Mutations and the Genetic Code
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Direct answer
Swapping a single adenine for thymine at codon 6 of the β-globin gene — GAG to GTG — replaces glutamic acid with valine and produces sickle haemoglobin: one transversion, one missense mutation, one disease. Point mutations are silent (no amino acid change, often at the wobble base), missense (substitution) or nonsense (a stop codon truncates, usually with nonsense-mediated mRNA decay); insertions or deletions not divisible by three shift the reading frame and demolish the protein downstream. Trinucleotide repeat expansions add a clock: CAG in Huntington disease, CGG in fragile X and CTG in myotonic dystrophy lengthen across generations, so disease arrives earlier and harder — anticipation. Transitions swap within base classes; transversions cross them, as in HbS.
What you must remember
- Mutation classes with exemplars: sickle cell disease (missense), Duchenne muscular dystrophy (deletions causing frameshift), many β-thalassaemias (nonsense), cystic fibrosis ΔF508 (three-base deletion, in-frame).
- Trinucleotide diseases: Huntington CAG over about 36 repeats (neuronal, paternal amplification), fragile X CGG over 200 repeats (FMR1 methylation silencing, maternal amplification), myotonic dystrophy CTG (muscle and cardiac, maternal), Friedreich ataxia GAA (intronic, frataxin).
- Gain versus loss of function: gain — Huntington (toxic protein), achondroplasia (FGFR3 constitutive activation), BCR-ABL fusion; loss — most inborn errors, cystic fibrosis, tumour suppressor cancers.
- Dominant negative: one mutant subunit poisons a multimer — type I osteogenesis imperfecta's collagen and some intermediate-filament diseases.
- Mutagens: ultraviolet light (pyrimidine dimers), alkylating agents such as EMS (transition bias), base analogues such as 5-bromouracil, intercalators such as acridine orange and ethidium (frameshifts), ionising radiation (double-strand breaks).
- Ames test: histidine-auxotrophic Salmonella typhimurium revertants counted after exposure to the test chemical with rat liver microsomal activation — a cheap screen for mutagenic (hence probable carcinogenic) potential.
- Mosaicism and somatic mutation: post-zygotic change explains segmental neurofibromatosis and uneven disease; cancer is fundamentally somatic mutation plus selection.
- Nonsense-mediated decay: mRNA carrying a premature termination codon is degraded, so nonsense disease is often from haploinsufficiency, not truncated protein.
A worked case: anticipation across three generations
A family chart shows the grandmother with mild late-onset hand stiffness, the mother with progressive myotonia and early cataracts, and a grandson with congenital myotonic dystrophy — floppy, feeding poorly, club feet. Each generation is worse and earlier: the CTG repeat in the DMPK gene has lengthened at each maternal meiosis, and beyond about 50 repeats the array becomes meiotically unstable, expanding into the thousands in the congenital case. The mechanism is toxic RNA: the expanded transcript sequesters RNA-binding proteins and splicing factors, which is why the disease touches muscle, heart, lens and endocrine pancreas simultaneously. Genetic counselling now states the risk numerically — amplification risk rises with maternal repeat size — and prenatal diagnosis by repeat-primed PCR is available. Contrast fragile X, where the full mutation over 200 CGG repeats silences FMR1 by methylation and amplification happens through healthy carrier mothers, and Huntington disease, where paternal transmission produces the juvenile form.
Where students slip
Anticipation's parental route is the classic discriminator: paternal amplification in Huntington disease, maternal in fragile X and myotonic dystrophy — a matched-pair viva question. Second, silent mutations are called harmless; most are, but some alter splicing or codon usage, and the exam-safe answer names the wobble-base mechanism. Third, ΔF508 in cystic fibrosis is mislabelled frameshift; it deletes exactly three bases (one phenylalanine), so the frame survives. Fourth, transition versus transversion: the HbS change is A to T, a transversion — candidates who call it a transition lose the defining letter. Fifth, loss-of-function heterozygotes manifest only when 50% output is insufficient (haploinsufficiency) or when the product is a multimer (dominant negative); inborn errors classically need both alleles hit, which is why most enzyme deficiencies are autosomal recessive.
Frequently asked questions
Which mutation produces sickle haemoglobin, and of what type is it?
A transversion (A→T) changing GAG to GTG at β-codon 6 — a missense mutation substituting valine for glutamic acid.
Why do trinucleotide repeat diseases worsen across generations?
Repeat arrays expand during meiosis (paternal in Huntington, maternal in fragile X and myotonic dystrophy), so offspring inherit longer arrays with earlier, severer disease — anticipation.
What is a dominant negative mutation?
A mutant gene product that poisons the normal product within a multimer, as in some collagen assembly defects of osteogenesis imperfecta.
What does the Ames test measure, and with which organism?
Reversion of histidine auxotrophy in Salmonella typhimurium after chemical exposure with liver microsomal activation, screening for mutagenic potential.
Why may a nonsense mutation produce no abnormal protein at all?
Premature termination codons usually trigger nonsense-mediated decay of the mRNA, so disease arises from loss of the gene product rather than from a truncated protein.