recent selection

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

Nicholas Wade gives some recent highlights of research into ongoing selection in humans.

We are at the center of this research [1], as we connected the widespread pattern of positive selection to human demographic history -- a growing population, with major ecological changes, has both the pressure and opportunity to respond by new adaptive mutations. The result was an acceleration of the rate of positively selected mutations, so that a large proportion of the genome shows evidence of ongoing selective sweeps in one or more human populations. So I'm excited to see the continuing interest in this topic.

According to Wade's account, the initial skepticism of many geneticists to this idea seems to have mostly evaporated. I think that much of the caution was reasonable conservatism -- few people expected to see such widespread effects of selection. Only those of us who were thinking of the changes in the Neolithic and later were really prepared to interpret the evidence. But now, the sheer accumulation of studies has shown that our initial estimates may have been too conservative.

About 21 genome-wide scans for natural selection had been completed by last year, providing evidence that 4,243 genes — 23 percent of the human total — were under natural selection. This is a surprisingly high proportion, since the scans often miss various genes that are known for other reasons to be under selection. Also, the scans can see only recent episodes of selection — probably just those that occurred within the last 5,000 to 25,000 years or so. The reason is that after a favored version of a gene has swept through the population, mutations start building up in its DNA, eroding the uniformity that is evidence of a sweep.

Unfortunately, as Joshua M. Akey of the University of Washington in Seattle, pointed out last year in the journal Genome Research, most of the regions identified as under selection were found in only one scan and ignored by the 20 others. The lack of agreement is “sobering,” as Dr. Akey put it, not least because most of the scans are based on the same Hap Map data.

From this drunken riot of claims, however, Dr. Akey believes that it is reasonable to assume that any region identified in two or more scans is probably under natural selection. By this criterion, 2,465 genes, or 13 percent, have been actively shaped by recent evolution. The genes are involved in many different biological processes, like diet, skin color and the sense of smell.

That's 13 percent with statistical evidence in two or more studies. Keep in mind that our present sample size is small enough that we can't reject the hypothesis of genetic drift on things that have frequencies lower than ten percent in a given population. So probably the variants we know about are the tip of a larger iceberg of rare selected variants, which originated within the last few thousand years and haven't had time to increase to higher frequencies. Some may have stalled out at lower frequencies, because of epistases or changes in the environment.

The proportion of affected genes should approach some asymptote, as lower-frequency variants will be likely to hit the same gene categories again and again. Diet, skin color, smell, disease, brain, all systems that have been under strong selection pressure in recent human evolution. That may provide a promising way to uncover functional relationships among genes. Wade's description of Anna Di Rienzo's work seems to be along those lines.

Many workers seem to realize now that humans don't live in hunter-gatherer environments. But a disappointment for me is that the article doesn't discuss the role of demography in generating this unique evolutionary pattern. Demography provides an important filter on the results of genome-wide analyses, also. The power of statistical methods is not uniform across different ages of adaptive alleles. Some methods miss older events while all methods miss very recent ones.

Statistical power is an important reason why some studies find more evidence of selection in Europe and East Asia compared to Africa. The demography of those regions means that Africa has a broader distribution of ages of positively selected mutations: more older events, fewer events corresponding to the peak population growth of early agriculturalists.

There is some stuff in the article about "soft sweeps" -- the hypothesis that much recent phenotypic change may result from selection on standing genetic variation in ancient populations. An allele that already existed neutrally in the population can come under new selection, and that kind of selection won't trigger the criteria for genome-wide selection scans.

I have some thoughts about this phenomenon that I'll write up and share. We know that there were some big phenotypic changes in the Late Pleistocene and early Holocene, and initially these changes should mostly have involved standing genetic variation. New adaptive mutations were coming into these populations at a relatively slow rate. When a new mutation is still rare, it doesn't have much impact on the average phenotype in the population. So if we see a fast change to the average phenotype, we know that new mutations aren't responsible, at least not initially.

But it doesn't take very many genes to cause phenotypic changes. And if small populations have few new adaptive mutations, they also have relatively little standing variation. So the importance of soft sweeps to our evolution may be great, even if their numbers are ultimately small.

References

My post about the Tibetan high altitude selection story last Friday summarized the research and included some criticism of the demographic model applied in the paper by Yi and colleagues. This weekend, I had some correspondence from study coauthor Rasmus Nielsen.

Nielsen was kind enough to provide a lot of information about how they arrived at their demographic model. Also, his comments are of substantial interest as a perspective on science journalism. I have posted them in their entirety, and have added my own perspective below them. Click through to read on:

Did the altitude of the Tibetan plateau lead to the fastest instance of human adaptation yet known?

That's the claim in the new paper by Xin Yi and colleagues [1]:

Given our estimate that Han and Tibetans diverged 2750 years ago and experienced subsequent migration, it appears that our focal SNP at EPAS1 may have experienced a faster rate of frequency change than even the lactase persistence allele in northern Europe, which rose in frequency over the course of about 7500 years (26). EPAS1 may therefore represent the strongest instance of natural selection documented in a human population, and variation at this gene appears to have had important consequences for human survival and/or reproduction in the Tibetan region.

I have a significant criticism of that conclusion, but first I want to say I think this is really cool work. They sequenced 50 whole exomes of people of Tibetan ancestry. An exome is the coding fraction of the genome, leaving out the non-coding stuff. This let them do a genome-wide association including every SNP they found. As it turns out, the key gene (EPAS1) has no coding SNPs that differentiate strongly in these samples. It's an intronic SNP that shows a really large frequency difference (87% in Tibetans, 9% in Han Chinese). That's a really big difference.

