As usual, I was looking for something else -- this time in the writing of Henry Fairfield Osborn -- and came across an interesting paper that he delivered as a lecture in 1927 [1]. He was addressing general evidence for human evolution, in particular as reflected in the anatomy of anthropoid apes. In the course of this, he rose to the defense of his own theory of human origins, which involved the evolution of our lineage from a Central Asian ancestor that had isolated from the other apes for many millions of years:

About three years ago I was a firm believer in the anthropoid ape theory of ancestry. I listened to a series of most able papers given by a number of investigators--Doctors Tilney, Morton, McGregor, all members of the Galton society--and felt then that their investigations of the anthropoid ape theory was quite established. A year later, however, I went into the central desert of Asia, in Mongolia; there I came under the influence of a new environment, a desert or semi-arid environment, and it flashed across my mind that this must have been the primitive home of man, that anthropoid apes could not have existed here. From that time to this the idea has been growing upon me, and last April, at the bicentenary meeting of the American Philosophical Society, I stated that I personally had abandoned the anthropoid ape theory and I advanced the opinion that man has a long line of Dawn Man ancestors and that the other theory rests upon a large amount of evidence which proves the kinship of anthropoid apes to man but does not prove the ancestry of man through an anthropoid ape type (Osborn 1927:221, emphasis in original).

Many people today make a point of saying that humans did not descend from apes, but that we share an ancestor with apes.

If we confine ourselves to living apes, that is of course true. Our common ancestors with chimpanzees and bonobos (the chumans) were not identical to either of these species, and may have been very different from both. That was one of the key issues raised in the interpretation of Ardipithecus. Lovejoy and colleagues [2] made the case that Ardipithecus is a better representative of many of the traits of our last common ancestor with chimpanzees. Chimpanzees have changed substantially since that ancestor lived, in some ways paralleling the evolution of gorillas and orangutans. If this interpretation is correct, then looking to living apes as models for our ancestors will mislead us on many aspects of their biology -- a point made at length by Lovejoy with Ken Sayers in a 2008 paper [3].

Still, we shouldn't misunderstand this line of argument. Saying that stem hominines were anatomically distinct from chimpanzees doesn't really change the plain English meaning of the word "ape." If we seek a high degree of phylogenetic precision, we shouldn't use the word "ape" anyway -- it's not a taxonomic term. But to introduce the concept of evolution, it's equally misleading to avoid plain language. We shouldn't shroud Miocene hominoids in mystery, as if phylogenetic branching could magically transform them into new organisms. They evolved. Where once there were only apes, now there are some different apes. And us.

Osborn's hypothesis marks the dark side of ape denial: If humans didn't evolve from apes, they may instead have evolved independently from some non-ape ancestor instead:

There is all the difference in the world between kinship and ancestry. When we come down to what we all believe in -- to an anthropoid stem stock, a group from which both the anthropoid apes and man were derived -- we get a neutral form which cannot be defined as either an anthropoid ape or man, but with that type, which has the potentiality of the human stock on the one hand and of the anthropoid ape stock on the other, we come to a parting of our ways, somewhere back in Oligocene time, millions of years ago (Osborn 1927:221, emphasis in original).

Were the chumans a "neutral form", definable neither as ape nor human?

In the 1920's, this was a serious scientific question. Living apes seemed to belong to a single family, humans to another. If orangutans and gibbons could be lumped with the chimpanzees and gorillas, then an independent lineage of apes might indeed go back to the Oligocene.

This idea stood against Darwin's view, and that of most of Osborn's contemporaries (Osborn mentions William Gregory and Arthur Keith explicitly). But it was more or less aligned with Alfred Russel Wallace's view of human evolution, which had been contemporary with Darwin's. Wallace had an independent line of human ancestry going back as far as the Eocene.

Today a heavy weight of genetic and fossil evidence supports a human-gorilla-chimpanzee clade. The ancestor of that clade, whether taxonomy calls it a hominid, hominine or something else, was in ordinary parlance an ape. In many characteristics it was "neutral" -- not assignable to either human or chimpanzee clades. Neither humans nor chimpanzees yet existed. But apes of many flavors did exist. Our ancestors were among them.

