Mutations
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Direct answer
The Philadelphia chromosome, a translocation between chromosomes 9 and 22 that fuses BCR with ABL, shows how a single structural mutation converts a regulated tyrosine kinase into a constitutively active oncogene. Point mutations are silent, missense (as in haemoglobin S), nonsense or splice-site; insertions and deletions shift the reading frame unless they are multiples of three; and trinucleotide repeat expansions add a new dimension of instability, producing anticipation in fragile X syndrome, Huntington disease and myotonic dystrophy. Whether a mutation causes loss of function, gain of function or a dominant-negative effect decides its inheritance pattern.
What you must remember
- Point mutation types: silent (degenerate code rescues), missense (HbS: beta-6 Glu to Val), nonsense (premature stop, often degraded by nonsense-mediated decay) and splice-site (exon skipping or intron retention).
- Frameshift from insertion or deletion of bases not in threes — the commonest mechanism in Duchenne muscular dystrophy (out-of-frame deletions abolishing dystrophin).
- Trinucleotide repeat expansions show anticipation: fragile X (CGG over about 200 repeats in the FMR1 5-prime UTR, methylation silencing, macro-orchidism), Huntington (CAG over about 36, polyglutamine, chorea), myotonic dystrophy (CTG, myotonia-cataract-balding), Friedreich ataxia (GAA intronic, frataxin).
- Chromosomal mutations: deletion, duplication, inversion (haemophilia A intron-22 inversion), translocation (t(9;22) BCR-ABL; t(8;14) MYC in Burkitt lymphoma; t(14;18) BCL2 in follicular lymphoma) and copy-number variants.
- Functional classes: loss-of-function (usually recessive), gain-of-function (dominant — Huntington, achondroplasia FGFR3), dominant-negative (collagen disorders) and haploinsufficiency (one working copy insufficient).
- Mutagens to pair with lesions: ultraviolet light (pyrimidine dimers), ionising radiation (double-strand breaks), alkylating agents, base analogues such as 5-bromouracil, intercalating agents such as proflavin (frameshift), and spontaneous deamination of 5-methylcytosine to thymine creating CpG hotspots.
- The Ames test screens mutagens using histidine-revertant Salmonella strains with rat liver microsomal activation.
- Somatic versus germline: only germline mutations transmit; somatic mutations drive cancer and mosaicism.
- DNA repair pathways (covered with replication) are the genome's editor — xeroderma pigmentosum and Lynch syndrome are effectively repair-deficiency phenotypes caused by mutagen overload.
Where students slip
Students call every mutation a frameshift; a three-base deletion keeps the frame and removes one amino acid (the classic example is the deltaF508 deletion of CFTR, a phenylalanine loss causing cystic fibrosis). Second, they forget that anticipation has a molecular address — repeat expansion — and try to invoke it for ordinary point-mutation diseases. Third, the direction of dominance trips candidates: gain-of-function and dominant-negative mutations present in heterozygotes, loss-of-function usually requires both alleles hit (or haploinsufficiency when one allele is not enough). And remember HbS is missense while beta-thalassaemia is usually a nonsense or splice mutation in the same gene family: the first alters the protein's shape, the second its quantity.
Frequently asked questions
What is a frameshift mutation and which classic disease results?
Insertion or deletion of nucleotides not divisible by three, shifting the reading frame so every codon downstream is misread, usually ending in a premature stop; Duchenne muscular dystrophy from out-of-frame dystrophin deletions is the standard example.
What is genetic anticipation and which diseases show it?
Earlier, often more severe presentation in successive generations due to repeat expansion through meiosis; fragile X (CGG), Huntington disease (CAG), myotonic dystrophy (CTG) and Friedreich ataxia (GAA).
Why is a nonsense mutation usually more severe than a missense?
A missense swaps one amino acid and may be conservative; a nonsense installs a premature termination codon, truncating the protein or triggering nonsense-mediated mRNA decay, typically abolishing function entirely.
What mutation creates the Philadelphia chromosome and why does it matter?
A reciprocal t(9;22) translocation fusing BCR to ABL, producing a constitutively active tyrosine kinase that drives chronic myeloid leukaemia; its inhibitor imatinib is the paradigm of targeted cancer therapy.
What does the Ames test detect?
Mutagenic potential of chemicals, by counting reversions of histidine auxotrophic Salmonella to prototrophy, usually with rat liver S9 fraction to mimic metabolic activation; a positive result flags potential carcinogenicity.