And it takes a big difference to test neutrality in this sample. Fifty exomes is a whole lot of sequencing, but it's really a small sample for finding selection. It takes a really big frequency change to exceed chance. Besides that, most new adaptive mutations will be missed because they haven't gotten off the ground yet. Finding one major allele that correlates strongly with population, and then doing the work to show its association with red blood cell production, that's all pretty neat stuff. This paper should be added to the paper last month by Cynthia Beall and colleagues [2], who also found an association with Tibetans and made a functional link with high altitude adaptation. This gene is part of the system that adapts people to hypoxia in the Tibet/Nepal area, although it certainly does not act alone and we don't yet know how the system works. It's a solid first step.

OK, so what's my problem with the paper? Hypoxia is a strong selective agent, affecting performance, health, and -- maybe most important -- birth weight. As soon as people began living on the Tibetan Plateau, they were in a compromised environment. That makes this a really great example of recent selection associated with a novel environment. But the archaeological evidence suggests that people have been living in this environment for a lot longer than 3000 years. The population model in the paper is a mess.

People have been living on the Tibetan Plateau for more than 15,000 years. They may have occupied the area intermittently before the Last Glacial Maximum, and certainly were in nearby medium-altitude areas of northwestern China before that time. The Paleolithic-era occupation of northeastern highland Tibet was reviewed by Madsen and colleagues [3] and Brantingham and colleagues [4]. Aldenderfer [5] reviewed what is known about Neolithic-era occupation of highland Tibet. Sites with ceramics, evidence of sedentary village occupation and domesticated animals occur between 4000 and 6500 calendar years B.P. That doesn't mean that today's Tibetan population derives entirely from these early Neolithic settlers or the even earlier Paleolithic occupants. But the archaeological record does show that the opportunity for genetic adaptation would have been present long before 3000 years ago.

So there's a potential inconsistency. The inconsistency could be resolved by recognizing that selection is stochastic. Selection cannot start changing the frequency of an allele until after the mutation has occurred.

The following passage comes from Nicholas Wade's account of the research, in the NY Times. Wade also picked up on the problem with the demography in the paper, and probed the authors about it:

Geneticists have a more elastic view of dates than do archaeologists, and the estimate of a Han-Tibetan population split at 3,000 years ago could probably have been adjusted to 6,000 if the geneticists had taken any account of any other kind of evidence.

Rasmus Nielsen, a Danish researcher at the University of California, Berkeley, did the statistical calculations for the Beijing study. “We feel fairly confident that something on the order of 3,000 years is correct,” he said. But in a later e-mail message, Dr. Nielsen said, “I cannot with confidence rule out that the divergence time is 6,000 instead of 3,000.”

There is similar flexibility in the estimates of population sizes. The Beijing team calculates that at the time of divergence there were only 288 Han Chinese and 22,642 Tibetans. These estimates have bewildered archaeologists, given that rice cultivation in southern China started 10,000 years ago and that there was an extensive civilization by 3,000 years ago. Dr. Nielsen said that the figure of 288 people was meant simply to indicate a bottleneck in the Han population, meaning a time when it was very small, and that this bottleneck could just as easily have occurred 10,000 years ago.

I think that's totally remarkable. "Geneticists have a more elastic view of dates than do archaeologists"! I think that phrase should be framed and hung in every classroom teaching anthropological genetics.

Look at the expansion model. In what universe were there only 288 ancestors of Han Chinese people in the last 3000 years? We're talking about the late Bronze Age, here! This is just after the end of the Shang Dynasty, whose capital at Anyang had a walled area of 1000 hectares. That's 1000 soccer pitches full of city, within an empire that spanned the northern half of China.

It is completely lame to claim that the model could represent a bottleneck as long ago as 10,000 years. You see, the size of the population determines the rate of differentiation under genetic drift. If the population was big, it shouldn't have changed very fast, so the present populations shouldn't be very different. Putting it into numbers, if there hasn't been a bottleneck for 10,000 years, then the divergence must be a lot older than 3000 years. Probably older than 10,000 years.

These hypotheses can be tested directly with genetics, and the data are certainly rich enough now to do it. If they point to a genetic bottleneck in China during the last 10,000 years, we should be very, very surprised. Because then who was farming all the millet and rice, and domesticating pigs?

Does it matter? For EPAS1, the timing really doesn't affect the interpretation of selection -- there's no way that drift made the populations as different as they are for this one locus. But it seems clear that this is not a new mutation because it has no long, linked haplotype around it that also differs in frequency in the two populations. Selection on a standing variant is indeed newsworthy, as these are hard to find. Since we don't have a long haplotype to date, the only way that we can estimate the timing of selection is with the population model. Use the wrong model, and you get the wrong time. That is probably what has happened here.

Also, using this weird population model vastly increases the chance that genetic drift could cause large frequency changes in Tibet or China. This makes us much less likely to recognize genes that really have been subject to selection in either population. With respect to EPAS1 the test is conservative, but the genome-wide comparison will miss a lot of genes and give less significant p-values to others. It's a waste, because it means that we have to collect that much more data to get the same result.

