acceleration

I couple of people have asked me about a new paper in PLoS Genetics by Graham Coop and colleagues, titled, "The role of geography in human adaptation." The paper is open access, and while the details of genetic measures and simulations can be hard to follow, I think it's a great example of the way recent work on selection and human diversity has been structured.

I'll just expand on a few of the topics in the paper, and discuss how they relate to the previous findings about the number and age of selected variants in human populations.

Here's the paper's abstract:

Various observations argue for a role of adaptation in recent human evolution, including results from genome-wide studies and analyses of selection signals at candidate genes. Here, we use genome-wide SNP data from the HapMap and CEPH-Human Genome Diversity Panel samples to study the geographic distributions of putatively selected alleles at a range of geographic scales. We find that the average allele frequency divergence is highly predictive of the most extreme F_ST values across the whole genome. On a broad scale, the geographic distribution of putatively selected alleles almost invariably conforms to population clusters identified using randomly chosen genetic markers. Given this structure, there are surprisingly few fixed or nearly fixed differences between human populations. Among the nearly fixed differences that do exist, nearly all are due to fixation events that occurred outside of Africa, and most appear in East Asia. These patterns suggest that selection is often weak enough that neutral processes—especially population history, migration, and drift—exert powerful influences over the fate and geographic distribution of selected alleles.

The paper looks for "nearly fixed" genetic differences between populations, and finds relatively few of them. That's relatively well-known; the F_ST-based test has been done on fewer populations with similar results (e.g., Williamson et al. 2007; Barreiro et al. 2008). This paper has the HGDP panel, which includes many more populations, and therefore is able to add geographic resolution to these older results. They find that the geographic distribution of near-fixed alleles is clinal; there aren't strong boundaries delimiting the geographic distributions of most apparently selected alleles. That means that the same demographic forces affecting neutral genetic variation have also affected recently selected alleles.

Is that surprising? As we pointed out in our 2007 paper, the recent demographic history of human populations has included a lot of population growth. This means that the number of adaptive mutations should have increased during the last 10,000--20,000 years. High-F_ST selected alleles can only reflect selected mutations that are older than this (old enough to reach near fixation in one population), or are extraordinarily strong. A few mutations are exceptionally strong in their selective advantages -- SLC24A5 and lactase persistence seem to be examples. But as long as adaptive mutations are intrinsically rare, very few of them could have occurred in the small populations of 20,000 years ago or earlier, even if many happened in the large populations of the Holocene. So I think the new paper actually reinforces the interpretation of acceleration. The pattern we're seeing today with new mutations just can't be a feature of human evolution before around 20,000 years ago.

If selection is affected by demographic processes, does that mean that it is "weak"? Clearly, "weak" is a matter of scale. Adaptive genes disperse through a spatially structured population very slowly, even if they confer very large fitness advantages. That means that their dispersal is highly dependent upon demographic conditions, such as the disproportionate growth of some populations or occasional long-distance gene flow. Locally, an allele may rapidly increase under selection, but that effect may have little influence on the evolution of distant populations.

We see that pattern with genes known to be under strong selection in humans, like the ones that help some people resist malaria. Sickle cell, hemoglobin C and E, alpha- and beta-thalassemia, ovalocytosis, G6PD deficiency all have restricted geographic ranges that parallel the clinal pattern of neutral genes. There is an important difference: the patterns of these genes diverge in areas where malaria risk changes rapidly with geography (like coastal versus inland areas of Mediterranean Europe), and some of them have wide geographic distributions compared to their young haplotype ages (like sickle cell). But even in the latter cases, most are too rare to elevate the F_ST of surrounding SNP markers. Malaria adaptations are a tremendous example of the way that demographic conditions limit strong selection.

Africa versus other populations

Derived alleles are expected to have lower frequencies on average than ancestral alleles. So if a population has a bias toward higher-frequency derived alleles, that may be evidence against neutral evolution. The paper finds that this bias is greater in non-African populations than within Africa:

The overall genic enrichment is present in all three population comparisons, and each tail seems to be similarly enriched for high- F_ST genic SNPs. However, the number of derived alleles in each tail does differ substantially and is biased towards derived alleles outside Africa and especially in east Asia. Thus, the statistical evidence for enrichment of events inside Africa is weaker than for the other two populations (we return to this point later).

