See Inside Becoming Human

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

In everyone with a founder mutation, the damaged DNA is embedded in a larger stretch of DNA identical to that of the founder. (Scientists refer to this phenomenon as identical by descent.) This entire shared region of DNA--a whole cassette of genetic information--is called a haplotype. Share a haplotype, and you share an ancestor, the founder. Furthermore, study of these haplotypes makes it possible to trace the origins of founder mutations and to track human populations.

The age of a founder mutation can be estimated by determining the length of the haplotype--they get shorter over time [see box on page 62]. The original founder haplotype is actually the entire chromosome that includes the mutation. The founder passes on that chromosome to offspring, with the founders mate contributing a clean chromosome. These two chromosomes, one from each parent, randomly exchange sections of DNA, like two sets of cards being crudely cut and mixed.

The mutation will still be embedded in a very long section of the founders version of DNA after only one recombination, just as a marked card would still be accompanied by many of the same cards that were around it in its original deck after only one rough cut-and-mix. But a marked card will have fewer of its original companions after each new cut-and-mix. And the haplotype that includes the mutated gene will likewise get whittled down with each subsequent recombination.

A young founder mutation--say, only a few hundred years old--should thus be found in the midst of a long haplotype in people who have it today. An ancient founder mutation, perhaps tens of thousands of years old, rests in a short haplotype in current carriers.

The hemochromatosis gene aberration is just one of a rogues gallery of founder mutations. A number of others are known and well studied in Europeans, and a few are now recognized in Native American, Asian and African populations [see box on page 64]. A striking fact is how common these mutations can be--hundreds or even thousands of times more frequent than typical mutations that cause disease. Most disease mutations exist at a frequency of one in a few thousand to one in a few million. But founder mutations can occur in as much as a few percent of the population.

This anomaly--shouldnt evolution get rid of these harmful genes rather than select for them?--offers an important clue as to why founder mutations persist and spread, over land and sea and across time.

The answer, perhaps not surprisingly, is that under some circumstances founder mutations prove beneficial. Most founder mutations are recessive: only a person with two copies of the affected gene, one from each parent, will suffer from the disease. The much larger percentage of people with only one copy are called carriers. They can pass on the gene to their children and have no symptoms of disease themselves, and the single copy of the founder mutation gives the carrier an advantage in the struggle for survival.

For example, carriers of the hereditary hemochromatosis mutation are thought to be protected from iron-deficiency anemia (a life-threatening condition in the past), because the protein encoded by that mutated gene makes the person absorb iron more effectively than can those who carry two normal copies of the gene. Carriers thus have an edge when dietary iron is scarce.

Perhaps the best-known example of a double-edged genetic mutation is the one responsible for sickle cell disease. The sickle cell mutation apparently arose repeatedly in regions riddled with malaria in Africa and the Middle East. A single copy of a sickle cell gene helps the carrier survive malarial infection. But two copies doom the bearer to pain and a shortened life span. The sickle cell mutation today can be found in five different haplotypes, leading to the conclusion that the mutation appeared independently five times in five different founders. (Although sickle cell disease usually results from a founder mutation, some cases do arise from other mutations.)

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