood alone with very questionable provenience.

Now we know that hominids did leave Africa by at least 1.8 million years ago. Dmanisi has almost singlehandedly changed the perspective.

And in doing so, it made much more convenient the hypothesis that large body size was both necessary and sufficient for dispersal from Africa. If the date of dispersal and the date of human origins are the same, then it is natural to propose that the coincidence is more than chance.

I would say this is more of a convenient hypothesis (and an easy story to tell) than it is a basic paradigm. The idea that large body size caused dispersal from Africa may have been a local minimum in terms of parsimony (at least as long as the body size of the Dmanisi fossils was not known), but it was only one alternative among many still in play.

And it remains a plausible hypothesis -- after all, the Dmanisi remains are a bit larger than australopithecines, and they might well have shrunk from a larger early-human-like size after reaching Asia instead of before.

But Dennell and Roebroeks give motivations for examining some alternatives.

The only reason why the earliest tool assemblages in Asia are attributed to H. erectus s.l. is that palaeoanthropologists have already decided that, in effect, it was the only hominin capable of migration out of Africa, and with sufficient Wanderlust to do so (Dennella and Roebroeks 2005:1099).

Homo erectus sensu lato (s.l.) means Homo erectus "in the loose sense", which would include not only the "strict sense" (sensu stricto) H. erectus. from Java and China, but also hominids like OH 9 and KNM-ER 3733 from Africa, and presumably the Dmanisi hominids.

A long passage reviews the total faunal evidence from Asia during the Late Pliocene. The thrust of the passage is that there are very few sites with extensive fauna, and of these most preserve mainly large-bodied herbivores. There are a few hints that a hominid-friendly fauna may have existed, including the presence of baboons. But there are no hominids of any kind at the vast majority of Asian localities -- Dmanisi is a real exception in the Plio-Pleistocene record.

This is the key taphonomic argument: if we have only found Early Pleistocene humans from continental Asia within the past ten years, then how can we preclude there having been australopithecines there? Dennell and Roebroeks argue that if there were australopithecines, we shouldn't necessarily expect to have found them yet -- we just haven't looked extensively enough.

A close read of the section raises a caution, though. One of the main arguments for the incompleteness of the Asian record is that sites don't preserve each others' fauna.

It is also likely that the full range of taxa is incomplete for the Indian subcontinent, because Megantereon and Pachycrocuta are not recorded in India but are present in Pakistan; in Pakistan, there is no evidence of Camelus and small primates, and in neither country is Homotherium recorded, although this is present to the west at Dmanisi, to the north at Kuruksay, central Asia and to the east at Longuppo, south China (Dennell and Roebroeks 2005:1100).

Of course, all of these species are recorded in Asia taking all the sites in aggregate; this is hardly an argument for the overall weakness of the record -- just an argument that no individual site is an adequate record of the continent's fauna.

To me, the important question is not whether australopithecines as currently known from Africa were in Asia. A more troubling possibility is that the australopithecines that we now know from Africa were not the only (or main) manifestations of early hominids in Africa. Large parts of Africa that we might expect to be congenial to hominids, like the Zambesi basin, have few or no fossils at all. The recovery of the Bahr el Ghazal mandible (Brunet et al. 1994) certainly makes clear that hominids were living across a much larger area than we have adequately sampled. But that mandible is, although not identical, certainly very similar to known contemporary hominids in its adaptation.

The question is whether hominids had adapted to other ecologies that are much less satisfactorily sampled than the East African rift. They probably weren't living where chimpanzee and gorilla ancestors did, but where else might they have been? Some such ecologies -- like the coasts -- would make early dispersal very plausible.

(In this regard, early humans are not the only hominids who lack a satisfactory ancestor. Who was the ancestor of A. aethiopicus? In what ecology did the first robust hominid arise?)

So what is the broader set of hypotheses that we should consider? Dennell and Roebroeks suggest:

If the above taphonomic review suggests that we cannot show the absence of hominins from areas in Asia at a time before the little evidence we have indicates their presence, we need to consider alternatives to the current Out of Africa [that is, their "Out of Africa 1"] model. There are three issues here. The first is when hominin(s) first left Africa -- might they, for example, have left shortly after they acquired the ability to make stone tools, the earliest of which are currently 2.6 Myr old? Or could they have left even earlier, about 3.0Ð3.5 Myr ago, when some australopithecines were already living in the African grasslands? The second issue is whether we yet know the full range of hominins that inhabited both Africa and Asia in the Late Pliocene and Early Pleistocene. Even in east Africa, several new taxa have been claimed in the past decade (for example, A. anamensis, A. garhi, Ardipithecus ramidus and Kenyanthropus platyops) and doubtless more will be found. (An indication of how little we know about Pleistocene east Africa is that only recently has the first fossil evidence for chimpanzee been found.) In Asia, the recent discoveries of H. georgicus and H. floresiensis should make us very wary of assuming that H. erectus s.l. was the only player on the Asian stage in the Early Pleistocene. Third, Asia might not have been the passive recipient of whatever migrated out of Africa but might have been a major donor to speciation events, as well as dispersals back into Africa. Such two-way traffic is well documented for other mammals in the Pliocene and Early Pleistocene, such as Equus and bovids, with more taxa migrating into than out of Africa. There is no reason why hominin migrations were always from Africa into Asia, and movements in the opposite direction might also have occurred, as has been suggested for the Olduvai OH9 (refs 13, 58) and Daka specimens. We should even allow for the possibility that H. ergaster originated in Asia and perhaps explain its lack of an obvious east African ancestry as the result of immigration rather than a short (and undocumented) process of anagenetic (in situ) evolution (Dennell and Roebroeks 2005:1100-1101).