UPDATE (2010-07-06): Rasmus Nielsen has written me to clarify his remarks to the Times and give more information about the demographic model in the paper. I have posted his full remarks along with some comments of my own. It is well worth reading.

References

Before the Neandertal genome release last week, I was reading (thanks to a correspondent) an essay that James Noonan wrote for the current Genome Research. The piece, titled, "Neanderthal genomics and the evolution of modern humans" is well worth reading. It's a snapshot of what we might reasonably have anticipated would come out of the efforts to sequence Neandertal genomes, without the punchline -- no recognition that we would ultimately turn out to have Neandertal genes.

It will take a while for paleoanthropologists to come to any kind of informed opinion about the importance of the current genome results. The quotes I've gathered from various newspaper sources include a pretty wide range of silly ideas. Maybe some of mine fall in that category. But generally I try to be informed by both archaeology and genetics, and I find that tends to avoid some of the silliest statements.

Note however, there is really no excuse at all for archaeologists saying silly things about the archaeological record.

Noonan's point of view is that of a mainstream geneticists, and is clearly stated. It represents a widespread school of thought about Neandertal genetics, but (understandably) is mostly uninformed by the archaeological record. For example,

The primary motivation behind generating a Neanderthal reference genome is to determine how distinct modern humans really are from all earlier versions of humanity. We are the only remaining human species, and thus we do not know if Neanderthals or our other extinct relatives shared our capacity for invention, abstract reasoning, or language. We have had to speculate on these matters based on the bones, the settlements, and the artifacts Neanderthals left behind. The question of modern human and Neanderthal biological similarity is particularly compelling given the recent common ancestry of both species: Based on both genomic and mitochondrial sequence comparisons, the lineages leading to modern humans and Neanderthals likely diverged in Africa ∼300,000–700,000 yr ago (Krings et al. 1997; Serre et al. 2004; Green et al. 2006, 2008; Noonan et al. 2006). This genetic evidence has become folded into a narrative of modern human and Neanderthal evolutionary history that continues to frame comparative studies of both species. In its simplest form, the modern human and Neanderthal lineages continued on parallel evolutionary tracks subsequent to their divergence, with the descendants of one branch migrating to Europe and giving rise to Neanderthals, and the other branch remaining in Africa and eventually producing us (White et al. 2003; Mellars 2004; Hublin 2009; Tattersall 2009). The modern human colonization of Europe ∼40,000 yr ago potentially brought both lineages back into widespread contact (Mellars 2004).

Given their very recent common ancestry, how much did the species have in common at this point? Were modern humans and Neanderthals capable of interbreeding, and, if so, did it happen to any appreciable extent? Or were the species so different that no meaningful exchange of information could occur?

Well, you know my answer to those questions.

I quoted this part because I think the earlier part of the passage deserves comment. Will the genetics tell us more about the cognitive relations of Neandertals and their contemporaries? Maybe eventually, but for the time being there is a tremendous void in our understanding of functional genetics. We really know nothing about the relationship of genetic variants to the "capacity for invention, abstract reasoning or language."

Compare the situation to "personalized genomics." If we sequence somebody's genome and find new variants, for the most part we have no way of predicting what they do. And even the genes have functionally apparent properties -- for example, a stop codon -- there still may be no practical way to test the hypothesis that it influences a given phenotype.

The archaeological record is actually pertinent to cognition in a way that the genetic evidence isn't yet. That doesn't mean we have many answers -- we're still groping the dark. But if I want to know about the evolution of human cognition, the archaeology is a much better place to start.

What we know about the archaeology seems very clear: Most of the things that later MSA Africans did, Neandertals also did. There were differences, which may have been important -- but those differences don't exceed the variation of material culture in later human populations.

That doesn't rule out that Neandertals may have been cognitively different from us in some important ways. But when we look at the complexity of the material record within Africa, I think it is fair to say that Neandertal behavior fits comforably within the continuum represented by MSA people. "Behavioral modernity" is broadly shared, and doesn't clearly track lines of biological differences. Rachel Caspari and Sang-Hee Lee's work on mortality differences are another concrete illustration of the ways that material culture and behavior do not track with anatomy in these populations.

In the short term, the most important influence of understanding the Neandertal genome will be what it tells us about phylogenetics and demographic history. That is what got all the attention last week, and will continue to occupy many of us in the next few months.

Even though the news of interbreeding is fascinating, working out the phylogenetic relationships of Pleistocene humans is only a first step towards understanding their evolutionary history. Noonan focuses on strategies for uncovering which genetic changes were important to recent human and Neandertal phenotypic evolution. In this respect, the essay could serve as an introduction to the two papers released in Science last week. It explains a bit about why the Neandertal genome is useful for uncovering functional changes in the human genome, and what may prove useful to drive this inquiry further. For example, from near the end of the essay:

These studies illustrate a general strategy toward an understanding of biological differences between modern humans and Neanderthals, in which the first step is the reverse genetic analysis of genes and gene regulatory elements showing human-specific or Neanderthal-specific sequence changes. In this approach, changes in basic molecular functions, such as enhancer activity, protein-DNA interactions, or receptor-ligand binding affinity are identified in synthetic assays. The phenotypic consequences of these molecular changes can then be assessed in mouse models: A recent study describing the introduction of a "humanized" version of FOXP2 into the mouse genome by gene targeting is one early example (Enard et al. 2009). The data from such studies, combined with a growing body of information on human gene function, the effects of genetic variation on human phenotypes, and comprehensive efforts to functionally annotate the human genome, would provide the foundation for more sophisticated hypotheses concerning the biological similarity of modern humans and Neanderthals than can be generated from the paleoanthropological record alone.