In general, populations outside Africa have a genome-wide bias toward higher frequencies of derived alleles. The causes of that bias aren't clear -- ascertainment may account for some of the bias but cannot account for all of it; it's possible that early demographic events may explain some of the bias but the pattern isn't obvious.

The F_ST-based tests of neutrality are most powerful when a new allele has swept several rare mutations with it to near-fixation. Rare mutations tend to be derived ones. So the power of the test depends on how many rare mutations there are to start with, and what their frequencies are in other populations that didn't have the same selected allele.

It's one of many issues that make finding selection in African populations slightly different from elsewhere. I think that Africans have undergone as much, and very possibly more, selection by new adaptive mutations as other populations. But our 2007 work suggested that the modal age of the selection we ascertain in Africa may be older than in other regions. That would be consistent with demographic history, since Late Pleistocene African populations were larger than others. But it's possible that genome-wide features like faster LD decay, higher heterozygosity, and more ancestral versus derived variants may also influence our estimates of the timing and number of selected alleles in Africa.

Polygenic adaptation

Toward the end of the paper, the authors discuss the pattern of local adaptation in a more general sense. Why should there be relatively few near-fixed genetic differences between populations, if human ecological changes suggest that local adaptation should have been a powerful force in our recent evolution? One possibility is acceleration -- most of the variants are too recent to have reached near-fixation in any single population.

But the authors mention another possible influence that we've also been thinking about: epistatic interactions among new variants. For example, lots of skin pigmentation loci are known to have been under recent selection, but only a couple of them have reached near-fixation in any population. The rest are at lower frequencies. Since these alleles all affect the same phenotype, they're subject to diminishing returns. As one lighter-pigment allele becomes common, it reduces the strength of selection on the others. The population doesn't have to fix for any of them; in fact, selection probably cannot drive more than one or two up to fixation since the rest of them compete with each other.

Over the very long term, this situation would be sorted out. A handful of loci that optimize skin pigmentation might ultimately go to high frequencies or fixation, for some alleles the costs may exceed the benefits and they will disappear. Others, relatively neutral to each other, may fix by drift. But the "very long term" is a span of hundreds of thousands of generations. Here we're talking about a few hundred generations at most. So human populations aren't anywhere near an optimum, they're in a transient where epistatic interactions may be quite important.

Greg Cochran and I have been discussing this idea for some time. We call it the "Stooge effect". Think of the Three Stooges all trying to run through a door at the same time and getting stuck in the middle. That's what these genes are doing -- all of them are competing to respond to selection, but each is slowed by the presence of the others.

It's not a new idea -- Frank Livingstone used to talk about this general concept with different malaria adaptations. What's new is the increasing evidence that humans are really in a transient with a lot of genes out of equilibrium. It's very possible that for some phenotypes, standing variation has been an epistatic block on the selection of new mutations. For others, the emergence of some new mutations has limited the trajectory of selection on others.

Conclusion

All in all, I think this paper is a nice contribution to our understanding of the pattern and rate of recent positive selection in human populations. Certainly, the HGDP sample will continue to be a very informative addition to our understanding of spatial dynamics in ancient humans. The addition of the new HapMap v.3 samples may be even more important, because these represent further regions with roughly the same discovery power as the initial three HapMap samples. And of course, we have the 1000 Genomes sample coming up, adding significant potential for discovering rarer selected variants.

References:

Coop G, Pickrell JK, Novembre J, Kudaravalli S, Li J, et al. 2009. The Role of Geography in Human Adaptation. PLoS Genet 5(6): e1000500. doi:10.1371/journal.pgen.1000500

While I was browsing papers for a research project, I happened to re-open the paper, "Stone Agers in the fast lane," written by S. Boyd Eaton, Melvin Konner, and Marjorie Shostak in 1988. This paper reviewed the idea that many chronic disorders like diabetes and cardiovascular disease are actually "diseases of civilization" -- brought on by a mismatch between the human genetic heritage and the current cultural milieu.

