On Human Diversity: Why has the genetics community discarded so many phenotypes?

HEAD CASES:
The physical phenotypic differences between this
Sudanese skull (right) and this European skull (left)
are apparent. (From J.L.A. de Quatrefages, E.T.
Hamy, Crania ethnica: les Cranes des races
humaines, Baillere et fils: Paris, 1882.)

Henry Flower became director of the British Museum of Natural History in 1884, and promptly set about rearranging exhibits. He set a display of human skulls to show their diversity of shape across the globe. A century later, the skulls had gone, and in their place was a large photograph of soccer fans standing in their terraces bearing the legend: "We are all members of a single species, Homo sapiens. But we are not identical." In 2004 even this went, and so it is that the world's greatest natural history museum has nothing to say to the public about the nature and extent of human biological diversity.

Of course, The Natural History Museum, as the British Museum of Natural History is now known, is not the only institution to relegate such demonstrations to the basement. After the 1960s, physical anthropologists, struggling to bury the idea of race, buried phenotypes as well – sometimes literally so, as human remains have been reinterred by aboriginal claimants. They turned, instead, to comfortably neutral genetic markers to unravel the highways and byways of human history. This magnificent enterprise has charted our species' path out of Africa using successive generations of markers: blood type, allozyme, mitochondrial DNA, the Y chromosome, and nuclear single nucleotide polymorphisms (SNPs). But is it enough? I would argue not. I would argue that it is time to resurrect the study of human phenotypic diversity.

It is one of the oddities of human genetics that, for all we know about the basis of inherited disease, we know very little about the causes of normal physical variety. Online Mendelian Inheritance in Man lists the molecular causes of about 1,800 inherited diseases. Yet we know very little about why the Dinka of the Sudan are so tall and African pygmies so small, why the Yakut of Siberia have such high basal metabolic rates, why the Sea Gypsies of Indonesia can see so well underwater, why the Yoruba of Nigeria have so many dizygotic twins, or even why the colors of our skin, eyes, and hair vary across the globe.

A NOSE FOR VARIETY:
The distribution of nasal prominence (nasodacryl subtense) in African and
European skulls. The 317 European skulls are Hungarian, Norwegian, and Austrian;
the 283 Sub-Sahara African skulls are Dogon, Zulu, and Teita. Data from Howells
(1989).

Three reasons, I believe, underlie the neglect of these traits. First, they are associated with racial biology, now unfashionable. Second, they are often of little relevance to human health. And third, they are probably genetically complex traits, influenced by multiple loci that interact with each other, and sometimes with the environment, in complex ways.

A new approach to analyzing quantitative traits, called admixture mapping, seems ideal for studying normal human variety. The principle is simple. Suppose that two isolated populations differ in some heritable attribute. Now suppose that individuals from these populations meet and mate so that, after many generations, a thoroughly admixed population of descendants exists. Each descendant will have some unique mix of the ancestral genomes, and the attributes of each will depend on what that mix is. By studying many descendants it is then possible, in principle, to map the gene (or genes) responsible for the attribute by showing that it appears only in those who have inherited a given genomic region from one, but not the other, of the ancestral populations.

David Reich's group at Harvard Medical School provided a set of ancestral genetic markers for African and European genomes.1 Screening through the hundreds of thousands of biallelic SNPs in the genomic databases, they identified 2,154 that showed substantial (>30%) differences in allele frequency between West Africans and Europeans. Moreover, software to cope with noncausal linkages that population stratification throws up has now been developed.2,3

Many think that admixture mapping will be a valuable adjunct to more traditional methods of mapping complex traits. In one promising test run, Neil Risch's group at Stanford University showed that African Americans with hypertension have a higher probability of African ancestry for two genomic regions – 6q24 and 21q21 – than their nonhypertensive relatives.4 If this result is replicated it will no longer be possible to claim that the racial disparity in the rates of this disease is due entirely to socioeconomic factors or even the direct effect of racism itself.

For admixture mapping to work, ancestral populations must differ substantially in the frequencies of disease-causing alleles. It's unclear how often this is true. Yet even if the technique isn't ultimately useful for hunting disease genes, there is another application for which it could have been tailor made: the study of normal racial variety. Recently, Mark Shriver's group at Pennsylvania State University used a form of admixture mapping in African Americans to show that two genes, TYR and OCA2, were linked to skin colors. It was the first hint of the genes underlying the diversity that is at once so commonplace and so mysterious. Even more delightful, the two genes identified were already known to be involved in pigmentation: Strong loss-of-function mutations in each cause albinism.

