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.
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.)
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?
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.
The extensive length of the modern haplotype indicates that the founder mutation is quite young. Exactly how young has been a subject of much discussion among scientists. The methods for estimating the age of these mutations make a number of assumptions and give us an age range, rather than an exact age. In the case of the hemochromatosis mutation, the majority of the estimates suggest that it arose 60 to 70 generations ago, around A.D. 800 and long after the fall of the Roman Empire. Such a young age suggests that our founder mutation most likely originated in northwestern Europe and spread southward. Other evidence, including the mutations high frequency in Norway, has led to an alternative hypothesis that it is older, perhaps even predating the Roman Empire. Further use of DNA markers in European populations is likely to settle this question.
Anthropologists, notably Luigi Luca Cavalli-Sforza of Stanford University, have previously studied other types of DNA variants to trace populations. Founder mutations now add a new dimension to DNA studies: calibrating the haplotype length dates the mutation, and calculating the frequency of the haplotype in the population measures the geographic spread of the founders descendants.
Each of us bears biochemical witness to the fact that all humans are indeed members of a single family, bound together by the shared inheritance of our genome. In addition to confirming the Out of Africa hypothesis, analyses of founder mutations have revealed the common ancestry of various other seemingly unrelated groups--research by David B. Goldstein of Duke University, for instance, has revealed an unexpected genetic connection between the Celts and the Basques. Further investigations of founder mutations and their haplotypes will no doubt reveal more of the genetic relationships that give us new insights into where we came from and how we arrived at our modern locations. Such study also reveals surprising kinships that may inspire a deeper appreciation for the shared roots of humanitys family tree.
DENNIS DRAYNA received his bachelors degree from the University of WisconsinMadison in 1975 and his Ph.D. from Harvard University in 1981. He did a postdoctoral fellowship at the Howard Hughes Medical Institute at the University of Utah and then spent 14 years in the biotechnology industry in the San Francisco Bay Area, where he identified a number of different human genes involved in cardiovascular and metabolic disorders. In 1996 he joined the National Institutes of Health, where he currently serves as a section chief in the National Institute on Deafness and Other Communication Disorders. His primary research interests are the genetics of human communication disorders, work that has taken him to eight different countries on four continents in pursuit of families with these disorders. In his spare time he enjoys technical rock and ice climbing in equally far-flung places.