I'm citing this work as part of my continuing observations on biologists who predicted that human evolution must have stopped sometime in the Pleistocene. Eaton e-mailed me very soon after our acceleration paper was published, and it is only fair to say that the 2009 views of these authors may be very different from their 1988 publication. With that note, here's a quick review:

The current genetic variation in any species is a product of evolutionary forces that affected that species' ancestors in the past -- that's a basic precept of evolutionary theory. So it's hardly more than a syllogism that if the human environment has undergone recent rapid changes, then our genes may do little to protect us from undesirable biological side effects of our new environment.

But Eaton and colleagues, like many human biologists, went rather further than this observation. They made a point of emphasizing that the pace of human adaptation has been incredibly slow. The hypothesis of very slow human evolution had an desired corollary: the "diseases of civilization" are not merely bad side effects of recent dietary Westernization, but may ultimately be traced to the transition to agriculture -- an event that occurred 10,000 years ago in some societies. Let's consider how they emphasized this idea that human evolution had been glacially slow:

The gene pool from which modern humans derive their individual genotypes was formed during an evolutionary experience lasting over a billion years. The almost inconceivably protracted pace of genetic evolution is indicated by paleontologic findings that reveal that an average species of late cenozoic [sic] mammals persisted for more than a million years, by biomolecular evidence indicating that humans and chimpanzees now differ genetically by just 1.6 percent even though the hominid-pongid divergence occurred seven millino years ago, and by dentochronologic data showing that current Europeans are genetically more like their Cro-Magnon ancestors than they are like 20th-century Africans or Asians. Accordingly, it appears that the gene pool has changed little since anatomically modern humans, Homo sapiens sapiens, became widespread about 35,000 years ago and that, from a genetic standpoint, current humans are still late Paleolithic preagricultural hunter-gatherers (Eaton et al. 1988:740).

Not only was the pace of evolution slow when it was happening, but we may have reason to think that recently our gene pool hadn't been changing at all:

The Late Paleolithic era, from 35,000 to 20,000 B.P., may be considered the last time period during which the collective human gene pool interacted with bioenvironmental circumstances typical of those for which it had been originally selected (Eaton et al. 1988:740).

The word "originally" in this passage may admit of later changes in selection and thus in some genes. But the paper does not examine known cases of recent change, even on those genes where some kind of recent dietary adaptation was well-known in 1988 -- such as lactase persistence or ALDH2.

Reading the paper from my current vantage point, where do I think it went wrong? The basic point in the paper is undoubtedly correct -- many of today's chronic diseases reflect the reaction of human biology to novel environments for which our genes are not well adapted. But we don't need to exaggerate the slowness of human evolution to arrive at that conclusion. Recent rapid evolution of humans does not mean that humans are perfectly adapted to the present. Far from it -- if human populations have undergone rapid genetic changes into the past thousand years, it is a strong sign that fitness has not yet maximized in the post-agricultural environment.

Besides that, dietary influences on health may implicate the rapid cultural and ecological changes of the past 200 years. Westernization of diet is a characteristic of post-industrial economies, not early agriculturalists. Given the reduction in variance of mortality in the last 100 years as well as the short time, it is pretty likely that the genes of human populations have changed little in response to dietary Westernization.

I think that the rapidity of recent adaptive evolution does imply a different perspective on the "diseases of civilization." For one thing, some people may be resistant to these diseases because they have inherited new protective alleles. If humans had hardly evolved in the post-agricultural environment, we would expect all populations to be equally susceptible to type 2 diabetes, cardiovascular disease, and cancer. Instead, we find that different populations have different characteristic rates of these diseases after adoption of a Western diet.

Another insight is that some undesirable phenotypes may themselves be the consequences (or side effects) of recently selected alleles. Overdominant alleles like sickle cell naturally stand out in this regard. But the flushing reaction to alcohol, common in Asians with the selected ALDH2 allele, is a less fatal example.

References:

Eaton SB, Konner M, Shostak M. 1988. Stone Agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med 84:739-749.

Larry Moran has been writing a series of posts about quality science journalism. These have included descriptions of some well-written journalistic accounts of evolutionary science, and other that are in his opinion not so well-written.

In this latter category -- what Moran considers to be poor examples of journalism -- he puts a recent article about my work, by writer Kathleen McAuliffe, which appeared in the March 2009 issue of Discover.