What might be studied next? Although a controversial topic, skulls seem an obvious choice. Studies by the American anthropologist Franz Boas nearly a hundred years ago convincingly suggested that skull shape was not heritable. He found that differences in the skulls of European immigrants arriving at Ellis Island were less evident in their American-born children. But recent reanalysis of Boas' data show that ancestral differences in skull shape were hardly influenced by environment.6

Skulls are easy to obtain, easy to measure, and vary richly in shape. In a classic study, the doyen of modern craniometry, William Howells, measured (among others) 317 European skulls and 283 Sub-Saharan African skulls in 81 different ways.7 If his data are representative they imply, for example, that European noses are, on average, more prominent than African noses, but many Africans and Europeans do not differ in this trait. Other well documented differences: European noses are set higher on the face, and are longer and narrower than African noses. Europeans have higher cheekbones, wider crania and more prominent foreheads than Africans. Europeans also have slightly longer crania than Africans, but the difference is mostly one of shape, Europeans being more brachycephalic than Africans. African jaws protrude more from the face than do European jaws (the former are more prognathic). Africans have wider orbits and wider interorbital spaces than Europeans.

These kinds of differences are simply those that we see when we look at the faces around us. They are not large, much less absolute, yet power calculations suggest that they should be amenable to admixture mapping (Leroi unpublished data). And we can make some guesses as to what sort of genes might underlie such variety. Many inherited disorders affect the face and skull, and the mutations responsible for many of them are known.8,9 For example, if one were studying interorbital distance (the distance between the eyes), 7q36 would be a good place to look, for that is the location of the gene encoding Sonic Hedgehog, which developmental and clinical geneticists have shown controls the width of our faces.

Of course, identifying the genes responsible for normal human variety is only the first step. There is a long tradition of speculation about whether racial differences in appearance are due to drift, natural selection, or even sexual selection. Such hypotheses can be tested by searching for the traces of selection in the genes that give us our looks. That, however, is for the future. And enthusiasm must be tempered by the recognition that such studies come with their own ethical and sociological problems. Medical geneticists rightly worry that misinterpretations might promote racial divisions or inflame the sensitivities of historically disenfranchised minority groups. Such concerns become even more acute when studying traits of no medical relevance and which have, as skull dimensions do, the taint of 19th-century racist science. My own view, or rather, hope, is that such concerns can be allayed given sufficient care, sensitivity, and candor on the part of researchers. Humans are, after all, the most phenotypically diverse species of mammal, perhaps animal, on earth. It would be a shame were we never to know why.

Armand M. Leroi is a reader in evolutionary developmental biology at Imperial College London. He wrote Mutants: On Genetic Variety and the Human Body, and the Channel 4/Discovery UK's series Human Mutants.

1. MW Smith et al, "A high-density admixture map for disease gene discovery in African Americans," Am J Hum Genet 2004, 74: 1001-13. [PubMed Abstract][Publisher Full Text][PubMed Central Full Text]
2. CJ Hoggart et al, "Design and analysis of admixture mapping studies," Am J Hum Genet 2004, 74: 965-78. [PubMed Abstract][Publisher Full Text][PubMed Central Full Text]
3. N Patterson et al, "Methods for high-density admixture mapping of disease genes," Am J Hum Genet 2004, 74: 979-1000. [PubMed Abstract][Publisher Full Text][PubMed Central Full Text]
4. X Zhu et al, "Admixture mapping for hypertension loci with genome-scan markers," Nat Genet 2005, 37: 177-81. [PubMed Abstract][Publisher Full Text]
5. MD Shriver et al, "Skin pigmentation, biogeographical ancestry and admixture mapping," Hum Genet 2003, 112: 387-99. [PubMed Abstract][Publisher Full Text]
6. CS Sparks, RL Jantz "A reassessment of human cranial plasticity. Boas revisited," Proc Natl Acad Sci 2002, 99: 14636-9. [PubMed Abstract][Publisher Full Text][PubMed Central Full Text]
7. WW Howells Skull Shapes and the Map, Cambridge: Mass., Peabody Museum of Archaeology and Ethnology 1989.
8. MM Cohen "Malformations of the craniofacial region: Evolutionary, embryonic, genetic, and clinical perspectives," Am J Hum Gen 2002, 115: 245-68.
9. AM Leroi Mutants: On Genetic Variety and the Human Body, Viking: New York 2003.

