Gene Mutations

A gene mutation is a random, spontaneous change in the base sequence of DNA. Because proteins are made by translating mRNA transcripts of genes, a change in DNA sequence can change the sequence of amino acids in a polypeptide, and hence the structure and function of a protein. Mutations are therefore the ultimate source of all genetic variation; without them, evolution by natural selection could not occur. However, most mutations that affect a protein are deleterious or neutral — truly beneficial mutations are rare. OCR A-Level Biology A specification module 6.1.1(a) requires you to understand the types, causes and consequences of gene mutations.

Key Definitions:

• Gene mutation — a change in the base sequence of DNA (strictly speaking, any heritable change at a single locus).
• Point mutation — a mutation affecting a single base (substitution, insertion or deletion of one nucleotide).
• Mutagen — a physical, chemical or biological agent that increases the natural mutation rate.
• Silent mutation — a base change that does not alter the encoded amino acid.
• Missense mutation — a base change that alters one amino acid in the polypeptide.
• Nonsense mutation — a base change that creates a premature stop codon.
• Frameshift mutation — an insertion or deletion (not a multiple of three) that shifts the reading frame.

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Why Mutations Happen

DNA replication is remarkably accurate — DNA polymerase has a proofreading activity and the post-replication mismatch-repair system removes most errors. Even so, roughly 1 in 10⁹ nucleotides is mis-incorporated per cell division in humans, which over a 3 × 10⁹ bp genome gives a handful of new mutations per cell generation. Mutations arise:

• Spontaneously during replication (tautomeric shifts in bases, slippage at repeat sequences).
• Induced by mutagens (UV light, ionising radiation, chemicals such as benzene, alkylating agents, base analogues, reactive oxygen species).
• Transposon activity — "jumping genes" that insert into other loci.

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Types of Point Mutation

flowchart TB
    A[Original DNA: ATG TTC GCA]
    A --> B[Substitution: ATG TAC GCA - missense Tyr replaces Phe]
    A --> C[Insertion: ATG TTA CGC A - frameshift]
    A --> D[Deletion: ATG TCG CA - frameshift]

1. Substitution

One base is replaced by another.

• Transition — a purine → purine (A ↔ G) or pyrimidine → pyrimidine (C ↔ T).
• Transversion — a purine ↔ pyrimidine.

Substitutions produce three possible outcomes at the protein level:

Outcome	Meaning	Example	Effect
Silent	New codon codes for the same amino acid	GAA → GAG (both Glu)	None — degeneracy of the code absorbs the change
Missense	New codon codes for a different amino acid	GAG → GTG (Glu → Val)	One amino acid substitution; effect depends on position
Nonsense	New codon is a stop codon	CAG → TAG	Premature termination — usually severe

2. Insertion

One or more extra bases are inserted into the sequence. If the number is not a multiple of three, the reading frame shifts downstream of the insertion — a frameshift. Every subsequent codon is changed, and usually a premature stop codon is encountered within a few dozen bases.

3. Deletion

One or more bases are removed. Again, a frameshift occurs unless the number removed is a multiple of three. An in-frame deletion of 3 bases removes one amino acid without shifting the frame — the resulting protein may still function partially (e.g. the common ΔF508 deletion in the CFTR gene causes cystic fibrosis by removing a single phenylalanine).

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Why the Genetic Code Softens the Blow

The genetic code is degenerate — most amino acids are encoded by more than one codon, and the "wobble" rules mean that many third-position changes are silent. For example:

Codon	Amino acid
GCU	Ala
GCC	Ala
GCA	Ala
GCG	Ala

A mutation at the third position of any of these codons does not change the amino acid. This degeneracy acts as a buffer against mutation.

