Mutations have been happening over the entire several billion year history of life on earth. Mutations can result in new alleles, which may or may not eventually become a significant part of the gene pool for any species. We will focus today on one particular example, the genetics of cystic fibrosis, which is the most common lethal recessive inherited disease in humans.

1. What is the basic inheritance information for cystic fibrosis?

The gene CFTR is at locus 7q31.2 in the human genome and codes for a "transmembrane regulator protein". This protein functions as a channel for chloride ions through the plasma membrane of our cells, and its proper functioning is necessary for good ion-balance physiology. We will use F to designate the wild-type allele, and f to designate any mutant allele that gives rise to a defective CFTR protein. The CFTR gene shows standard Mendelian inheritance. That is, for phenotypically normal parents who are both Ff (heterozygous carriers of a mutant allele f ) , there is a 1/4 chance that a child will be genotype ff, and thus have the cystic fibrosis phenotype (severe complications due to excessive mucus build-up in the lungs due to incorrect ion balances, usually leading to death before the age of 20).


2. What do we know about the wild-type dominant allele F of the CFTR gene?

The CFTR gene is "very big" and "complicated", as shown in detail in the figure (bottom of page).
The gene is a bit over 200 thousand base pairs (200 kbp) in size, much bigger than the average size of human genes. Most (over 95%) of the gene consists of over twenty intron regions (some big, some small). These introns get removed from the primary transcript RNA to result in an mRNA of about 6 thousand nucleotides (6 kb), which then gets translated to give a protein of 1480 amino acids. While being made, the protein undergoes folding and insertion into the endoplasmic reticulum membrane, followed by transport to the plasma membrane on the cell surface. Having just one F allele gives production of enough functional CFTR protein to give the normal phenotype.


3. What do we know about the recessive alleles ?

In addition to the dominant, wild-type F allele (present in everybody who does not have the disease), sequencing has also been done on lots of f alleles cloned from many cystic fibrosis patients. A summary of the results of lots of sequencing by lots of labs in the 1990's is shown near the bottom of the figure. Well over a hundred different mutations of five major types have been found in the population. Any one of these mutations results in the synthesis of a defective CFTR protein.
In the human population as a whole, the most common CFTR mutation ("the most common f allele") is the three-base-pair deletion mutation designated "delta-F-508", which results in a protein that is missing amino acid #508.


Problem S-11: "f alleles of CFTR gene".

(a)The database of sequences of the f alleles shows that essentially none of them have the mutation in the first or last exon regions. What do you think is the most likely explanation for this result?

(b) In the vicinity of exons 12 and 13, there are examples of all five general types of mutations. For EACH TYPE, describe in detail the protein that results when this particular f allele (with mutation in the exon 12-13 region) gets expressed. (How big is the protein produced from this f allele? How does this physiologically-defective protein differ at the molecular-structure level from the protein produced by the wild-type F allele?)