A gene responsible for a serious inherited illness can also provide a survival advantage to its carriers. This paradox is central to cystic fibrosis (CF), a genetic disorder that causes persistent lung infections and limits breathing over time. The scientific theory of heterozygote advantage explains the persistence of the CF-causing gene in some populations. This concept suggests that carrying one copy of the defective gene, without having the disease, offered protection against other historical threats.
The Genetics of Cystic Fibrosis
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7. This gene provides instructions for making the CFTR protein, which functions as a channel in cells that produce mucus, sweat, and digestive enzymes. The channel transports chloride ions, a process that helps control water movement in tissues and is necessary for producing thin, free-flowing mucus.
The inheritance pattern for CF is autosomal recessive, meaning a person must inherit two copies of the mutated CFTR gene—one from each parent—to develop the disease. Individuals with two mutated copies are homozygous recessive, and their bodies produce non-functional CFTR proteins, leading to thick, sticky mucus.
In contrast, a person who inherits one normal CFTR gene and one mutated copy is a heterozygote, or a CF carrier. These individuals do not have cystic fibrosis because their one functional gene produces enough CFTR protein to prevent symptoms. A person with two normal copies of the gene is homozygous dominant and neither has the disease nor is a carrier.
The Evolutionary Advantage Against Disease
The heterozygote advantage hypothesis for cystic fibrosis is that being a carrier offers protection against infectious diseases that were historical causes of death. The leading candidates for this protective effect are cholera and typhoid fever. Before modern sanitation and antibiotics, epidemics of these diseases swept through populations. Both illnesses cause severe diarrhea, leading to rapid and life-threatening dehydration.
This threat of death from dehydration created a selective pressure. In an environment where a cholera or typhoid outbreak could kill a large portion of the population, any inherited trait that increased survival would be more likely to be passed on. This survival advantage for heterozygotes is believed to explain why a gene with serious effects in its homozygous state has been maintained at a high frequency in certain populations.
The Biological Mechanism of Protection
The protective benefit for CF carriers lies in the cellular function of the CFTR protein within the intestines. In a healthy individual, CFTR channels regulate the secretion of chloride ions from intestinal cells into the gut, and water follows these ions to maintain liquidity. This system can be hijacked by the toxin from Vibrio cholerae, the bacterium that causes cholera. The toxin locks CFTR channels open, causing an uncontrolled flood of chloride and water out of the cells, which manifests as severe diarrhea.
The mechanism for typhoid fever, caused by Salmonella Typhi, is also linked to the CFTR protein, as the bacteria use it to enter intestinal cells. In a CF heterozygote, intestinal cells produce about half the number of normal CFTR protein channels because they have only one functional copy of the gene. This reduced number is still sufficient for normal digestive function.
During a cholera infection, this reduction becomes an advantage. The cholera toxin can only act on the channels that are present, so with half the number of functional channels, the efflux of chloride and water is blunted. The resulting diarrhea is less severe, reducing the risk of fatal dehydration. Similarly, having fewer CFTR proteins on the cell surface may limit entry points for the typhoid bacterium, reducing the severity of that infection.
Evidence and Population Genetics
Support for the heterozygote advantage theory comes from population genetics. The mutated CFTR gene is found with high frequency in people of Northern European descent, where as many as 1 in 25 individuals is a carrier. A mutation that causes a lethal disease would normally be weeded out of a population, so the high prevalence of the CF carrier state implies it conferred a significant survival benefit in the past.
This geographic distribution aligns with the history of major cholera and typhoid epidemics in Europe. These diseases thrived in the crowded, unsanitary conditions that became common as populations grew, creating the environment where a protective gene would offer an advantage. While direct proof from ancient populations is difficult, one study analyzed DNA from a Sicilian skeletal sample of individuals who died in a 1837 cholera epidemic.
Further evidence comes from modern laboratory studies. Experiments using mouse models have shown that mice heterozygous for the most common CF mutation (ΔF508) exhibit increased resistance to cholera toxin. These mice lose significantly less fluid into their intestines when exposed to the toxin compared to mice with two normal copies of the gene. Cell culture experiments have also corroborated these findings, showing that intestinal cells from CF carriers secrete less fluid in response to cholera toxin.