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Named Examples of Gene Mutations

Disease	Gene	Mutation type	Effect
Sickle-cell anaemia	HBB (β-globin)	Missense (GAG → GTG, Glu6Val)	Hydrophobic valine replaces glutamate, haemoglobin polymerises in low O₂, sickles erythrocytes
Cystic fibrosis	CFTR	In-frame 3-bp deletion (ΔF508)	Misfolded CFTR chloride channel is degraded before reaching cell surface
Duchenne muscular dystrophy (DMD)	DMD (dystrophin)	Frameshift deletion	Little or no dystrophin protein; progressive muscle wasting
Huntington's disease	HTT	Expansion of CAG trinucleotide repeat	Toxic gain of function; polyglutamine tract aggregates in neurons
Phenylketonuria (PKU)	PAH	Missense, nonsense or splice site	No functional phenylalanine hydroxylase; Phe accumulates

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Effect on Phenotype

Whether a mutation actually changes the phenotype depends on:

• Where in the gene it falls — mutations in the active site of an enzyme are usually catastrophic; mutations in surface loops may have little effect.
• Nature of the substitution — swapping glycine for alanine is usually tolerated (both small, non-polar), but swapping glycine for arginine (a large, charged residue) is often not.
• Whether the gene is haplosufficient — if one functional copy is enough, a recessive loss-of-function mutation will be silent in heterozygotes.
• Whether the mutation is in a coding, regulatory or intronic region — regulatory mutations can change how much protein is made rather than what it is.
• Cell type — a mutation in a gene expressed only in the liver will not affect the brain.

Mutations may be beneficial (a new function, e.g. lactase persistence in adult humans), neutral (most silent and many intronic mutations) or deleterious (most amino-acid-changing mutations in essential genes).

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Mutagens

Mutagens increase the mutation rate. OCR expects you to know several examples:

• Physical mutagens: UV light (causes pyrimidine dimers — adjacent T–T bonds), ionising radiation (X-rays, γ-rays: cause double-strand breaks), heat (accelerates depurination).
• Chemical mutagens: nitrous acid (deaminates C → U and A → hypoxanthine), alkylating agents (mustard gas, ethyl methanesulfonate — add alkyl groups to bases), base analogues (5-bromouracil — mimics T but pairs with G), reactive oxygen species.
• Biological mutagens: certain viruses can insert their DNA into host genes; transposable elements.

Many mutagens are also carcinogens because mutations in proto-oncogenes or tumour suppressor genes can lead to cancer.

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Somatic vs Germ-Line Mutations

• Somatic mutations occur in body cells after fertilisation. They are only passed on to the daughters of that one cell by mitosis, and cannot be inherited. They are, however, the cause of almost all cancers.
• Germ-line mutations occur in the cells that give rise to gametes. They can be inherited by offspring and by all their descendants.

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Exam Tip

Be precise with your language. "A substitution of one base by another" is not the same as "the swapping of an amino acid". The mutation is at the DNA level; its consequence (silent, missense, nonsense) is at the protein level. Always link cause to effect in your answers: "a substitution of A for T in the second base of codon 6 of the β-globin gene changes the codon from GAG to GTG, so the amino acid changes from glutamate to valine, producing haemoglobin S, which polymerises in low-oxygen conditions and distorts erythrocytes into a sickle shape."

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Common Exam Mistakes

• Saying "all mutations are harmful". Many are silent; some are neutral; a few are beneficial.
• Forgetting that a substitution at the third base of a codon is often silent because of the degeneracy of the code.
• Claiming that frameshifts change one amino acid. They change every amino acid downstream.
• Confusing an in-frame deletion (3 bp) with a frameshift deletion. An in-frame deletion removes one amino acid but leaves the rest unchanged.
• Saying UV light causes substitutions. UV causes pyrimidine dimers, which during replication lead to errors but the primary damage is a covalent cross-link.
• Forgetting that regulatory mutations exist. Mutations in promoter or enhancer regions can change transcription rates without changing the protein sequence at all.

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Quick Recap

• A gene mutation is a change in base sequence: substitution, insertion or deletion.
• Substitutions may be silent, missense or nonsense.
• Insertions and deletions that are not multiples of three cause frameshifts.
• The degeneracy of the genetic code makes many substitutions silent.
• