Gene Mutations and Single-Gene Disorders

One letter out of three billion

Your genome has about 3 billion base pairs in each set of chromosomes. Change just one of them in the right place and a person can have sickle cell disease. Delete just three bases in another gene and the result is the most common form of cystic fibrosis. In the last lesson you studied changes to whole chromosomes. This lesson zooms in to changes in single genes.

Kinds of gene mutations

Remember from the first lesson: genes are read in groups of three bases (codons), and each codon stands for one amino acid in a protein.

• Substitution: one base is swapped for another. The result may be:
• silent: the new codon codes for the same amino acid (no change in the protein);
• missense: a different amino acid (the protein may work less well, or not at all);
• nonsense: a "stop" codon, so the protein is cut short.
• Insertion or deletion of one or two bases causes a frameshift: every codon after the change is read wrongly, usually producing a useless protein. (Inserting or deleting three bases adds or removes one amino acid without a frameshift.)

Mutations happen naturally when DNA is copied, and mutagens make them more likely. A mutation in a body (somatic) cell affects only that person, and may contribute to cancer. A mutation in a cell that makes eggs or sperm (germ line) can be passed to children. Not every mutation is harmful: many are neutral, and some are helpful. Mutations are the original source of all new alleles, which matters a lot in the Evolution unit.

Single-gene disorders

Notice the pattern: most of these are recessive. A carrier (one working allele) usually makes enough of the protein to be healthy. People with two non-working alleles do not. Huntington disease is dominant: one altered allele is enough, and because symptoms often start after people have had children, the allele can be passed on before anyone knows it is there.

Why is the sickle-cell allele common in some regions?

People who carry one sickle-cell allele (sickle-cell trait) usually do not have the disease, and they are more resistant to malaria. In regions where malaria has long been common (parts of Africa, the Mediterranean, the Middle East and India), carriers have survived and had children more often, so the allele became more common there. This is a real example of natural selection, which you will meet again in the Evolution unit. At the molecular level, a carrier makes both normal and sickle hemoglobin: the alleles are codominant for the protein.

A Canadian breakthrough: the cystic fibrosis gene

In 1989, a research team led by Lap-Chee Tsui at the Hospital for Sick Children (SickKids) in Toronto, working with John Riordan in Toronto and Francis Collins at the University of Michigan, identified the gene that causes cystic fibrosis, CFTR, on chromosome 7. They also found the most common mutation, a three-base deletion.

Why did this matter?

• Testing: carrier testing and diagnosis by DNA became possible.
• Understanding: knowing the protein (a chloride channel) explained why mucus becomes thick.
• Treatment: decades later, scientists designed CFTR modulator drugs that help faulty CFTR proteins fold and work better. For many people with CF, these medicines have improved lung function and quality of life.

This is a good example of how basic research (finding a gene) leads, slowly, to new treatments.

Newborn screening in Ontario

Shortly after birth, babies in Ontario are offered a newborn screening test: a few drops of blood from a heel prick are tested for a list of treatable conditions, including PKU, cystic fibrosis and sickle cell disease. Finding PKU early, for example, lets a baby start the special diet before any brain damage happens. That is why foods and drinks sweetened with aspartame carry the warning "contains phenylalanine": the label is for people with PKU.