The reason why they don't study it is that too many biologists of the 19th century, filled with Darwinist zeal, tried to use phenology to arrange human races into an evolutionary model of more and less advanced humans on an evolutionary scale, going so far as to look at Tasmanians as a "missing link". The same thing happened with the study of general intelligence or IQ. Basically, both areas of study were used toward (generally unwarranted) racist and have thus cast a racist shadow over the whole enterprise. People feel that even talking about such issues seriously is to step upon a slippery slope that ends no place good.

Zeal they had, but it was racist zeal not Darwinist. Evolution through natural selection would make one assume that each human population was suited to the climate its recent ancestors had come from. Darwin, who was quite progressive for a man of his day (he related the bravery of a woman who killed herself rather than submit to slavery and questioned that if her skin where white wouldn't her sacrifice be compared to a Roman matron rather than brute animal obstinacy in the Voyage of the Beagle), Darwin was convinced by the shoddy "science" of racist skull shapers that some human populations would eventually prove unfit or evolve. Modern science shows that there is very little actual genetic difference and that we are all more recently one people than anyone had imagined.

Darwinism colored the way in which that racism was carried out (pseudo-scientifically) much as Christianity colors the way that some modern racism is carried out. And the idea that they got from Darwinism, and you can certainly argue that they were missing the point, was that if humans evolved from apes, that some humans might be more "ape like" than others if they were more primative on the evolutionary scale.

Going back to my broader point, it was meant to explain why science is so reluctant to talk about physiological racial differences or even the entire topic of general intelligence. It's because those theories have a long history of being abused by racists to give their racism some credibility by tying it to science. The idea is that certain ideas end no place good, and I think you'll find some of those same sentiments in the opposition to evolution.

There is no "primitive on the evolutionary scale" or 'advanced on the evolutionary scale'. There is no progress in evolution, only adaptation.

I agree that one reason that people don't get into this field is due to the racist that have so thoroughly muddied the water, but there is really little utility in it OTHER than assigning skulls to one group or the other in groups that are not otherwise different in much of a relevant degree. The motive behind this is usually racist to begin with.

Its hard to show how such a small difference between human populations is worth discussing, worth investing the time and money to research, or is going to actually help anybody. There are not medicines that will or will not help you dependent upon the shape of your skull. There is, however, medicine that will or will not help you based upon your genotype. Thus allelic differences get studied because they are useful. Skull shape differences are not useful except to archaeologists or racists.

Skull shape differences are not useful except to archaeologists or racists.

And like I said, once you've come to that conclusion, you've put the burden of proof upon anyone who claims otherwise to prove it, which becomes a matter of proving that they aren't secretly engaged in the though crime of racism, which is an impossible task. Even if certain questions are normally asked for entirely racist reasons, is it really scientific to declare engire ranges of questions and knowledge off limits because it might be misused by racists?

In a society where a sports team can get sued for having no athletes of a particular race or sex or a company can be sued for having no employees of a particular race or sex in a particular job category, determining where the discrepancy comes from can lead to issues of morphology and general intelligence. Since we are a society that is so obsessed with racial and ethnic differences, they should be studied, and it could be useful to know if the prevailing dogma (which may very well be true) that there are no important differences between the races really is true if we are going to base public policies on top of those assumptions.

For the record, I do think it's important to scrutinize such research to some degree to make sure that it's not simply racist pseudo-science but I think that the assumption that any researcher who studies such issues must be racist or motivated by racism and a refusal to accept any explanation or assurances that it isn't is going way too far.

They don't have to prove that they are not a racist, they just have to prove that their study will be of some possible use if it is to receive funding.

I recommend "The Mismeasure of Man" by Steven Jay Gould for a history of this widely discredited theory of skull shape and racial differences. The situation got so bad that people actually used the shape of someone's skull to determine if they were the "criminal type" or not, and therefore capable of rehabilitation, or even if they were capable of committing a crime.

