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

These archaic hominids would almost certainly have had their own forms of the PTC gene, selected for as a response to natural toxins in the local flora. If other hominids produced offspring with H. sapiens partners, we would then expect to find different forms of the PTC gene in European, East Asian or Southeast Asian populations. But there is a conspicuous absence of such variation. We therefore believe that the examination of founder mutations in humans alive today shows that no successful interbreeding between H. sapiens and other human groups took place during this great out-migration tens of thousands of years ago.

Finding a Founder

A CLOSER LOOK at the haplotype at the root of hereditary hemochromatosis shows how the conjunction of historical records and genetic analysis of current populations can provide new insights into the causes and history of a particular condition. In the 1980s, before the gene for this disease was identified, medical geneticists found that almost everyone with the condition had a virtually identical stretch of DNA on one part of chromosome 6. This finding was stunning because most of these patients were apparently unrelated to one another and would thus have been expected to have random differences at any place in the sequence. Because of this unique stretch of DNA, researchers realized that patients with hereditary hemochromatosis most likely were all descendants of a common, long-lost ancestor and that the gene responsible for the condition probably sat within the shared area.

Operating on this hypothesis, our research group in the 1990s performed a detailed analysis in 101 patients of the genes we could find in the relevant region of chromosome 6. We also looked at the DNA of 64 control subjects who did not have hemochromatosis. Most patients shared a long region of several million base pairs. A few, however, matched in only a smaller fraction of this region. When we compared the part of chromosome 6 that matched in all the patients, we found that this region contained 16 genes. Thirteen of the genes coded for proteins known as histones, which bind to and wind up DNA into sausage-shaped structures visible under the microscope during cell divisions. Histones, and the genes for them, are virtually identical throughout living things, so we thought it was unlikely that they were involved in hemochromatosis. That left three genes of interest.

Two of the genes were the same in the hemochromatosis patients and the healthy control subjects. But in one of those genes, now designated HFE, we discovered a mutation that was present in people who had the disease but conspicuously absent from those who did not have an iron problem. This gene thus had to be the one containing the founder mutation that causes hereditary hemochromatosis.

Our discovery of the hemochromatosis founder mutation immediately led to several questions, including, Who was this founder? When and where did this person live? Chasing the answers to these questions led medical geneticists to join forces with anthropologists and historians. Surveys showed that hereditary hemochromatosis occurs all across Europe but is somewhat more common in northern Europe. In addition, the founder mutation was present in virtually all patients in the north but appeared in less than two thirds of the eastern and southern European patients. That result meant that the other third had some other mutation in the HFE gene or perhaps actually had a different iron disorder altogether.

Focusing in on northwestern Europe, more detailed genetic surveys revealed that the highest frequency of the founder mutation occurs in Ireland, western Great Britain and across the English Channel in the French province of Brittany. This pattern almost perfectly overlaps the current distribution of a particular group of people: the Celts.

The Celts rose to power in central Europe more than 2,000 years ago. Some were displaced northward and westward by the expanding Roman Empire, whereas others intermixed with southern Europeans and remained in their original location. Did the hemochromatosis founder mutation arise in central Europe and move north with its migrating carriers? Or did it originate in the north? Additional studies of the surrounding DNA on chromosome 6 led to the probable answer.

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