Here's Osborn's ending paragraph:

Science works by trial hypotheses. I have one hypothesis, my opponents another. To my mind there is a very strong evidence of the prolonged independent ancestry of man, an ancestry not of anthropoid ape type, but of a neutral, common type. I agree to many arboreal traces in human descent, but I dissent as to the geologic length of arboreal life which my opponents claim resulted in resemblance between apes and man; I dissent as to our ancestry from a type which had specialized as far in arboreal life as the anthropoid ape. My theoretic ancestor belongs to a pro-ape stage, which I call the Dawn Man line. But we are all keeping our minds open; only in that way can we get at the truth (ibid., 230).

References

Bray and colleagues [1] report on genotyping of 471 people of Ashkenazi Jewish descent. This is one of the largest samples of a single human population, and is therefore very interesting for studies of population history and recent natural selection.

There's a lot in the paper. One of the key findings in the paper is that the Ashkenazi population doesn't look bottlenecked -- in fact, it looks outbred compared to Europeans generally. The paper also documents a high amount of admixture with non-Ashkenazi Europeans, ranging from 35% to 55%. Figuring out the actual history of the population -- when and where its ancestors lived and how they interacted with other people -- is beyond the scope of this kind of analysis. But I expect that somebody can put together a really compelling historical account using these data.

I turned quickly to the issue of selection. They are able to substantiate evidence of positive selection on several disease-causing alleles in the Ashkenazi population, including the Tay-Sachs allele. The lack of evidence for bottlenecks or founder effects pretty much takes away the alternative explanation. Yet they were unable to show statistical evidence of selection on some other disease-causing alleles in Ashkenazi populations:

To explore whether regions of selection in the AJ population included any loci of known Ashkenazi diseases, we examined 21 disease- and cancer-susceptibility loci with known mutations found at higher frequency in the Ashkenazi population. Only 6 of the 21 genes fell in or near (within 500 kb) the top 5% of the AJ iHS windows (Table 2). Among these is the Tay-Sachs disease gene, HEXA, whose selection has been widely debated (4, 5, 14–16) and was found ~400 kb downstream of a window on chromosome 15 identified in the top 1% of the AJ iHS hits. Although none of the SNPs interrogated immediately adjacent to the HEXA locus showed elevated iHS signals, it is possible that the nearby region may contain regulatory elements under selection that affect HEXA expression. Cochran et al. (14) speculated that selection of many of the AJ- prevalent disease loci, especially the lysosomal diseases, conferred an increase in intelligence that was necessary historically for the AJ economic survival. Our data shows evidence of strong selection at or near only six disease loci, including only one out of the four AJ- prevalent lysosomal storage diseases, thus arguing that most AJ disease loci are not under strong positive selection, but rather rose to their current frequency through genetic drift after a bottleneck. However, we cannot exclude the possibility that selection of some AJ disease loci are outside the limits of detection by the extended haplotype tests, which are known to have less power to detect se- lection of lower frequency alleles (38, 41).

It seems to me that this passage probably wasn't written by the same author who showed the lack of evidence for founder effects a few pages before. In this case, the confusion probably comes from the fact that the "detection of positive selection" is actually a refutation of the hypothesis of genetic drift. With a larger sample it will be possible to test the hypothesis with greater power.

Ddisease-causing alleles are at low frequencies currently, making them unlikely to rise to the top percentages of the statistics. It would be interesting to control for current frequency, but I haven't seen a test that uses frequency information in this way.

It's quite remarkable to reflect on the idea that positive selection has now been demonstrated on six disease-causing alleles in the Ashkenazi population. Every one of these is a case of overdominance -- where the heterozygote carrying an allele has some selective advantage, while the homozygote carrying two copies has a disorder. I was having a conversation with a very prominent geneticist a few months ago, who claimed that no case of overdominance in humans had ever been demonstrated except sickle cell. Now, that was obviously false even at the time -- as I pointed out, the many hemoglobinopathies are fairly clear examples. But we've come an awfully long way.

