Cystic know to exist within CFTR, some
Cystic Fibrosis is an autosomal recessive disorder found very commonly amongCaucasians (Bosch et al., 2017). A mutation to the Cystic Fibrosis TransmembraneConductance Regulator (CFTR) gene is what causes the disease (Morral et al., 1994). TheCFTR gene leads to the transcription of a CFTR protein, which is an ATP-gated ion channelfound on cell membranes (Callebaut et al.
, 2017). Mutation to CFTR result in nonfunctionalCFTR, thus causing patients to develop the disease cystic fibrosis.CFTR is a part of a superfamily of proteins, called ATP-binding cassette (ABC)proteins, which are transmembrane transport proteins (Callebaut et al., 2017). Thissuperfamily evolved from a mutation to a particular protein motif, called a Walker B motif(Callebaut et al., 2017).
This mutation, allowed for the proteins specific ATP bindingcharacteristics without having water attack the ATP molecule (Callebaut et al., 2017).CFTR evolved from the other genes encoding proteins in this family, because CFTR doesnot involve active transport, as to all the other members of the CFTR family (Callebaut etal.
, 2017). The mutations acquired by CFTR allowed for CFTR to be made as a chlorideanion channel found in cell membranes.There are currently thousands of mutations know to exist within CFTR, some ofwhich affect the protein’s function in the cell membrane and some that affect the correctfolding of the protein into it’s native configuration, so the protein is targeted forEvolution of the CFTR genein Cystic Fibrosisdegradation before being incorporated into the cellular membrane (De Boeck et al.
, 2014).The frequency of these different mutations varies greatly in different populations andethnicities, and the vast majority of these mutations to CFTR cause cystic fibrosis (DeBoeck et al., 2014). This demonstrates the evolutionary selective advantage for thesemutations since they are being kept in populations in significant amounts and are notdecreasing in frequency, as would be expected by harmful disease-causing mutations.The most common mutation in CFTR for Caucasian European populations is thecystic fibrosis causing F508del mutation, which is a three base pair deletion from thewildtype allele (Morral et al., 1994; Cabello et al.
, 1999). This mutation is contained in thevast majority of chromosomes in North American and Northern European populations, butis contained in less than half of the chromosomes in certain Mediterranean populations(Morral et al., 1998). The evolution and origin of this mutation as well as the evolutionaryselective pressures placed on it attempt to explain the different frequencies of this mutationin various populations and its extreme prevalence in Caucasian populations.Based on microsatellites sequenced on the chromosomes containing CFTR, it wasdetermined that the origin of the F508del mutation was upwards of 52,000 years ago(Morral et al.
, 1994). With this information, it is clear that the F508del mutation providesan advantage, as it would not have been maintained in such a high frequency based onwhen it originated if the mutation was strictly harmful (Morral et al., 1994). The mutationpredates the current European population, and so if there were no evolutionary pressureson the mutation, it would have been present in equal numbers throughout the population(Morral et al.
, 1994). Since there is a clear difference in the allele frequency between populations, there is likely environmental selective pressures acting on the F508delmutation in CFTR.Suggestions have been made that being a carrier of one F508del mutation, confersa genetic resistance to various diseases (Bosch et al.
, 2017). This genetic resistance wouldgive rise to a heterozygote advantage for the F508del mutation, thus explaining thepersistence of the mutation over time, though it causes disease when a person has twomutated alleles. A study conducted by Bosch et al., examined the relationship between theoccurrence of tuberculosis and the prevalence of the F508del allele in Brazilian populations(Bosch et al., 2017). It was found that there is a significant negative relationship betweenthe frequency of the F508del mutation and the infection rate of tuberculosis (Bosch et al.
,2017). This provides evidence that the F508del mutation provides genetic resistance totuberculosis, causing it to be selected for in populations with high tuberculosis infectionrates. It is hypothesized that White Plague, a large tuberculosis outbreak in Europe, causedthe mutation to be selected for and accounts for the high F508del mutation frequency inCaucasian populations (Bosch et al., 2017).
Other populations likely did not have the sameenvironmental selective pressure, and so some populations including two Brazilianpopulations have F508del mutations significantly lower than the average frequency(Giselda et al., 1999).CFTR has evolved to have many different haplotypes with many differentmutations pertaining to those haplotypes (Callebaut et al., 2017). CFTR is still evolvingtoday, as seen by many of the frequencies of different mutations are not under HardyWeinbergequilibrium (Cabello et al., 1999).
The CFTR gene evolved to be an ion channelin the cell membrane, and then evolved to carry many different mutations that inhibit its function to do so. CFTR is still under selective pressures and is evolving today in responseto environmental factors incurring a benefit to have certain alleles over others.