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Founder Mutations [Preview]

A special class of genetic mutations that often cause human disease is enabling scientists to trace the migration and growth of specific human populations over thousands of years

Two middle-aged men who live thousands of miles apart in the U.S. and have never met each other may have a common trait: a propensity to absorb iron so well that this seeming benefit can actually become unhealthy, potentially causing multiple-organ damage and even death. Someone with this condition, called hereditary hemochromatosis, often has it because each of his parents passed on to him the same mutation in a specific gene, an error that originated long ago in a single individual in Europe. The mutation was then carried through time and space in that Europeans descendants, who now include some 22 million Americans possessing at least one copy of the gene--including the two men, who might be surprised to learn that they are related. The long-gone ancestor is known as the founder of this population, and his or her genetic legacy is called a founder mutation.

Geneticists have discovered thousands of mutations responsible for diseases in humans, but founder mutations stand apart. The victims of many genetic diseases die before reproducing, stopping the mutant genes from reaching future generations. But founder mutations often spare their carriers and therefore can spread from the original founder to his or her descendants. And some of the disorders resulting from these mutations are common, such as the hereditary hemochromatosis caused by the mutation mentioned above, as well as sickle cell anemia and cystic fibrosis. (Why does evolution preserve rather than weed out such seemingly detrimental mutations? Natures logic will be illustrated presently.)

Medical researchers study disease mutations in the hope of finding simple ways to identify at-risk groups of people, as well as coming up with new ideas for preventing and treating the conditions related to these mutations [see box on page 63]. But in a remarkable by-product of such efforts, investigators have discovered that founder mutations can serve as the footprints humanity has left on the trail of time--these mutations provide a powerful way for anthropologists to trace the history of human populations and their migrations around the globe.

The Uniqueness of Founder Mutations

AN APPRECIATION of the unusual status of founder mutations and why they can provide so much information requires a brief examination of mutations in general. Mutations arise by random changes to our DNA. Most of this damage gets repaired or eliminated at birth and thus does not get passed down to subsequent generations. But some mutations, called germ-line mutations, are passed down, often with serious medical consequences to the offspring who inherit them--more than 1,000 different diseases arise from mutations in different human genes.

Founder mutations fit in the germ-line category but are atypical. Inherited diseases ordinarily follow two general rules. First, different mutations in the same gene generally cause the same disease. As a consequence, different families affected by the same disease usually have different mutations responsible for that disease. For example, the bleeding disorder hemophilia is caused by mutations in the gene encoding factor VIII, a component of the blood-clotting system. In general, each new case of hemophilia carries a discrete, single mutation in the factor VIII gene--researchers have spotted mutations at hundreds of locations in the gene.

In a few disorders, however, the same mutation is observed over and over. And there are two ways this identical mutation can arise--as a hot-spot mutation or a founder mutation. A hot spot is a DNA base pair (the individual units of DNA) that is especially prone to mutation. For example, achondroplasia, a common form of dwarfism, usually occurs as a result of a mutation at base pair 1138 in a gene called FGFR3 on the short arm of human chromosome 4. Individuals who harbor hot-spot mutations are usually not related to one another, and thus the rest of their DNA will vary, as is typical of unrelated people. Founder mutations, which get passed down intact over the generations, are quite distinct from spontaneous hot-spot mutations.

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