From data like these, we're going to learn a huge amount about low-frequency selected alleles. The Tay-Sachs-causing allele is one of the most common recessive lethal genes in any human population, but like all genes subject to strong selection in homozygotes, it remains rare. Finding selection on these kinds of alleles is very hard unless sample sizes increase to several hundred individuals. Here we are seeing evidence of selection in historic populations -- within the last 2000 years. More will be coming.

References

Marie-France Deguilloux and colleagues [1] present a short analysis of ancient mtDNA recovered from a Neolithic burial at Prissé-la-Charrière, between the Loire and Garonne valleys of western France.

The mtDNA sample in the end was only three individuals -- one haplogroup X2, one U5a and one N1a. Each is intriguing, as far as a single sequence can be, because all are rare or absent from France today. I think one shouldn't go far interpreting three samples, but they contribute to the view that Neolithic mitochondrial variation in Europe was very different from recent Europeans. The N1a and U5b sequences fit within the already-known Neolithic (and for U5a, Mesolithic) variation in central and northern Europe.

It is from the U5a that Deguilloux and colleagues make a point about possible Mesolithic population continuity.

Subhaplogroup U5b has also been encountered in German Neolithic remains from the Corded Ware Culture (Haak et al., 2008) and in the hunter-gatherers studied by Bramanti et al. (2009), although in both instances, the branches concerned were distinct from the U5b in the Prissé sample. It is, however, worth noting that haplogroup U5 has been encountered in surprising frequency in the hunter-gatherers studied by Bramanti et al. (2009) and could correspond to a Mesolithic heritage.

The story of N1a is that it was very common in the central European Neolithic, even though it is very rare today. That was first noted by Wolfgang Haak and colleagues [2], and has in subsequent years been joined by the observation that the pre-Neolithic hunter-gatherers had yet other common haplogroups. The population history of Europe was a lot more interesting than we suspected 10 years ago.

Deguilloux and colleagues attempt a conservative explanation for the frequencies of N1a in Neolithic samples:

The widespread distribution of the N1a lineage in Early and Middle Neolithic northwestern Europe may indicate genetic continuity from Mesolithic populations. This scenario would support a Mesolithic contribution to the earliest Neolithic of Atlantic Europe. This would imply that the N1a lineage was already common in indigenous north European populations and that the spread of the Neolithic was principally the result of cultural diffusion. Although so far the N1a lineage has not been encountered among late European hunter-gatherers in central and north Europe (Bramanti et al., 2009; Malmström et al., 2009), it is worth noting that less than half of the hunter-gatherers' paleogenetic data come indeed from the pre-Neolithic period (predating LBK expansion). Finally, no paleogenetic data currently exist for the Mesolithic period in Western Europe. This prevents any conclusion being drawn about N1a occurrence during the Mesolithic period in those regions.

I will note this -- the more that N1a is replicated across the Neolithic of Europe, the less and less likely that its subsequent vast reduction in frequency could result from genetic drift. When there was only one or two samples from Central Europe with high N1a, it was at least possible that this was a local founder population that did not spread its mtDNA diversity very far. If it were localized, even in the central Danube (a fairly big region) it might be possible to maintain that the later decline of N1a to its present low frequency had been due to population replacement.

Now N1a seems like a real marker of the LBK, spread widely into Western Europe. It may be, as Deguilloux and colleagues suggest, that it will be found at substantial frequencies in earlier samples somewhere in Europe. We do want some explanation for how it got to be common in this culture area.

Dienekes has written about the study. His point is a good one: If N1a were present somewhere in pre-Neolithic Europe, it would require some kind of "partition" of the pre-Neolithic population, along with its propagation -- presumably southeastward -- into the LBK of central Europe. Seems doubtful.

The study includes an illuminating paragraph about the sources of contaminating sequence in these Neolithic extractions.

