transition mutation

**Definition:** A transition is a type of base substitution (point mutation) where a purine (A, G) is swapped for the other purine, or a pyrimidine (C, T/U) for the other pyrimidine. Examples: A→G, G→A, C→T, T→C. By contrast, a transversion swaps a purine for a pyrimidine or the reverse (e.g., A→C, G→T).

**Frequency:** Transitions are about 2x as common as transversions in the genome, even though random chance would predict transversions to be about 2x as common (8 possible transversions vs 4 possible transitions). This is because of the underlying chemical mechanisms.

**Mechanisms:** - **Spontaneous deamination of cytosine → uracil**: if not repaired by base excision repair (uracil-DNA glycosylase), U pairs with A in replication, giving a C→T transition (G:C → A:T). - **Deamination of 5-methylcytosine → thymine** at CpG islands: the most common cause of point mutations in humans, a CpG "hot spot." Because T is a normal DNA base, it is not recognized by uracil-DNA glycosylase, making it harder to repair. - **Tautomeric shifts** (rare base forms) causing mispairing during replication. - **Chemical mutagens:** nitrous acid (deaminates bases), 5-bromouracil (base analog), and alkylating agents (e.g., EMS causes G→A). - Depurination is more often associated with transversions, not transitions.

**Consequences (by effect on the protein):** - **Silent**: often at the wobble (3rd) position of the codon, with no amino acid change. - **Missense**: a different amino acid. Can be conservative or nonconservative. - **Nonsense**: creates a stop codon (e.g., CGA→UGA from C→U), giving a truncated protein. - Transitions never cause a frameshift (those need insertions or deletions that are not multiples of 3).

**Clinical associations:** - CpG C→T transitions underlie many hereditary diseases and tumor mutations, e.g., **TP53** hot spots (R175, R248, R273) in Li-Fraumeni syndrome and sporadic cancers, and the **CFTR** nonsense mutation R553X. - **UV light** causes pyrimidine dimers, with a characteristic C→T (or CC→TT) transition signature in skin cancers (basal cell and squamous cell carcinoma, melanoma). Defective nucleotide excision repair, as in xeroderma pigmentosum, increases these. - **Sickle cell disease** is a transversion (A→T, GAG→GTG, Glu6Val), a classic contrast with transitions. - **Mismatch repair defects** (Lynch syndrome, HNPCC) lead to accumulating replication errors, including transitions. - **Hypermutator or APOBEC signatures** in cancers include C→T transitions.

**Board pearls:** - Know the distinction: transition = purine↔purine or pyrimidine↔pyrimidine; transversion = purine↔pyrimidine. - Mnemonic: purines = "PURe As Gold" (A, G); pyrimidines = "CUT the Py" (C, U, T). - Cytosine deamination → uracil; 5-methylcytosine deamination → thymine. - Repair for deamination: base excision repair (BER). Repair for pyrimidine dimers: nucleotide excision repair (NER). Repair for replication mismatches: mismatch repair (MMR). - Point mutations (transition or transversion) are all single nucleotide substitutions. Their effects range from silent to nonsense, with severity: nonsense > missense > silent.