Now, in light of last week's data release, we know some things about these general topics. The evolution of human-specific changes in conserved regions, for example, apparently mostly preceded the human-Neandertal common ancestor. There are few amino acid changes in recent (post-Neandertal) evolution that have become fixed worldwide -- the new studies counted only 88. There are only 212 estimated selective sweeps not present in the Neandertal genome.

Those are manageable numbers.

Of course, we shouldn't underestimate how hard it will be to untangle the interactions among these human-specific changes. It may require testing not each change one by one, but many possible combinations of the changes, since we don't necessarily know their order. And it is not only the fixed changes that are important to morphological and behavioral evolution, polymorphisms will also be important. Among those polymorphisms will be later, strongly selected changes that may substantially modify the "fixed" substitutions -- in a few cases, may even reverse them.

But this isn't a hopeless prospect anymore, it's a practical research program. The genetic changes that are nearly fixed in living people but absent in Neandertals represent one of the earliest -- possibly the first -- instances of geographic isolation and selection in Homo sapiens. They are one aspect of a pattern that has become increasingly important in later human populations, as the pace of adaptation has accelerated beyond the ability of gene flow to disperse adaptive alleles. Reconstructing this history will tell us about the shared evolutionary dynamics of humans and Neandertals, and the ecological particularities that may have made both populations phenotypically different.

References:

Noonan JP. 2010. Neanderthal genomics and the evolution of modern humans. Genome Res 20:547-553. doi:10.1101/gr.076000.108

Alon Keinan and David Reich [1] have tested an obvious prediction of the hypothesis that recent selection has had a major effect on variation across the genome, and in doing so have provided some strong support for our hypothesis of a recent acceleration.

A new mutation that increases rapidly under positive selection will carry with it a lot of nearby variants that are physically linked to it. The region of this "genetic hitchhiking" will depend on the local rate of recombination -- the lower the recombination rate, the longer the extent of the hitchhiking region.

Meanwhile, a new mutation takes a while, sometimes many thousands of years, to spread widely beyond its population of origin. We can measure population differences for a single locus as F_ST. The F_ST attained by a new selected variant depends on what frequency it has reached in different populations. For many selected alleles, they have not yet attained high frequencies anywhere, and so F_ST is low. But for a few, the selected variant has reached a high frequency in a few populations, but remains rare elsewhere. These are recognizable as high F_ST loci.

What is true of the selected allele itself will also be true, to a lesser extent, of the linked haplotype that is hitchhiking along with it. And so, if selection has been sufficiently common in recent human history, there should be a relationship between the local rate of recombination and measures of population differentiation like F_ST.

Which is exactly what Keinan and Reich found.

Further, they found that this relationship is true of regions of the genome that contain a lot of coding loci, and much less true of gene-poor regions:

We cannot envision any demographic or mechanistic explanation that would produce a correlation between recombination rate and allele frequency differentiation as observed and we hypothesize that our observations reflect a history of natural selection. Natural selection is usually expected to increase population differentiation at linked neutral sites, an effect that is expected to extend over longer physical distances in regions of lower recombination rate. A prediction of an explanation based on natural selection is that the effect would be more marked in regions that are more likely to be influenced by selection, such as genes.

The observed F_ST in these categories is not super-high -- we're not looking predominantly at genes for which more than 20 percent of the variation is the between-population component. Therefore, the comparison can encompass quite a bit more of the selected variation in the genome, instead of the extremely stringent cutoffs required to identify an individual candidate gene. It's a bit like getting a measure of wind speed as opposed to looking at the few highest-flying kites.

Perhaps the most interesting aspect of the study is that they compared the Phase 3 HapMap samples, which include some pairs of nearby populations. They found that the apparent effect of selection on population differentiation was much higher for those nearby pairs of populations:

In addition to qualitatively replicating our findings, analysis of HapMap 3 data allows us to generalize them to additional populations. A striking result is that the relationship between FST and recombination rate is stronger for FST between pairs of closely-related populations, whether within or outside Africa: FST between a West African sample and Maasai (of mixed West African and East African ancestry [57]) decreases by an average of 6% for every 1 cM/Mb (Figure 4D), FST between Italians and individuals of North-Western European ancestry decreases by 10% for every cM/Mb (Figure 4E), and FST between Japanese and individuals of Chinese ancestry decreases by 4% (Figure 4E). In view of the large effective population size in recent human history since each of these pairs of populations have split, these observations support the possibility that the different patterns observed between different pairs of populations are due to natural selection operating more efficiently in the context of larger population sizes.

That's a direct sign, in other words, of the recent acceleration of positive selection in human populations. There are a lot more genes that are geographically circumscribed and low in frequency affecting F_ST at a more localized level, and fewer affecting major allele frequencies between continental regions. It's a neat comparison, and it helps to answer the comment that selection is somehow "weak", or insignificantly different from drift, because the new selected alleles haven't spread very far. The point is, most of them are so new that they haven't had time to disperse widely and reach appreciable frequencies very far from their origins.

UPDATE (2010-03-28): A reader pointed out an error in the post; I had written "lower" recombination rate at one point that should have been "higher". I have corrected the text.

