18.2 Mutation: Types & Consequences

Mutation: Types and Consequences

A mutation is a heritable change in the nucleotide sequence of DNA. PA-CAT Bulletin of Information, rev. 20240815, Table 8, groups mutation under Molecular Properties of Genes. Mutations range from single-base substitutions to large chromosomal rearrangements and are the raw material for both evolution and inherited disease.

Point Mutations (Substitutions)

A point mutation alters a single base. Within a coding region, the protein consequence depends on which codon changes:

A missense mutation can be conservative (the new amino acid has similar chemistry, e.g., Asp→Glu) or non-conservative (e.g., Asp→Val). Silent mutations are not always neutral: they can affect splicing, mRNA stability, or translation speed.

Frameshift, Insertion, Deletion

Insertions and deletions (collectively indels) add or remove nucleotides. When an indel within a coding region is not a multiple of three, it causes a frameshift — the reading frame shifts, every downstream codon changes, and a premature stop codon usually appears soon after, producing a nonfunctional truncated protein. Tay-Sachs disease (a 4-bp insertion in HEXA) is a classic frameshift. Indels that are multiples of three add or remove whole amino acids without frameshifting.

Spontaneous vs Induced Mutations

• Spontaneous mutations arise from replication errors, tautomeric shifts, depurination, or deamination. A notable spontaneous event is deamination of 5-methylcytosine to thymine, which creates CpG→TpG transition hotspots. The baseline rate is ~10⁻⁸ per base per generation in humans.
• Induced mutations are caused by mutagens:
  • Base analogs (e.g., 5-bromouracil) — mimic normal bases and mispair during replication.
  • Alkylating agents (e.g., EMS, nitrogen mustard) — add alkyl groups that mispair; typically cause transitions.
  • Deaminating agents (e.g., nitrous acid) — convert adenine to hypoxanthine (pairs with C), causing A:T→G:C transitions.
  • Intercalating agents (e.g., ethidium bromide, proflavin, acridine orange) — insert between stacked base pairs and cause frameshift insertions or deletions during replication.
  • Ultraviolet (UV) radiation — produces pyrimidine dimers (most often thymine–thymine) that distort the helix and block replication.
  • Ionizing radiation (X-rays, gamma rays) — induces single- and double-strand breaks and base damage.
  • Reactive oxygen species — oxidize guanine to 8-oxoG, which mispairs with adenine, causing G:C→T:A transversions.

Transition vs Transversion

• Transition — purine↔purine (A↔G) or pyrimidine↔pyrimidine (C↔T). More common, often due to tautomeric mispairing or deamination.
• Transversion — purine↔pyrimidine (e.g., A→C, G→T). Less common but often more disruptive.

Consequences: Loss of Function, Gain of Function, Conditional

Functional consequences of mutation are classified by effect on gene product:

• Loss-of-function (LoF) — reduced or abolished activity; usually recessive at the organism level. Example: CFTR ΔF508 in cystic fibrosis.
• Gain-of-function (GoF) — new or increased activity; often dominant. Example: oncogenic RAS alleles that are constitutively active.
• Dominant-negative — the mutant allele product interferes with the wild-type product, often because the protein forms multimers (e.g., mutant p53, mutant collagen in osteogenesis imperfecta).
• Conditional — phenotype manifests only under certain conditions, such as temperature-sensitive mutants at restrictive temperature or lactose persistence depending on diet.
• Lethal — kills the organism; may be recessive (carriers survive and transmit).

Repair Systems Counter Mutations

Cells limit mutation load with repair pathways: mismatch repair (MMR) fixes replication mispairs; base excision repair (BER) handles small base lesions (e.g., deaminated or oxidized bases); nucleotide excision repair (NER) removes bulky lesions such as UV dimers; double-strand break repair uses homologous recombination (error-free) or non-homologous end joining (error-prone). Defects in these pathways raise cancer risk (e.g., XPA mutations → xeroderma pigmentosum; MLH1 mutations → Lynch syndrome, covered in §18.6).

Repeat Expansions and Dynamic Mutations

A special class of mutation is the trinucleotide repeat expansion. Expansion of a CAG tract in HTT beyond ~36 repeats causes Huntington disease; CGG expansions in FMR1 (beyond ~200 repeats) cause fragile X syndrome; GAA expansions in FXN cause Friedreich ataxia. These disorders often show anticipation — earlier onset and greater severity in successive generations as the repeat length grows during gametogenesis, particularly through paternal (CAG) or maternal (CGG/GAA) transmission. The repeat threshold for disease varies by gene, and the molecular mechanism typically involves loss of gene function (fragile X, Friedreich) or a toxic gain of function (Huntington), illustrating how a single mechanism class can produce both recessive-like and dominant-like phenotypes.