transversion mutation

**Definition:** A transversion is a type of base substitution (point mutation) in which a purine is exchanged for a pyrimidine, or a pyrimidine for a purine (A or G ↔ C or T). A transition is the substitution of purine for purine (A↔G) or pyrimidine for pyrimidine (C↔T).

**Mnemonic:** "Transversion = crossing over between the two base classes." Purines = PURe As Gold (A, G). Pyrimidines = CUT the Py (C, U, T).

**Frequency:** Transitions are about 2x more common than transversions in practice. There are only 4 possible transitions but 8 possible transversions, so transversions would be expected to be more common if mutations were random. Transitions are favored for chemical reasons, such as spontaneous deamination of 5-methylcytosine to thymine at CpG sites.

**Mechanisms and causes:** - Oxidative damage: 8-oxoguanine (8-oxoG) mispairs with adenine, giving a G→T transversion. This is the classic example. It is repaired by base excision repair (OGG1, MUTYH). - Bulky adducts from carcinogens: Benzo[a]pyrene in tobacco smoke causes G→T transversions, as seen in TP53 and KRAS mutations in lung cancer. Aflatoxin B1 causes G→T transversion at codon 249 of TP53, which is linked to hepatocellular carcinoma. - Apurinic or apyrimidinic (AP) sites, which often cause insertion of A opposite the lesion. - UV light mainly causes C→T transitions, which are called the "UV signature." These are not transversions.

**Consequences (by effect on the protein):** - Silent: no amino acid change (often at the wobble position). - Missense: a different amino acid is incorporated. - Nonsense: a premature stop codon. - Because a transversion changes the chemical class of the base, it is more likely than a transition to produce a nonconservative amino acid change. Transitions more often preserve similar amino acids, since the genetic code is organized to buffer them.

**Classic clinical examples:** - Sickle cell disease: A→T transversion in codon 6 of the β-globin gene (GAG→GTG), which changes glutamic acid to valine (missense). - Hemoglobin C: G→A transition at the same codon (Glu→Lys). This is a transition, not a transversion, and a common exam contrast. - KRAS G12 mutations (for example G12C or G12V) in lung and colon cancer are commonly G→T transversions.

**High-yield board points:** - Transversion: purine ↔ pyrimidine. Transition: purine ↔ purine or pyrimidine ↔ pyrimidine. - Both are point mutations, which are base substitutions and are not frameshifts. Frameshifts come from insertions or deletions that are not multiples of 3. - Sickle cell disease is the standard transversion example. - Base excision repair fixes oxidative or deaminated bases. Nucleotide excision repair fixes bulky lesions and thymine dimers (defective in xeroderma pigmentosum).