Cystic fibrosis is the most common genetic disease among people of European descent. It is an autosomal recessive disorder caused by a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. When a child inherits two copies of the mutated gene, the cystic fibrosis disease develops. People who have just one copy of the mutation are carriers, and are generally not affected by symptoms of cystic fibrosis.
The CFTR protein regulates the transport of salts into and out of cells. When mutated, the protein does not function normally, and the balance of fluids and salts is disrupted. As a result, cells produce a thick, sticky type of mucus that can obstruct airways and harbor the growth of infectious bacteria. Cystic fibrosis affects the lungs quite severely, but also affects many other organs of the body.
Until recently, children born with cystic fibrosis rarely survived past the age of five. However, 1 in 20 people of European ancestry are carriers. That suggests that the gene may confer a survival advantage, in addition to causing a deadly disease, since a gene leading to such a deadly disease would otherwise tend to dwindle in the population due to selective pressure against it.
There is precedent for that type of double-edged evolutionary gift. The mutation that causes sickle cell disease leads to illness when a person has two copies of the gene. However, people who carry just one copy enjoy resistance to a deadly form of malaria.
In the case of cystic fibrosis, the evolutionary advantage it confers is still a matter of debate. One theory is that it may give resistance to cholera or other illnesses that cause diarrhea and dehydration. The logic of this theory is that the altered salt and water balance may protect against dehydration during bouts of severe diarrhea.
Vibrio cholerae, the organism that causes cholera, binds to the cells of the small intestine and causes all of the transmembrane regulatory proteins, including CFTR, to pour salt and water out, resulting in diarrhea. A study in mice with cystic fibrosis showed that their intestines did not secrete fluid when infected with V. cholerae. Those mice carrying only one copy of mutant CFTR expelled half as much fluid as normal mice.
Another theory points to typhoid as the source of the advantage of the cystic fibrosis gene. Salmonella typhi, the bacteria that causes typhoid fever, binds to CFTR to gain entry into intestinal cells. In a study in mice with defective CFTR, S. typhi bacteria were prevented from entering the intestinal cells.
However, scientists have subsequently calculated the effects of such a survival advantage against cholera and typhoid and determined that a gene offering protection against those illnesses would not confer enough of a selective advantage to drive the prevalence of the gene to its high levels among Europeans.
The model did show that a gene that was protective against tuberculosis would give enough advantage to result in a 1 in 20 carrier rate. Tuberculosis was very common in Europe in the 17th, 18th, and 19th centuries. During that time, 20 percent of all deaths were caused by tuberculosis. A gene that gave an advantage against tuberculosis could mathematically have increased in prevalence to the current levels.
The most common mutation leading to cystic fibrosis is f508del. Researchers have traced the origins of the mutation to two separate events. It was first introduced into European populations about 50,000 years ago, possibly through the Basques of Spain, who have a notably high rate of cystic fibrosis today.
A second introduction of the gene occurred with the inception of agriculture in Europe, about 10,000 years ago.
The evolution of cystic fibrosis as a mutation that confers an advantage in carriers and a deadly disease in those with two copies, is likely to be complex, and may involve protection against more than one type of illness. Scientists are still exploring the evolutionary role of the cystic fibrosis gene.
Reviewed by Liji Thomas, MD.
- The New York Times, Cause of Cystic Fibrosis is Traced to the Stone Age, http://www.nytimes.com/1994/06/01/us/cause-of-cystic-fibrosis-is-traced-to-the-stone-age.html
- Science, A Silver Lining for Cystic Fibrosis? http://www.sciencemag.org/news/1998/05/silver-lining-cystic-fibrosis
- Bryn Mawr, Selective Advantages of the Mutant CFTR Gene, http://serendip.brynmawr.edu/biology/b103/f02/web1/emyers.html
- Discovery, Hidden Benefits, http://discovermagazine.com/1995/mar/hiddenbenefits485
- New Scientist, Cystic fibrosis gene protects against tuberculosis, https://www.newscientist.com/article/dn10013-cystic-fibrosis-gene-protects-against-tuberculosis/