Naturally I disagree. After speaking with McAuliffe several times and showing her around my lab here in Madison, I believe she has done an excellent job of describing our research, as well as putting it in the context of recent studies of human variation and evolution.

I think that Moran's criticism can be split into three points:

1. The article opposes our work against the straw-man view that "human evolution stopped."

2. The article does not spend enough space describing the views of scientists who doubt that human evolution accelerated, or who doubt the amount of acceleration.

3. The article includes some speculative "just so stories" for the causes of selection on some genes.

Those three points are too many for a single blog post, so I will focus on the first.

Moran agrees with me and many others that human evolution has been continuing in recent times. He does not specify what he means by recent, but he does mention a few examples of genes, like lactase and sickle cell, that have been strongly selected within the last few thousand years. He also mentions a few examples -- like mitochondrial Eve, which date back into the Middle Pleistocene. I do not tend to call these recent, but in the context of the 6 million years of hominid evolution, they are also comparatively new.

Given this well-known evidence for recent human evolution, Moran questions the article's introductory sentence:

For decades the consensus view—among the public as well as the world’s preeminent biologists—has been that human evolution is over.

He also questions a direct quote from me that appears in the article:

“It beats me how leading biologists could look at the fossil record and conclude that human evolution came to a standstill 50,000 years ago,” Hawks says.

Moran offers:

Beats me how John could possibly think that "leading biologists" have ignored the data.

If I were being snarky, I would simply point you to the long post that Moran wrote in 2007, which began this way:

We frequently hear claims that humans have stopped evolving. Most of these claims have to do with medical advances that are now allowing people to survive who might have died in earlier times. The idea is that natural selection is no longer working so we have stopped evolving.

I am left to wonder where we "frequently hear" this idea, if no "leading biologists" actually believe it. Or why we would give this idea any credence or attention?

McAuliffe's article helps to fill in this blank. For example, it includes a direct quotation from Stephen Jay Gould:

Since modern Homo sapiens emerged 50,000 years ago, “natural selection has almost become irrelevant” to us, the influential Harvard paleontologist Stephen Jay Gould proclaimed. “There have been no biological changes. Everything we’ve called culture and civilization we’ve built with the same body and brain.”

Moran can't be bothered to look up the source of that quote, and intimates that it may not be accurate. I do silly things like finding sources of quotes. The source is

Gould, SJ. 2000. "The Spice of Life: An Interview with Stephen Jay Gould" Leader to Leader. 15 (Winter):14-19. (online).

McAuliffe provides another quote along the same lines from Leda Cosmides and John Tooby. I don't imagine that most readers of Discover would like a long list of direct quotes in support of the first sentence of an article, but I can cite a number of others.

For example, in his book, Children of Prometheus, Christopher Wills gives us a quote from an obscure text:

To be sure, there may have been an improvement of the brain without an enlargement of cranial capacity [over the last 100,000 years] but there is no real evidence of this. Something must have happened to weaken the selective pressure drastically. We cannot escape the conclusion that man's evolution towards manness suddenly came to a halt.... The social structure of contemporary society no longer awards superiority with reproductive success.

That's from Ernst Mayr's 1963 book, Animal Species and Evolution. Of course, that's decades ago. Here's another, from Ashley Montagu, which accompanied the UNESCO Statements on Race, last in 1972:

It is only during the last 15,000 years of his history that some populations developed agriculture and some went on to develop an urban way of life.... In the course of man's evolution the selective pressures acted not toward the development of any particular ability, but toward the generalized ability of adaptability. Hence, there would have been no development of genetically based special abilities in one population differing from those developed in other groups. Since there was no particular premium placed upon the development of such abilities, there would have been no selection for them in any group.

Montagu is very important not because of his prominence as a biologist -- although he had studied with Karl Pearson as an undergraduate, his training was primarily in the Boas school of cultural anthropology. He is important because he worked so hard to establish in biology and the public the idea of genetic equality of human races. As McAuliffe's article points out, this is a major reason why biologists have resisted the idea of recent human evolution. It is a false idea -- as Dobzhansky pointed out, genetic identity is irrelevant to equality. But it is an entrenched idea within human biology research.

