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DiversityWhy has the genetics community discarded so many ph
On Human DiversityWhy has the genetics community discarded so many phenotypes?
By Armand M. Leroi
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.
ON HUMAN 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.
Armand M. Leroi
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.
GETTING PAST THE SKULLDUGGERY
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.
He can be contacted at [email protected]..
http://www.the-scientist.com/2005/10/24/16/1
References
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.
