Monday, October 24, 2005

Why has the genetics community discarded so many phenotypes?

Armand M. Leroi:

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.

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. 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.

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. 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.

A High-Density Admixture Map for Disease Gene Discovery in African Americans

Skin pigmentation, biogeographical ancestry and admixture mapping

The Specter of Difference

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