Explain how a range of mutagens operate, including but not limited to: electromagnetic radiation sources, chemicals, naturally occurring mutagens; and classify different types of mutation including point, silent, frameshift and chromosomal mutations

What this dot point is asking

NESA wants you to classify mutations into the standard categories and explain the structural difference between each type. Most exam questions ask you to compare two types, often with a named example.

The answer

A mutation is a permanent, heritable change to the DNA sequence of an organism. Mutations are classified by scale (point vs chromosomal) and by effect on the protein product (silent, missense, nonsense, frameshift).

Point mutations

A point mutation changes a single base pair in the DNA. There are three structural sub-types.

Substitution

One base is replaced by another (e.g. A to G). The reading frame is unchanged; at most one codon is altered.

Insertion

An extra base is inserted into the sequence.

Deletion

A base is removed from the sequence.

Insertions and deletions of one or two bases shift the reading frame of the ribosome, so all codons downstream are read in the wrong groups of three. This is called a frameshift mutation.

Classifying substitutions by effect

Substitutions are further classified by what they do to the protein.

Worked example. Sickle cell anaemia is a single substitution (A to T) in the beta-globin gene, changing codon 6 from GAG to GTG. This is a missense mutation: glutamic acid becomes valine. The altered haemoglobin polymerises under low oxygen, deforming red blood cells.

Frameshift mutations

A frameshift is caused by an insertion or deletion of a number of bases not divisible by three. Every codon downstream of the mutation is shifted, so the amino acid sequence past that point is essentially random and a premature stop codon usually appears within a few codons. The resulting protein is truncated and non-functional.

Worked example. Many cystic fibrosis alleles involve deletions in the CFTR gene. The most common, ΔF508, deletes three bases (one codon) and is technically an in-frame deletion, but other CF alleles are true frameshifts that abolish CFTR function entirely.

Chromosomal mutations

A chromosomal mutation changes the structure or number of whole chromosomes. These affect many genes at once.

Structural chromosomal mutations

1. Deletion. A segment of the chromosome is lost (e.g. cri-du-chat syndrome, partial deletion of chromosome 5).
2. Duplication. A segment is copied so that two copies are present on the same chromosome.
3. Inversion. A segment breaks off, flips and rejoins in reverse orientation.
4. Translocation. A segment moves from one chromosome to a non-homologous chromosome (e.g. the Philadelphia chromosome in chronic myeloid leukaemia, a translocation between chromosomes 9 and 22).

Numerical chromosomal mutations (aneuploidy)

These arise from non-disjunction during meiosis, where homologous chromosomes (meiosis I) or sister chromatids (meiosis II) fail to separate.

• Trisomy 21 (Down syndrome). Three copies of chromosome 21.
• Monosomy X (Turner syndrome). A single X chromosome (XO).
• Trisomy XXY (Klinefelter syndrome). Two X and one Y chromosome.

Germline vs somatic mutations

A mutation in a gamete (egg or sperm) is a germline mutation and is passed to offspring. A mutation in a somatic (body) cell is not inherited but can still cause local effects such as cancer.

Examples in context

Example 1. Sickle cell anaemia, a single missense mutation. A single A to T substitution in the sixth codon of the HBB gene changes the codon GAG (glutamic acid) to GTG (valine) in beta-haemoglobin. This one amino acid swap replaces a polar acidic residue with a hydrophobic one, causing haemoglobin molecules to polymerise into long fibres under low-oxygen conditions and distorting red blood cells into the characteristic sickle shape. The mutation is missense, not silent, because the amino acid identity changes. Sickle cell carriers (heterozygotes) are largely asymptomatic and gain some resistance to Plasmodium falciparum malaria, a classic example of balancing selection that maintains the mutated allele in African and Mediterranean populations.

Example 2. Down syndrome and non-disjunction in chromosome 21. Down syndrome (trisomy 21) is a chromosomal mutation, not a point mutation. It arises when a homologous pair of chromosome 21 fails to separate during meiosis I (or sister chromatids fail to separate in meiosis II), producing a gamete with two copies of chromosome 21. After fertilisation, the resulting zygote has 47 chromosomes (2n + 1). Australian Bureau of Statistics data show roughly 1 in 700 live births in Australia have Down syndrome, with maternal-age-related non-disjunction the dominant cause (risk rises from 1 in 1500 at age 20 to 1 in 100 at age 40). The phenotype reflects extra dosage of all the roughly 230 genes on chromosome 21.

Try this

Q1. Classify each of the following mutations: (a) a single base substitution that changes UCU to UCC, both coding for serine; (b) deletion of two bases in the middle of a gene; (c) duplication of an entire chromosome arm. [3 marks]

• Cue. (a) Silent (synonymous) point mutation. (b) Frameshift point mutation (indel). (c) Chromosomal duplication.

Q2. A 1500 bp gene undergoes a single base insertion at position 200. The original reading frame contained 500 codons including the stop. Predict how many amino acids will be altered compared to the original protein, assuming the new reading frame produces no premature stop until the end. [3 marks]

• Cue. Positions 1 to 199 are normal (~66 amino acids correct), then every codon downstream shifts; roughly 433 of the 500 amino acids will be altered.

Q3. Compare the likely phenotypic consequences of (a) a silent point mutation in the centre of a coding sequence, (b) a nonsense mutation in the second codon of a gene, and (c) a translocation between chromosomes 9 and 22 in a haematopoietic stem cell. [2+2+2 marks]

• Cue. (a) No phenotypic effect typically. (b) Severely truncated protein, usually non-functional. (c) Philadelphia chromosome producing the BCR-ABL fusion oncoprotein, causing chronic myeloid leukaemia.