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Editor, con't
comprehend. 2) a section where we profile a Cystic Fibrosis researcher and his or her research group each month in a more personal and relaxed manner than is usual. 3) an on-line journal kept in real time by a graduate student. (From our lab) This person is working on a project involving CFTR expression, purification and structure analysis. You will be able to find out what happens to him or her the day it happens: the good, the bad, the fascinating as well as the frustrating. 4) just about everything you want to know about this important protein whether you are a CF researcher, a CF patient, or someone who knows one. |
The Latest on DeltaF508 While it might seem strange at first to contemplate that a change of a single amino acid in a protein (a deletion of a phenylalanine in position 508 in CFTR) could be responsible for a disease such as CF, nature has other examples. Sickle Cell Anemia is caused by a change of a single amino acid in hemoglobin, and there are known cases of the anti-cancer protein p53 having changes in single amino acids leading to many types of cancer. Even though life has much built in redundancy, it seems that with more complex multicellular organisms like humans that complexity comes with a price. Evolution has taught us that mutations which have high frequency in the population can often be shown to confer some kind of selective advantage for members of the species carrying only one copy of the mutation (are heterozygotes). And since any member of a species has a far greater chance of carrying only one copy of a mutation of a gene than carrying two copies, it turns out it may be strictly a numbers game. This is the reason for the various theories floating around in the CF research community for the existence of the deltaF508 mutation. The first example was the Cholera hypothesis, which was suggested by Rodman and Zumudio in 1991 and subsequently received experimental support by Gabriel, et.al in 1994. Since the bacterium which causes Cholera has been shown to make CFTR in the intestines overactive, causing diarrhea, less CFTR would undoubtedly be an advantage. Someone with only one copy of a mutation in CFTR would probably be less likely to suffer as severe a case of diarrhea. One problem with this idea is that Cholera is believed to have been a disease in the human population only hundreds or a few thousands of years at most. Yet the deltaF508 mutation has been calculated to have arisen about 50,000 years ago using microsattelite data and known molecular clock estimates for mutation. In 1998, the Typhus connection was put forth by Pier, et al. It was found that CFTR has the ability in the intestines to bind the bacterium that causes this disease and helps to get it into the bloodstream easier. So someone with less CFTR in their intestinal epithelium (a heterozygote) should be at an advantage. At present, Typhus and Cholera are the two main possibilities for the high prevalence of this mutation. In the May 2000 Journal QJM (93:313-315) commentary by Dawson and Frossard entitled "A Hypothesis Regarding the Origin and Spread of the Cystic Fibrosis Mutation deltaF508" the authors come to the conclusion that the "origional founder deltaF508 mutation giving rise to CF occurred in those inhabiting the Iranian Plateau and traveled from there eventually to Europe.." They point out that it is difficult to obtain data from various ethnic groups in Asia in order to determine ancient migration patterns among various peoples, such as the |
Baluchi people. CF patients from this
genetically isolated group in Pakistan, Iran, and Afghanistan have been
found to carry only the deltaF508 mut., and their ancient homeland is
said by many to be the Iranian Plateau.
In addition, previous population studies have shown that the farther Northwest one travels from Turkey, the less likely one will find CF patients with mutations other than the deltaF508. This is explained by the notion that the longer a particular allele is in the population, the more likely it is to mix with other alleles. For example, it the Faroe Islands in NW Europe, the frequency of the deltaF508 alone occuring among CF patients is 100%, while in Turkey it is only around 27%. In the European Journal of Pediatrics (2000, 159: 496-499) these same authors present, in addition to a theory about the deltaF508 mutation, data on two other common mutations: G542X and N1303K. They also provide a possible explanation as to why the ancient and isolated Basque people, which probably represent the oldest settlement in Europe do not exhibit the genetic heterogeneity for CF mutations as would be expected in a population around for a long time, as in Turkey. They state that as further waves of immigrants from the Middle East brought with them more CF mutations, these mutations somehow avoided mixing with the Basques, leaving them genetically isolated. The mutation G542X is hypothesized by Loirat et al. to have been spread to Turkey, the Canary Islands, Sardinia and Sicily by the Phoenicians (from Carthage) between 2500 and 3000 years ago because these areas have a much higher rate of the mutation in their populations. Another mutation, the 3120 1G to A, has been found in Greek, Saudi, and West African populations. Since there is believed to have been a continuous gene flow between Arabia and Africa for many centuries, this was not surprising. However, the mutation in the Greek population needed another explanation: that "Alexander the Great or the ancient Minoan civilisation may have been the source of contact which linked these populations with the ancient CF mutation of Africa". This second article by Dawson and Frossard goes into more detail (yet it's only 3 pages long), and provides for fascinating and added insight into population movements of the ancient world. It concludes with the following summary: "The commonest CF mutations in Europe and one rare African mutation arose as the result of initial founder effects that seem to have occurred between 30,000 and 50,000 years ago. The current spatial distribution of these mutations appears to reflect some of the history of population migrations. The survival and spread of these mutations appears to reflect some of the history of population migrations. The survival and spread of these mutations adds weight to the "gene advantage" hypothesis, whereby CF mutations may have conferred selective advantages be they against cancer, typhoid or against any other diseases that yet remain to be identified. References
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