The symptoms of cystic fibrosis are anything but pretty. Thick mucous in the lungs clogs the airways and provides a comfortable breeding ground for bacteria to thrive.
Before the 1960s, patients with cystic fibrosis died of lung infection before they reached the age of four. Yet it remains one of the most common genetic diseases in people of European descent. What could have allowed the cystic fibrosis gene-and other deadly hereditary diseases-to persist for so long?
“There was pressure in the population-either now or in the past-that made the disease more common than you may anticipate by random chance,” explained Dr. Johanna Rommens, a geneticist at the Hospital for Sick Children and one of the scientists who had identified the gene responsible for cystic fibrosis, called CFTR.
One of such pressures may be that the ‘heterozygote advantage’, the situation in which a carrier of cystic fibrosis-a person with one healthy and one defective copy of the gene-has a better chance of survival than one with two normal or two defective copies. Scientists hypothesized that having a single copy of the defective gene protects against conditions such as cholera and tuberculosis, allowing carriers to survive these infections, so future generations inherit the defective copy.
The classic example of the heterozygote advantage is sickle-cell anemia. Those with two defective copies of the sickle-cell gene die prematurely when their deformed red blood cells clog blood vessels. However, carriers of sickle-cell anemia-having one copy of the defective gene-do not show symptoms of it and are more resistant to malaria than either normal individuals or those with sickle-cell symptoms. Though possessing two copies of the defective gene is fatal, possessing only one can protect a person against death from malaria. In Africa and other developing countries, infection with the malaria parasite is often fatal and still occurs today with high frequency.
Researchers propose that cystic fibrosis, like sickle-cell, has persisted for similar protective purposes. Cystic fibrosis is caused by a mutation in the CFTR gene, which is important in every surface of the body, including the lining of the lung, the pancreas, and the reproductive system. Normally, the CFTR gene is responsible for maintaining the proper balance of salt and water inside cells of the major organs.
Past research has shown that having the defective CFTR gene is beneficial in surviving a cholera infection. Vibrio cholerae, the bacteria responsible, produces a toxin that causes cells to release water, leading to diarrhea and dehydration. Carriers of the CFTR defect express only half the normal amount of the CFTR protein, but enough to evade the symptoms of cystic fibrosis. In a cholera infection, this genetic defect actually helps the body retain water and prevents dehydration. Cholera outbreaks, then, may have allowed this defect to flourish in human populations.
The cholera outbreak during the Industrial Revolution has been implicated as one of the main events that pushed the CFTR mutation to its current rates of appearance.
“You can have an effect that happened four generations ago but still see it in today’s population,” explained Rommens.
Today, tuberculosis is another candidate for cystic fibrosis prevalence. A recent publication has analyzed the historical demographic data and concluded the tuberculosis pandemic between 1600 and 1900 may have selected strongly for carriers. Cystic fibrosis patients have decreased activity in the arylsulfatase B enzyme, on which the tuberculosis bacteria relies.
If past malaria, cholera and tuberculosis outbreaks had shaped the gene pool of the present, it is no doubt that current pandemics like HIV/AIDS are exerting a selective pressure on the global population right now and will change the genetic variation of the future.
“AIDS can select for certain immunological responses,” Rommens said.
HIV may be driving the spread of certain mutations that confer resistance to AIDS, for example, the CCR5 gene. The gene determines how long after infection the symptoms of AIDS appear, and scientists postulate the CCR5 mutation that delays the onset of AIDS will become more predominant in the population over time. Whether the mutation is harmful on its own, like sickle-cell or cystic fibrosis, remains to be seen.
“AIDS influences the immune system dramatically,” said Rommens. “We will see its effects in a hundred years.”