References

Ann Gibbons has a long news article in the current Science reporting on an interdisciplinary conference on recent human diet evolution ("What's for Dinner? Researchers Seek Our Ancestors' Answers"). The article covers a lot of ground, from Michael Richards' work on the isotopic signature of diet in early Upper Paleolithic people, to Bill Leonard's work on diet adaptations in Siberian reindeer herders, to Jonathan Wells' work on maternal nutritional status and epigenetics.

It's a good "why evolution matters to today's nutritional choices" article.

A section of interest to me:

The agricultural revolution favored people lucky enough to have gene variants that helped them digest milk, alcohol, and starch. Those mutations therefore spread among farmers. But other populations remained more carnivorous, such as the Saami of frigid northern Norway, whose ancestors herded reindeer. Among Saami ancestors, genes to digest meat and fat efficiently were apparently favored. One gene variant, for example, makes living Saami less likely to get uric acid kidney stones—common in people who eat high-protein diets—than are people whose ancestors were vegetarian Hindus and lack this gene variant, says geneticist Mark Thomas of University College London (UCL).

I'll have more on a similar topic later -- recent shifts in genes due to agricultural subsistence has become a favorite subject of local interest. One would think I might get some funding from the Wisconsin dairy industry for this, but nothing so far...

There is an unresolved tension in the article: Is there a better diet for everyone? Clearly some populations have undergone large recent diet changes with bad consequences; the same bad outcomes occur in some people despite possibly adapting to new diets for thousands of years. And yet, every metabolic or diet-related syndrome is variable, and we know that some genes related to digestion and metabolism have rapidly changed. "Westernization" is not as simple as it seems, nor is agriculture (or, for that matter, pastoralism) -- and the responses to each vary for stochastic reasons in different populations.

It's a good interesting complexity, in a field where simple categorical statements can get a lot of attention.

Time has a story about Stephen Stearns and colleagues' work characterizing ongoing selection using the Framingham Heart Study sample:

If these trends were to continue with no cultural changes in the town for the next 10 generations, by 2409 the average Framingham woman would be 2 cm (0.8 in) shorter, 1 kg (2.2 lb.) heavier, have a healthier heart, have her first child five months earlier and enter menopause 10 months later than a woman today, the study found. "That rate of evolution is slow but pretty similar to what we see in other plants and animals. Humans don't seem to be any exception," Stearns says.

I haven't had a chance to see the new study yet, and I'll do a little review when I get it. Jerry Coyne has some more information based on a preprint.

My students have heard me say many times that it would take a sample of thousands of people to test the hypothesis of neutrality within today's population. Well, Framingham is one such sample, and it's not surprising that some things would be found significantly to affect fitness.

The Time article mentions our work on recent evolution in a very positive way. Of course, the Framingham sample isn't suitable for testing what has been going on during the last 40,000 years; it is about mass selection on phenotypes in the present American population. That will involve mostly selection on standing variants, things that are already common in the population. Some of those may be things that were increasing in the past, others not -- some may even be reversals in direction compared to pre-industrial times. And there's no predicting how they might change in the future, as we continue to change our environment out from under ourselves.

I've seen a few comments that we shouldn't trust the sample because it's unrepresentative, too small, etc. I think people may be overlooking the fact that the Framingham Heart Study is bigger than the census sizes of many species in nature. You can detect selection on phenotypes in this sample, and they surely know the heritabilities of many of them. But I'll have to see the paper.

François Balloux (2009) has a polemic in the online access area of Heredity presenting references about mtDNA selection, and arguing that the use of this single genetic marker is no longer warranted without support from other loci.

Yay! I've been saying that both here, and in peer-reviewed articles, for several years. I think serious workers know that one gene is not enough; two genes (mtDNA and Y chromosome, for example) aren't enough -- we have to integrate information across every possible source, genetic, skeletal, and anthropological, to really test hypotheses about the past.

Still, an industry of mtDNA sequencing has grown up, reviewing each others' grants and papers, and shutting down any discussion of adaptive changes. Balloux's commentary addresses this problem -- I'm going to quote the same paragraph as Dienekes:

Let us assume I gave a seminar. I would tell the audience about my latest results on the population history of the pigmy shrew. My findings would be based on a stretch of DNA comprising several metabolic genes, showing no signs of genetic recombination. Armed with sequences from a large number of individuals sampled over a broad geographical area, I would make some inference on the colonization routes and times. To make life easier, I would restrict my analysis to the mutations I liked best, with nice names having been given to related sequences, rather than relying on dull mathematical quantities. As I reach one of the key conclusions of the lecture, which would go as follows: 'It is obvious from the distribution of haplotypes Amanda, Eugenie* and Hector_2 that the Outer Hebrides were colonised about 50,000 years ago, this was followed by considerable population fluctuations, a bottleneck during the last Ice Age, a swift recovery and a dramatic recent expansion over the last 200 years and...'. Imagine that, at that climactic stage I was interrupted by someone in the audience. The impertinent would say, 'Sir, can I just ask you whether this confidence in your conclusions may not be misplaced; your analysis is based on a single genetic marker, which comprises genes with a central role in metabolism and is thus likely to have been affected by natural selection'. An awkward silence may ensue, as I would find it difficult to dismiss this criticism easily.

Well, let me tell you, I've been in dozens of audiences, and have raised that exact point. Here is a sample of the bogus responses I've gotten to this question:

Bogus answer 1: There are no functional differences between humans and chimpanzees in the mtDNA, so it can't have been selected during human evolution. False, false false!