Possibly this quote from Luca Cavalli-Sforza (writing with Francesco Cavalli-Sforza and Sarah Thorne) in The Great Human Diasporas, p. 246, is also relevant:

The forces of evolution have been altered radically by the developments of the last ten thousand years. The number of people living on the planet has increased over a thousandfold since agriculture began. As a result, the effects of genetic drift are now much more modest, and we could almost say shelved.

Some types of natural selection have also been shelved.... For natural selection to work, some have to die where others survive, and some have to die more easily than others. Plummeting infant mortality has almost eliminated the effects of natural selection due to differences in mortality.

These examples (and there are many, many others) are sufficient for me to wonder how "leading biologists" can think that human evolution came to a standstill 50,000 years ago. I think that Moran is right -- they must have been ignoring the data.

Or perhaps those biologists really agreed with Larry, but claimed otherwise for some purpose. Maybe they were all exaggerating -- human evolution hadn't really stopped, but had slowed down substantially. Some of them may have been lumping together what they didn't really know about the last 10,000 years with their thoughts about the last 100 years, when mortality rates in Western nations really have decreased. But it's clear that most of them weren't considering the actual data of the last 50,000 years of human evolution.

Still, I think Larry is overstating the extent that today's biologists think that humans have been evolving. Maybe he thinks that others all share his reasonable opinion that sickle cell and lactase are strong evidence of recent human evolution. Nevertheless, I have spoken to many biologists who disagree. In particular some remain skeptical that lactase persistence could have given a survival advantage to ancient people. This view is not tenable today, but until a few years ago, many human biologists simply assumed that such variations dated to the very distant past -- much longer than 50,000 years ago.

Even Larry throws "blood groups" in with his examples of recent evolution, when the most prominent blood group polymorphism, ABO, is millions of years old. The frequencies of this gene have evolved recently, but when Larry asks, "Haven't they heard of ... blood groups?" he should understand that many human biologists think of this as an example of very ancient evolution, not recent change.

That's one reason why I accentuate the prehistoric record of human morphological changes. Skeletal evidence of reductions in brain size, reductions in dental dimensions, progressive loss of third molars, and changes in the cranial index have been known for well over a hundred years. So there's really no excuse for midcentury and later evolutionary biologists to deny that human evolution has been rapid in the last few thousand years.

Yet despite the abundant evidence that human biologists have opposed the idea of recent human evolution, I still think that McAuliffe's opening sentence does construct a "straw man" argument. Many prominent examples don't prove that there has been a decades-long consensus that human evolution stopped. And our research is not about human evolution merely continuing -- we think it actually accelerated. Evidence that some biologists thought that human evolution stopped is interesting. But the reality is that almost no one has thought that human evolution accelerated.

That's curious, because the same theory that implies that human evolution must not have stopped also predicts that it should have sped up. There's no new theory here -- heck, the extent of our theoretical model is a linear equation! Larger populations make it more likely for adaptive mutations to happen. The only reasons that evolution wouldn't accelerate in recent humans are if adaptive mutations are in principle impossible, or if they are so common that they happen in small populations anyway.

Like Larry, I think that biologists are mostly convinced not by theory -- however simple -- but by concrete examples. That's precisely what McAuliffe describes at the end of her article:

Given such uncertainties, researchers are more likely to be persuaded that a mutation has been recently selected if they understand its function and if its rise in prevalence meshes well with known human migratory routes. Genetic variants fitting that description include those coding for lighter skin coloring, resistance to diseases such as malaria, and metabolic changes related to the digestion of novel foods. There is broad consensus that these represent genuine examples of recent adaptations.

Her clear description of these nuances -- scientists applying different analytical methods, possibly using different standards of evidence -- is one of the reasons why this is an good piece of science journalism. It describes the reasons for skepticism about our work as well as the ways that non-biologists may misinterpret it -- a part of the article that adds up to almost 1000 words.

Larry disagrees that this is enough to provide balance to the article, and suggests that this section actually contradicts the idea that most biologists accept a "static" view of human evolution. After all, if there is "broad consensus" that a few prominent evolutionary changes happened recently, that must mean that human evolution hasn't stopped, right?

Well, all I can say is that if all human biologists had the same attitude toward natural selection as Larry Moran, I doubt that we would have needed to publish our ideas about acceleration. Because they would already have been widely accepted!

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!