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Biology 103
2002 First Paper
On Serendip

Selective Advantages of the Mutant CFTR Gene

Erin Myers

Selective Advantages of the Mutant CFTR Gene

Cystic Fibrosis is the most common, lethal disease among Caucasian people.  In the United States4, Canada6 and the United Kingdom9 approximately 1 in every 2,500 children are born with cystic fibrosis.  1 in 25 Caucasians are carriers of the mutant gene that causes Cystic Fibrosis4.  Such a lethal disease that until recently killed its victims long before they could reproduce, should have died out long ago through natural selection.  But the CFTR (cystic fibrosis transmembrance regulator) mutant gene's survival for over 52,000 implies a selective advantage of the mutant gene that causes Cystic Fibrosis2.


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)



A    N




R     n









Cystic Fibrosis














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 Europe in the 1800's for the frequency of mutant CFTR carriers to be as high at 1 in 25.  Gerald Pier of Harvard Medical School aggress that heterozygote advantage caused the high frequency of mutant CFTR genes in the Caucasian population but the advantage is for the resistance to typhoid fever.  They found that Salmonella typhi, the causal agent for typhoid fever invades the gastrointestinal cells by attaching to the normal CFTR protein as the first step in eventual infection of the bloodstream, but blockage of these chloride channels also block entrance of the Salmonella typhi into the cells and Salmonella typhi cannot attach to the most common CFTR mutation.  The widespread incidence of typhoid fever over much of European History would account for the high frequency of CFTR mutation in Caucasian people of European decent.  On the other hand Michael Swift of New York Medical Center has proposed that CF heterozygotes are more resistant to asthma3.  All of these hypotheses explain the heterozygote advantage of Cystic Fibrosis but fail to explain why they would not be just as beneficial to other parts of the world.


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 University of California at Riverside argues that the cystic fibrosis mutation may not have survived outside Europe because in hot climates it entailed an additional disadvantage.  He asserts that salty sweat associated with Cystic Fibrosis is more of a disadvantage in hot climates than protection against diarrhea.  Experiments have shown that CF carriers have saltier sweat than people with two normal alleles.  The Human body is made to conserve salt, which until recently was a precious commodity.  Humans in hot climates that spent a lot of time running after prey could not afford to loose as much salt as a carrier would.  Carriers in this environment would be more susceptible to dehydration2.


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.




Internet Sources

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

9United Kingdom Cystic Fibrosis

10Scientific American CF article, genetic defects underlying the disease

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