Bogus answer 2: Metabolic processes are highly conserved, and humans couldn't have changed much. Hello? Have you noticed that your breakfast didn't exist in the Paleolithic?

Bogus answer 3: But the pattern of variation can be equally explained by a bottleneck. Some aspects can, others can't so easily.

Bogus answer 4: We examined only noncoding parts of the mtDNA, so there could be no selection. Yes, believe it or not, this is the most common response. I guess they don't teach people about linkage anymore.

Bogus answer 5: There's little or no evidence of selection on any gene in recent human evolution. Human evolution may have stopped entirely. Oh, lord. Yes, I've gotten this one many times.

There have been others over the years. Yet mtDNA is a big business -- people seem to be worried that the slightest criticism will bring down the whole thing like a house of cards. That's not true, even if mtDNA has sometimes been selected during human prehistory or history, that doesn't mean it isn't a useful marker for many purposes. But many seem more comfortable avoiding the issue entirely.

I think that taking the hypothesis of selection seriously would improve most of the work in this field. The possibility of selection doesn't eliminate demographic interpretation -- for example, the high ancient African mtDNA variation allows us to test hypotheses about African demography before 50,000 years ago, and there the data appear to reject the hypothesis of selection, at least after around 150,000 years ago. Gene genealogies don't allow us to see the whole past, just the time and forces that they experienced. If we ignore one of the major forces, we are reducing our knowledge.

There is an obvious problem testing the hypothesis of selection with mtDNA. When we consider any one single locus, it's always possible to find some demographic scenario that yields exactly the same predictions as selection. It's just a mathematical necessity -- selection is fundamentally a demographic phenomenon, and the increase in frequency of selected alleles looks similar to exponential growth of a small population.

So what can we do? Fortunately we have lots of options. We can test the proposed demographic hypotheses against the historical record. When we make observations that show that people 1000 years ago had very different frequencies of common haplotypes, well, we know it was selection. There hasn't been any genetically significant bottleneck in the last 1000 years! When we see small Neolithic population samples dominated by haplotypes that are very rare today, again, no historically possible bottleneck could have caused that.

Balloux with his colleagues (2009) has shown that one aspect of mtDNA patterning -- the association of haplogroup diversity with geography -- is very unlikely to have arisen by genetic drift. Here's part of their abstract:

We show that populations living in colder environments have lower mitochondrial diversity and that the genetic differentiation between pairs of populations correlates with difference in temperature. These associations were unique to mtDNA; we could not find a similar pattern in any other genetic marker. We were able to identify two correlated non-synonymous point mutations in the ND3 and ATP6 genes characterized by a clear association with temperature, which appear to be plausible targets of natural selection producing the association with climate. The same mutations have been previously shown to be associated with variation in mitochondrial pH and calcium dynamics. Our results indicate that natural selection mediated by climate has contributed to shape the current distribution of mtDNA sequences in humans.

They took a dual approach to testing the hypothesis of selection. First, they modeled the evolution of haplotype diversity under neutrality, and showed that the empirical distribution lies significantly outside that range of results. But even so, we might imagine some bottleneck scenario that would cause low diversity in high-latitude peoples, and this would be difficult to refute historically because many of those populations have poor historical documentation. But demography should have similar effects on other genes, and they were able to show that the rest of the genome doesn't share the mtDNA pattern.

It's really not that hard to test demographic hypotheses, using comparative genomics and anthropological knowledge. That's what anthropological genetics should be doing more and more. There was a time when obtaining a reasonable sample of mtDNA was an accomplishment, and comparing that sample to other genes was not feasible. But that time is past, and hopefully the review process -- journals and grants -- will start demanding some integration of mtDNA phylogeography with results from the rest of the genome.

Back to Balloux's conclusion:

Exploiting these new resources of autosomal variation will present significant challenges, but it will not help overcoming them if a large fraction of the community of human population biologists persists in sticking to mtDNA as the marker of choice.

Mitochondrial DNA isn't the tip of the iceberg -- it's an ice cube on top of the tip of the iceberg.

Related:

"Mitochondrial DNA selection review"

"Mitochondrial DNA and sperm"

"mtDNA selection in Iceland?"

"Complete Neandertal mitochondrial sequence, and selection on human (not Neandertal) mtDNA"

"Did Neandertals need better mitochondria?"

"Has the dam broken on mtDNA selection?"

Mitochondrial DNA adaptations in living human populations"

OK, that's enough related posts. But you can find a whole lot more by searching the topic!

References:

Balloux F. 2009. Mitochondrial phylogeography: The worm in the fruit of the mitochondrial DNA tree. Heredity (advance online): doi:10.1038/hdy.2009.122

Balloux F, Lawson Handley L-J, Jombart T, Liu H, Manica A. 2009. Climate shaped the worldwide distribution of human mitochondrial DNA sequence variation. Proc Roy Soc Lond B 276:3447-3455. doi:10.1098/rspb.2009.0752

Everybody's noticing the new article in PLoS Computational Biology about lactase persistence, which I've been emailed from several readers. Thanks for sending it, everyone -- it's always helpful even if I get it more than once!

The short version is that the authors place the origin in Germany around 7500 years ago, and using a 2-d forward-time dispersal model, find that fits well with the distribution of allele frequencies in Central Europe.

