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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

The frequency of a founder mutation in the population is governed by two competing forces--someone who has two copies will probably die before reproducing, but those who have only one copy will survive preferentially over those with no copies. This produces so-called balancing selection, in which the beneficial effects drive the frequency of the mutant gene up while the harmful effects damp down the frequency. Evolution giveth and evolution taketh away, so that over time the gene maintains a relatively steady level in the population.

Researchers still have not found the advantage conferred by some disease-related founder mutations, although a genes continuing presence does point to such a benefit. One example is the persistence of factor V Leiden, a mutation in the factor V gene, which is responsible for another blood-clotting component. This founder mutation, present in 4 percent of Europeans, leads to thrombosis, a condition of pathological blood clots. In 2003 Bryce A. Kerlin and his colleagues at the Blood Center of Southeast Wisconsin and the Medical College of Wisconsin demonstrated that carriers of this mutation are resistant to the lethal effects of bacterial infections in the bloodstream, a huge threat to survival in the preantibiotics past and still a cause of death today.

A Gene Spread Round the World

LONG BEFORE modern transportation, founder mutations migrated great distances, journeys that in many cases took dozens or even hundreds of generations. The sickle cell trait migrated from Africa west to America on slave ships and north to Europe. A common founder mutation in a gene called GJB2 causes deafness; this mutation has been traced from its ancient origins in the Middle East along two routes, one along the Mediterranean coast to Italy and Spain and the other along the Rhine and Danube River valleys to northern Europe. A founder mutation in a gene called ABCA4 that causes blindness appears to have arisen in Sweden about 2,700 years ago and spread to the south and west across Europe.

The most extreme example of migration, however, is probably provided by a genetic variability in our sense of taste. About 75 percent of everyone on earth perceives a substance called phenylthiocarbamide (PTC) as very bitter. The remaining 25 percent do not experience PTC as bitter at all. My colleagues and I at the National Institutes of Health and other institutions recently discovered that the combination of three different changes brings about the form of the gene that codes for the nontaster PTC receptor. Virtually all nontasters worldwide are descended from a founder individual who had these specific alterations in this gene. (Our sense of bitter taste exists to protect us from ingesting toxic substances in plants, but what might be the advantage of the nontaster variant of the gene? We suspect that the nontaster form codes for a version of the PTC detector that has switched to sensing some other toxic substance not yet identified.)

The nontaster mutation is embedded in an exceedingly short stretch of ancestral DNA, only 30,000 base pairs in some carriers, which tells us that the founder mutation is extremely ancient--probably more than 100,000 years old. In the past few years, worldwide studies have shown that seven different forms of the PTC gene exist in sub-Saharan Africa. But only the major taster and the major nontaster forms have been found at significant frequency outside of African populations. Of the five remaining forms, one is found only occasionally in non-African populations (and never in New World natives), whereas the other four are exclusively African.

The PTC nontaster mutation provides a remarkable amount of information about early human migration. Its current distribution and frequency confirm anthropological and archaeological evidence that the original population of modern humans lived in Africa and that a small subgroup of those Africans emerged about 75,000 years ago and spread across five other continents--the Out of Africa hypothesis. All existing non-African populations descend from them. But in addition to confirming previous findings, the nontaster form helps to answer one of modern anthropologys most controversial questions: As our Homo sapiens ancestors spread across the world, did they interbreed with the more archaic hominids they met in Europe and Asia?

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