Strict precautions were followed during all procedures (including precautions during excavation) and proved to be effective, because all researchers who directly participated in this study (from people working in the field to those working in the laboratory) were genotyped and their sequences were never observed during analyses. However, European sequences were randomly found in clones (28% of the sequences obtained). These specific sequences are regularly observed in the laboratory, whatever the project tackled (including samples from Polynesia or South America), in clones from samples or negative controls. They are not reproducible for a specific sample and are different from researchers' sequences. These facts lead us to suspect the contamination of PCR reagents (Leonard et al., 2007). It was relatively easy, however, to discard those contaminating sequences from our analyses because they were largely in the minority when compared with endogenous sequences.

It would not be very difficult to compare the results from different labs and do a forensic-quality analysis of these reagent contamination events. Surely a good fraction of ancient DNA results prior to the last few years must represent such contamination. Nowadays people have the expectation that Neolithic-era remains may have rare or exotic haplogroups, but it hasn't been so long since people assumed that French equals French. I expressed some concern about this criterion before -- "strange" stands in for "non-contaminated" in too many studies.

It might be very helpful to have a paper outlining the actual contamination pathways that have been found to affect multiple labs. Then the results could be compared against reports that have come out over the years. If people are reluctant to cull doubtful ancient DNA results, at the very least they can target a set for replication studies.

References

Murray Cox and Michael Hammer have a short commentary piece in the current BMC Biology, titled, "A question of scale: Human migrations writ large and small" [1]. They review a few recent papers concerning human migration and intermixture -- including the Neandertal genome draft [2], the paper by Chuanxiang Li and colleagues showing Bronze Age admixture in the Tarim Basin [3], and their own work quantifying historical gene flow inside and outside Africa [4].

It's a short review, but I thought their conclusion serves some thought -- they discuss some of the theoretical complexity of estimating ancient rates of gene flow. The simple model assumes constant rates, but human populations aren't simple.

We expand on just one of these points for illustration (Figure 3). Even when gene flow is inferred explicitly, existing methods invariably assume that it has remained constant through time. However, it seems more reasonable that two diverging populations might share more migrants initially (due to shared geography or existing social relationships), with gene flow subsequently decreasing exponentially as the two populations move apart (Figure 3a). Or gene flow might increase exponentially as two geographically separated populations begin to move closer together (Figure 3b). Alternatively, gene flow might suddenly resume between two long separated populations; for instance, where geographically disconnected populations came back into contact, either as hunter-gatherer groups during the late Pleistocene (Figure 3d), or as human mobility increased following the development of farming in the Holocene (Figure 3c). The important point is this: two populations can look very similar (FST = 0) or very different (FST = 0.3) even when they have exchanged the same number of migrants (that is, graph lines with the same color in figure 3). It is therefore insufficient to consider only how many migrants have moved between populations; we also need to know when these movements occurred.

I don't reproduce the figure, because it's complicated and I think the text is sufficient to establish the point. Averages aren't very meaningful. I'll point out that there is some hope of testing these hypotheses, if we consider selected genes -- which have a time that they originated.

References

Krzysztof Cyran and Marek Kimmel (2010) have presented a revised set of estimates of the human mtDNA most recent common ancestor (MRCA). It's an interesting theoretical paper, written for the purpose of developing a method that doesn't rely on the same assumptions as the usual coalescent models.

Their new method gives an estimate of 174,000 years ago for the human MRCA. They report an upper/lower range as 96,000 to 449,000 years ago. That range does not represent a confidence interval on the estimate, it's an upper/lower based on extreme assumptions about human/Neandertal genetic distance and the human/Neandertal MRCA.

The Neandertal mtDNA has really affected the way we estimate human MRCA, at least for the mitochondrial genome. Chimpanzees are just too distant. When we compare human and chimpanzee mtDNA genomes, there has been a lot of parallelism and reversal on both lineages, because mutations have hit the same place multiple times. Multiple hits and purifying selection make a mess out of rate estimation -- generally, they make the human MRCA seem a lot older than it truly was. The Neandertals are closer, and are therefore less of a problem.

But the Neandertal-human MRCA itself was poorly known, as long when we had only chimpanzees to calibrate the mutation rate....