There's only one little problem: It's hard to see how the same scenario gets the allele to India. Or, for that matter, Ireland. The authors posit that Indian lactase persistence will be found to be caused by a "diversity" of alleles. They seem to have missed this paper that found a greater diversity of lactase-associated haplotypes "north of the Caucasus" -- consistent with an initial steppe dispersal. OK, that's two problems, and they're not little.

Their potentially interesting finding -- the dispersal of lactase persistence in their model didn't increase the diffusion of other central European genes -- should inspire more modeling. How independent can a strongly-selected allele be of its genomic background? Can selection cause demographic events without affecting unlinked neutral variation? I imagine we can explore this issue with differential equations.

(see also, Dienekes, Yann Klimentidis, GNXP)

References:

Itan Y, Powell A, Beaumont MA, Burger J, Thomas MG. 2009. The Origins of Lactase Persistence in Europe. PLoS Comput Biol 5(8): e1000491. doi:10.1371/journal.pcbi.1000491

Enatteh NS and 26 others. 2007. Evidence of Still-Ongoing Convergence Evolution of the Lactase Persistence T-13910 Alleles in Humans. Am J Hum Genet 81:615-625. doi:10.1086/520705

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.

I have had a New York Review of Books essay by Richard Lewontin, titled, "Why Darwin?" on my desktop for a week without getting to the last section of it.

Like many essays in the NY Review of Books, Lewontin's shoehorns small points from the books into an argument of his own. As you might guess from the title, Lewontin's theme is that Darwin has been overrated -- a result of biologists overemphasizing a "great man" story of the history of their science, and an unjustified belief in the ubiquity and power of natural selection. Lewontin mobilizes his argument against Jerry Coyne's Why Evolution Is True.

I don't really find the "pluralist versus adaptationist" debate very interesting. Despite the vocal complaints of some, I can't ever seem to locate the mythical "adaptationists" who deny that non-adaptive evolution ever happens. So the "debate" always comes down to whether particular adaptive hypotheses are true. Since no scientific hypothesis is true a priori, and since "those adaptationists are always saying stupid things" is not a scientific argument, I don't see the point.

Still, I meant to get to the last section of Lewontin's essay, and this morning I finally read it. To close his case for the weakness of natural selection, Lewontin turns to another new book by Greg Gibson, titled, It Takes a Genome: How a Clash Between Our Genes and Modern Life Is Making Us Sick. The book is an extended account of "diseases of civilization", a topic that I discussed here last week ("Arrested adaptation and the 'diseases of civilization'"). Here's a passage from the book's promotional material (on the Amazon page):

In It Takes a Genome, Greg Gibson posits a revolutionary new hypothesis: Our genome is out of equilibrium, both with itself and its environment. Simply put, our genes aren’t coping well with modern culture. Our bodies were never designed to subsist on fat and sugary foods; our immune systems weren’t designed for today’s clean, bland environments; our minds weren’t designed to process hard-edged, artificial electronic inputs from dawn ‘til midnight. And that’s why so many of us suffer from chronic diseases that barely touched our ancestors.

Set aside for a moment how "revolutionary" this hypothesis is -- I'll revisit the idea in another post. The question is whether this mismatch between our environments and our genetic variation means that human evolution "stopped" or that we are still "adapted to the Pleistocene". As I pointed out in my earlier post, both propositions are true: human populations are mismatched with their current environments, and human populations have been recently adapting very rapidly to new environments. Here's what I wrote last week:

[M]any 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.

I can contrast my point of view with Richard Lewontin's, who perfectly reiterates the "human evolution stopped in the Pleistocene" version of events.

An important property of adaptive evolution is that it is usually a slow process. Certainly there are cases where a single genetic change can mean the difference between life and death in a hostile environment. The classic cases are the mutations that give pathogenic microorganisms the ability to resist antibiotics or mutations that allow crops to resist pathogens, for example insects or herbicides. But these are not representative models for how species adapt, by accumulation of mutations of small effect, to changes in food availability, temperature modifications, and the thousand shocks that flesh is heir to. The usual small differences in fitness among genotypes are therefore manifest as detectable evolutionary change only after thousands of generations.

This deliberate tempo has presented the human species with a problem of adaptation. With a human generation of about twenty-five years, there have been roughly only one hundred generations since the founding of the Roman Republic. Yet the changes in the human environment caused by changes in human activity have been enormous. Changes in diet, habitation, working conditions, the pollution of air and water, and especially the considerable increase of lifespan that result in major alterations and breakdowns in the bodily machinery have all been too rapid for genetic adaptation.

Notice the false premises: Adaptive evolution is "usually a slow process." Species adapt by "accumulation of mutations of small effect." It's as if he were transported back in time to 1908 where no one had heard of the breeder's equation.

There's nothing impossible about long series of small changes. But they are not the only mode of adaptation, or even the most likely one. Populations with additive genetic variation that correlates with fitness will change rapidly under selection. The structure of the additive variation may lead to strong selection on one gene of large effect, or selection in parallel across many genes of varying effects. Series of small changes may be required for some adaptations, but a rapid environmental change (as Lewontin observes for humans) may cause bursts of rapid changes in allele frequencies.

To maintain the slowness of human evolution, Lewontin must do three things:

1. Assume humans are genetically uniform.

2. Where humans obviously are not uniform, argue that variations are uncorrelated with fitness.

3. Ignore any historical or genetic evidence that might contradict 1 and 2.

Keeping in mind the short length of this section of the essay, Lewontin does manage all three of these conditions.

