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2002 First Paper
Cystic Fibrosis is the
most common, lethal disease among Caucasian people. In the
Cystic Fibrosis is an autosomal recessive disease. For one to have Cystic Fibrosis both of his or her parents must have the mutant gene (ignoring the minute chance of spontaneous mutation). He or she has inherited two mutant genes, one from each parent (he or she has no normal CFTR genes. When two carriers have a baby there is a 25% chance their baby will not carry a mutant CFTR gene (homozygote dominant), a 25% chance their baby will have cystic fibrosis, carrying two mutant CFTR genes (homozygote recessive), and a 50% chance their baby will be a carrier of a mutant CFTR gene (heterozygote), as illustrated in the diagram below.
normal (N) mutant (n)
Cystic Fibrosis affects the respiratory and digestive systems. The CFTR protein normally forms channels in cell membranes, though these channels flow chloride ions. In the lungs this washes away bacteria, mucus and other debris. In the intestines it washes away pathogens and brings digestive enzymes in contact with food. In sweat glands these channels recycle salt out of the glands and back into the skin before it is lost to the outside world2. In a person with Cystic Fibrosis thick mucus blocks these channels. Their body cannot perform these functions. This leads to mucus buildup in the lungs, a prime breeding ground for bacteria. In the small intestine the enzymes that break down fat cannot get to the food and digestive problems arise. On a hot day a person with Cystic Fibrosis is at risk to dehydration10.
For years scientists have been studying the possible benefits of the mutant CFTR gene. In 1967 A.G. Knudsen, L. Wayne, and W.Y. Hallett published an article in the American Journal of Human Genetics. They collected data of the numbers of live offspring of the Grandparents of CF children. They found that the mean number of offspring for grandparents of CF children was higher (4.34) than the grandparents of a control group (3.43) with only 0.30 standard error, concluding that CF heterozygotes was associated with successful childbirth, and selectively beneficial.
In more recent years scientist identified the advantages of mutant CFTR carriers surviving cholera. The lethal strain of Cholera, Vibrio cholerae, produces a toxin that binds to the cells of the small intestine opening all of the transmembrance regulating ducts pumping out considerable amounts of chloride ions and water — about five gallons a day1. If the salt and water are not quickly replaced the infected person dies of dehydration. Sherif Gabriel, a cell physiologist of UNC Chapel Hill, experimented with mice that carried the CF mutation and cholera. Not surprisingly, the intestines of mice with cystic fibrosis infected with cholera secreted no fluid. They lacked chloride channels. The amazing discovery he found was that mice that carried one mutant CFTR gene secreted only half the liquid than the non-carrying mice. Gabriel concluded that when cholera infected humans that carried a mutant CFTR, half as much fluid secretion may have been enough to flush the intestines of the toxin without succumbing to diarrhea, dehydration and death2. This selective advantage to the many European outbreaks of cholera may explain the high frequency of the gene mutation in Caucasian people of European decent. This argument, however, has been challenged recently on the basis of time.
Not enough time has
past since Cholera reached
The reason the
frequency of CFTR heterozygotes4 in the
Caucasian Populations is so much higher at 1 in 25 than those of Hispanics
(1/46), Blacks (1/60), and Asians (1/150) has to do with a comparative
disadvantage that out ways advantages in the indigenous areas of these people. Physiologist Paul Quinton of the
It seems that one way or another, dehydration is the variant in the frequency of cystic fibrosis. In the cooler climate of Northern Europe the mutant CFTR gene protected people from many fatal diseases that cause diarrhea and dehydration (cholera, typhoid, E. coli), but in the warm climates of the Americas, Southern Europe, Africa and Asia this advantage was out weighed by the threat of heat related dehydration. It is interesting to see the advantages of diversity even in something as small as a gene.
1How Cholera Became a Killer, the one deadly strain of Vibrio Cholerae
2Hidden Benefits, the 52,000 year survival of the mutant gene that causes CF
3Cystic Fibrosis and Typhoid Fever, rejection of the cholera hypothesis
4US Population Frequency, statistics of the frequency of CF affected and carriers
5Selective Advantage of CF Heterozygotes, 1960's study of live births among CF carriers
6Canadian Cystic Fibrosis Foundation, tons of basic facts with search option
7WebMD—Cystic Fibrosis, symptoms, cause, treatment, references
8Cystic Fibrosis Research Directions, more sophisticated fact sheet
10Scientific American CF article, genetic defects underlying the disease
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