Mutations

Change one A to a T in the 20th base of the beta-globin gene, and the result is the variant behind sickle cell disease.

Copying mistakes and damage

Every time a human cell divides it copies about 6 billion base pairs, and the copying enzyme, DNA polymerase, sometimes puts in the wrong base. OpenStax describes three lines of defence. The polymerase proofreads as it goes, checking each new base and cutting out a wrong one before adding the next. Mismatch repair enzymes find mispaired bases after copying is done. Nucleotide excision repair cuts out damaged stretches, such as the linked pairs of thymines that ultraviolet light can create, and fills the gap. A change that slips past all of this and stays in the sequence is a mutation.

Mutations are either induced or spontaneous. Induced mutations come from outside agents such as certain chemicals, ultraviolet rays or X-rays. Spontaneous mutations arise from ordinary chemical reactions in the body, with no outside cause. Where a mutation happens also matters. A mutation in a body cell, such as a skin cell, affects only that person and the cells that descend from it. A mutation in a germ cell, an egg or sperm, can be passed on to children.

Small changes, different results

A point mutation changes a single base pair. Because the genetic code has 64 codons for 20 amino acids, one base change can have three quite different results. If the new codon means the same amino acid, the protein is unchanged; this is a silent mutation, and it most often happens in the third base of a codon. If the new codon means a different amino acid, it is a missense mutation, and the protein may work differently. If the new codon is a stop codon, it is a nonsense mutation, and the protein ends early.

Adding a base (an insertion) or removing one (a deletion) is often worse. The cell reads the gene in groups of three from the start, so one extra or missing base shifts every codon after it. This is a frameshift. Think of the sentence THE CAT ATE THE RAT. Delete the first E and, still reading in threes, you get THC ATA TET HER AT, which is nonsense from that point on. Inserting or deleting three bases together keeps the frame and changes the protein less. Larger changes also happen, such as a piece of one chromosome moving to another, called a translocation.

One letter in beta-globin

Hemoglobin, the oxygen carrier in red blood cells, is built from two alpha-globin and two beta-globin chains. The beta chain is made from the HBB gene, whose first 27 coding bases are in the model: ATG GTG CAT CTG ACT CCT GAG GAG AAG, which read Met, Val, His, Leu, Thr, Pro, Glu, Glu, Lys. In the variant called hemoglobin S, the A in position 20 is replaced by T. The codon GAG becomes GTG, and glutamic acid becomes valine. It is a missense mutation of a single base.

MedlinePlus describes the effect: the changed beta-globin chains stick together into long rigid fibres that bend red blood cells into a sickle shape. The sickled cells die early and can block small blood vessels. Sickle cell anemia is inherited in an autosomal recessive pattern, so a person is affected when both copies of HBB carry the variant. You may see the change written as Glu6Val, counting from the first amino acid of the finished protein, which loses its starting methionine, or as Glu7Val, counting from the start codon as the model does. This lesson is general information; questions about a diagnosis belong with a doctor.