I think it's downright sneaky the way Lewontin reinforces the assumption of human genetic uniformity. He refers to "the human genotype" as if there were only one! By emphasizing that "parts of the human genome are out of correspondence with modern life", he precludes the possibility that some human genomes may be more in correspondence than others. Sure, if humans share a single genome, they can't possibly differ in any adaptive way.

But diversity is the reality. Examples of recent human evolution are fixtures in biology textbooks, from sickle-cell to lactase persistence. These are traits that have rapidly changed in frequency during the last 2500 years, due to changes in recent human environments -- disease for the former, diet for the latter. These rapid transformations in precisely those that Lewontin says are impossible -- environmental changes being "too rapid for genetic adaptation." A number of morphological changes are also evident when comparing archaeological and recent skeletal samples in many parts of the world. Somehow the relevance of these recent changes goes unmentioned in the essay.

One of the best-characterized examples of evolution in recent populations is the rapid Holocene evolution of pigmentation phenotypes. It's a textbook example of human variation, and several adaptive hypotheses may explain it. So pigmentation would seem an unlikely example of how human evolution has been too slow to cope with the environment. But Lewontin finds a way:

[H]igh doses of solar radiation that is experienced by surfers on the California beaches might induce an eventually fatal skin cancer, but the cancer death almost always occurs well after reproductive age, so there is no opportunity for selection to act.

I agree that current patterns of cancer mortality of light-skinned surfers may have little impact on their fitness. In other words, this chronic disease is a sign of an environmental "mismatch" that future genetic evolution is unlikely to erase.

But why turn to false arguments about the speed of evolution to make this point? Surely Lewontin knows that "reproductive age" in humans is not synchronous with reproductive effort? Skin cancer is one of the earliest-killing cancers, with a good fraction of victims dying at ages when they might otherwise be helping raise their kids or grandchidlren. Lewontin must also know that human populations vary greatly in their skin cancer susceptibility, and that some surfers (the dark pigmented ones) have lower skin cancer rates after the same sun exposure. Skin cancer may or may not be the best explanation for dark pigmentation in low-latitude human populations (there are others, none mutually exclusive), but this example works strongly against Lewontin's claims that natural selection is "slow" and that human environmental changes have been "too rapid for genetic adaptation." We aren't perfectly adapted today, and the rate of our evolution in the recent past was very fast.

References:

Lewontin RC. 2009. Why Darwin? New York Review of Books 56(9) May 28, 2009. Online

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.

After the last post, you might wonder what the big deal is about these information theoretic measures of linkage. After all, we’ve got lots of other measures of linkage to choose in population genetics, with many years of theory behind them. The basic conclusion about genetic drift was that it adds mutual information to samples over short regions, but that recombination over longer areas washes it out. If the net effect is no linkage, why would we bother to come up with some non-standard linkage measure?

One answer: If the existing linkage measures were so great for testing neutrality, then we might expect some of the recent genome-wide selection scans to have used them. But they didn’t – instead we have several partially incompatible methods, all of which eschew the usual measures of linkage.

Colin Renfrew is an archaeologist, in recent years well-known for his work on Neolithic Europeans and Indo-European origins. Last week, someone pointed me to his recent book, Prehistory: The Making of the Human Mind. I read a short review somewhere, but I've lost the link!

The book was first published in 2007, so its writing would have predated the publication of recent scans of the genome for selection. Renfrew of course has his own distinctive point of view, and he is not himself a geneticist. However, he has worked to integrate his work with genetic insights, interacts closely with many geneticists, and even coined the term, archaeogenetics, to describe a certain kind of gene-driven investigation of population history. So he's no neophyte when it comes to how geneticists describe the evolution of recent human populations.

A number of passages of the book are very interesting, from the perspective of the conventional wisdom about recent human evolution. I wanted to cite these paragraphs from page 92:

The genetic composition of living humans at birth (the human genotype) is closely similar from individual to individual today. That was an underlying assumption of the Human Genome Project and it is being further researched in studies of human genetic diversity. We are all truly born much the same. Moreover a child born today, in the twenty-first century of the Common Era, would be very little different in its DNA -- i.e., in the genotype, and hence in innate capacities -- from one born 60,000 years ago.

Then on page 93, after some additional discussion of Neandertal genetic results:

The implication here must be that the changes in human behaviour and life that have taken place since that time [between 60,000 and 100,000 years ago], and all the behavoural diversity that has emerged -- sedentism, cities, writing, warfare -- are not in any way determined by the very limited genetic changes which, as we understand the matter, distinguish us from our ancestors of 60,000 years ago. So the differences in human behaviour that we see now, when contrasted with the more limited range of behaviours then, are not to be explained by any inherent or emerging genetic differences. Modern molecular genetics suggests that, apart from the normal distribution range present in all populations in matters such as IQ, all humans are born equal.

This represents a widespread point of view, one with a long pedigree in archaeology and human genetics (refer also to my post on Ashley Montagu). Renfrew quite clearly claimed that human evolution stopped once humans became "modern". He emphasizes this point as the basis of a "paradox" -- the observation that no large anatomical changes correlate with the increase in archaeological complexity of the last 30,000 years.

I believe there is no paradox: rapid archaeological change certainly is no proof of evolutionary stasis!