Yes, I know all about "The Mismeasure of Man". I've seen it used to claim that IQ tests are inherently racist. It's basically playing "guilt by association". I've already given you the non-racist use. If we are going to set public policy based on the assumption that there are no significant differences between the races (or even the sexes -- yeah I've heard people claim that), it would be nice if science could determine if this is a reasonable assumption to have or not.

If black kids are scoring one standard deviation lower than white kids on IQ tests, it would be useful to know if the cause is something we can do something about (culture, instruction, etc.) or something we can't do something about (genetics) because if we make the wrong assumption, the policies inacted will, at best, be useless and, at worst, be racist. You can't do that if the entire subject area is considered off limits.

For the record, I don't believe that average IQ differences between blacks and whites as populations are genetic. I do think they are cultural and/or environmental. Perhaps that's why I don't fear such research, so long as it's done properly. I can see great value in demonstrating that IQ and achievement differences between the races is cultural rather than simply assuming it and declaring the subject off limits. That only makes the real racists think that science has something to hide. Basically, I think that such research could provide a fatal blow to some racist ideas that have been carried forward from those early days of measuring skulls.

But there has been much good Science done on the subject and the verdict is in. There is much less actual difference on a molecular level between all human populations than anyone ever assumed. Anyone who says that the work hasn't been done, or that the definitive answer is to be found in the shape of skulls rather than in genotype, is trying to sell something and it usually isn't something nice they are trying to sell.

And the difference is cultural, not genetic. Middle class black children raised in houses with books do much better than lower class white children raised in houses without books in just about every measure. Family income and literacy are far better indicators of academic success than skin color.

But there has been much good Science done on the subject and the verdict is in. There is much less actual difference on a molecular level between all human populations than anyone ever assumed.

The quantity or quality of differences on a molecular level do not necessarily relate the the quantity or quality of differences on a gross physical level. The molecular differences that lead to certain genetic diseases can be very small but the effects can be profound.

Anyone who says that the work hasn't been done, or that the definitive answer is to be found in the shape of skulls rather than in genotype, is trying to sell something and it usually isn't something nice they are trying to sell.

Please note that I'm not simply talking about skull shapes, though I don't think it's unreasonable to wonder whether the shape and size of a brain affects the function of the brain and whether the shape and size of the brain's container (the skull) reflects or determines the shape and size of the brain and thus how it functions. I'm talking about studying the distribution of just about any trait along racial or sexual lines. All such research has become off-limits on the basis that it must inherently be racist or sexist.

And the difference is cultural, not genetic. Middle class black children raised in houses with books do much better than lower class white children raised in houses without books in just about every measure. Family income and literacy are far better indicators of academic success than skin color.

As I said, I believe this, too. And it's my relatively certainty that this is true that makes me not fear such research. Properly done, such research should show that skull shape and brain size really do have no impact on general intelligence.

"Properly done, such research should show that skull shape and brain size really do have no impact on general intelligence."

There is a correlation between size of the brain and intelligence, but if you think correlation is causality you can have Andre the Giant for your academic decathlon, and I'll take the small skulled Steven Hawking. And once again I reiterate, there is no real payoff in doing this type of work. Even if you discover a high correlation between some skull feature and high intelligence how do you use this data to profit anyone?

To anyone relying upon actual scientific data, the racists have already been silenced.

I'm not really sure they have been, otherwise you wouldn't see mention of things like The Bell Curve and articles like this popping up so frequently, particularly on conservative web sites and magazines. It also doesn't help that the actual scientific data is stretched, thanks to people like Gould, into a general attack on the very idea of general intelligence. Have you read Jensen's responses to Gould? Further, Scientific American had an issue about intelligence not all that long ago that painted a much less certain picture of current views general intelligence than Gould's proponents often claim exists. And if you want to know why I think letting social implications drive science can be problematic, I'll point you to this old favorite, which comes frighteningly close to how a lot of liberals I've had discussions with online seem to view any linkage between biology and behavior. They consider the whole subject off limits, holding up Gould as support.

As far as how to use the information to "improve intelligence"; I'm not sure exactly what you are advocating. How would you use the data to improve intelligence?

For example, I've read about some recent studies which suggest that that the density of certain brain tissue, as well as size, is important. If we can understand what contributes to intelligence and then understand the environmental factors that might encourage or discourage that sort of brain development, we might be able to give children, either before birth or even after, a better environment in which to achieve intelligence rather than simply guessing with things like "Listening to Mozart makes kids smarter."

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