Cystic know to exist within CFTR, some
Cystic Fibrosis is an autosomal recessive disorder found very commonly among
Caucasians (Bosch et al., 2017). A mutation to the Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR) gene is what causes the disease (Morral et al., 1994). The
CFTR gene leads to the transcription of a CFTR protein, which is an ATP-gated ion channel
found on cell membranes (Callebaut et al., 2017). Mutation to CFTR result in nonfunctional
CFTR, 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). This
superfamily 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 binding
characteristics without having water attack the ATP molecule (Callebaut et al., 2017).
CFTR evolved from the other genes encoding proteins in this family, because CFTR does
not involve active transport, as to all the other members of the CFTR family (Callebaut et
al., 2017). The mutations acquired by CFTR allowed for CFTR to be made as a chloride
anion channel found in cell membranes.
There are currently thousands of mutations know to exist within CFTR, some of
which affect the protein’s function in the cell membrane and some that affect the correct
folding of the protein into it’s native configuration, so the protein is targeted for
Evolution of the CFTR gene
in Cystic Fibrosis
degradation before being incorporated into the cellular membrane (De Boeck et al., 2014).
The frequency of these different mutations varies greatly in different populations and
ethnicities, and the vast majority of these mutations to CFTR cause cystic fibrosis (De
Boeck et al., 2014). This demonstrates the evolutionary selective advantage for these
mutations since they are being kept in populations in significant amounts and are not
decreasing in frequency, as would be expected by harmful disease-causing mutations.
The most common mutation in CFTR for Caucasian European populations is the
cystic fibrosis causing F508del mutation, which is a three base pair deletion from the
wildtype allele (Morral et al., 1994; Cabello et al., 1999). This mutation is contained in the
vast majority of chromosomes in North American and Northern European populations, but
is 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 evolutionary
selective pressures placed on it attempt to explain the different frequencies of this mutation
in various populations and its extreme prevalence in Caucasian populations.
Based on microsatellites sequenced on the chromosomes containing CFTR, it was
determined 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 provides
an advantage, as it would not have been maintained in such a high frequency based on
when it originated if the mutation was strictly harmful (Morral et al., 1994). The mutation
predates the current European population, and so if there were no evolutionary pressures
on 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 F508del
mutation in CFTR.
Suggestions have been made that being a carrier of one F508del mutation, confers
a genetic resistance to various diseases (Bosch et al., 2017). This genetic resistance would
give rise to a heterozygote advantage for the F508del mutation, thus explaining the
persistence of the mutation over time, though it causes disease when a person has two
mutated alleles. A study conducted by Bosch et al., examined the relationship between the
occurrence 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 between
the 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 to
tuberculosis, causing it to be selected for in populations with high tuberculosis infection
rates. It is hypothesized that White Plague, a large tuberculosis outbreak in Europe, caused
the mutation to be selected for and accounts for the high F508del mutation frequency in
Caucasian populations (Bosch et al., 2017). Other populations likely did not have the same
environmental selective pressure, and so some populations including two Brazilian
populations have F508del mutations significantly lower than the average frequency
(Giselda et al., 1999).
CFTR has evolved to have many different haplotypes with many different
mutations pertaining to those haplotypes (Callebaut et al., 2017). CFTR is still evolving
today, as seen by many of the frequencies of different mutations are not under HardyWeinberg
equilibrium (Cabello et al., 1999). The CFTR gene evolved to be an ion channel
in 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 response
to environmental factors incurring a benefit to have certain alleles over others.