Of course, most of the evidence indicating the presence of hominids is not fossil but archaeological. On this topic, Dennell and Roebroeks have much to say:

Any stone tool assemblage in Asia dated as older than 1.9 Myr ago (the earliest date that Homo is supposed to have left Africa) is either dismissed or (more usually) ignored; undated Oldowan tools are assumed to date from after 1.9 Myr ago and not from 2.6 Myr ago (the date of their first appearance in east Africa); and stone tool assemblages in Asia dated to the Olduvai Event (1.77Ð1.95 Myr ago) and not associated with hominin remains are automatically attributed to Homo erectus s.l. However, there is no reason why Oldowan assemblages in Arabia cannot be older than 1.9 Myr old, or why the tools from Ain Hanech (Algeria) or Erq el Ahmar (Israel) were made by H. erectus s.l. [instead of other hominids] (ibid:1102, references omitted).

There is a section about what exactly absence of evidence can tell, a short critique of using continents as proxies for biogeographic units:

As noted earlier, Pliocene grasslands extended all the way from west Africa to north China, and 'Savannahstan' might prove a more useful spatial unit for modelling early hominin adaptations and dispersals within them than simply an undifferentiated 'Africa' or 'Asia'. For example, the African hominins 1.9Ð1.7 Myr ago at Koobi Fora (Kenya) and Ain Hanech (Algeria), and their slightly later counterparts in Asia at 'Ubeidiya (Israel), and Majuangou (north China) were all living in broadly comparable grassland environments, and it makes sense to place them within the same frame of reference.

I think there is much of value to consider here; but it is less a revolution and more a statement of the field in transition. There are also alternatives that are not considered in this paper but that may be equally plausible -- most notably, the idea that early humans themselves may have been substantially polymorphic (witness KNM-ER 42700), or that brain size rather than body size may have been a prerequisite to dispersal (since habilines, Dmanisi, and H. erectus s.l. are all allometrically similar in brain size).

National Geographic News also has an article about the paper.

References:

Dennell R, Roebroeks W. 2005. An Asian perspective on early human dispersal from Africa. Nature 438:1099-1104. Full text (subscription)

Hawks J, Hunley K, Lee S-H, Wolpoff M. 2000. Population bottlenecks and Pleistocene human evolution. Mol Biol Evol 17:2-22.

This LiveScience article reviews some recent research.

A new study finds that a cell once believed to serve neurons instead may perform the crucial function of regulating blood flow in the brain.

The discovery challenges a basic assumption in neuroscience and could have implications for interpreting brain scans and understanding what occurs during brain trauma and Alzheimer's disease.

Neuroscientists have long known astrocytes help to support neurons. Wikipedia is terser than the neuroscience text on my shelf, but it will serve:

Astrocytes are sub-type of the glial cells in the brain. They are also known as astrocytic glial cells. Star-shaped, their many arms span all around neurons. They outnumber the neurons ten to one. Astrocytes are classically identified histologically by their expression of glial fibrillary acidic protein (GFAP). Previously in medical science, the neuronal network was considered the only important one, and astrocytes were looked upon as gap fillers. But recently they have been reconsidered and are now thought to play a number of active roles in the brain.

The current research has found that astrocytes can regulate blood flow themselves with no neural involvement:

Recent experiments, however, revealed that astrocytes form connections with blood vessels and control the flow of nutrients, including oxygen, to neurons. When brain activity increases, neurons trigger astrocytes to release calcium, which in turn affects other chemical messengers that can cause blood vessels to either dilate or contract.

From start to finish, the process takes about 1 second.

"That's amazing; no other organs can increase their blood flow so fast," Nedergaard said.

While neurons and astrocytes usually work closely with one another, the new finding raises the possibility that there may be times when astrocytes increase blood flow on their own without any prompting from neurons.

The article discusses the possibility that Alzheimer's may be initiated by astrocyte malfunction rather than neuron death.

Reading it, I wonder whether it is neuroscience or genomics that poses the greatest unsolved problems right now. I guess studying the evolution of the brain tends to stack both sets right on top of each other.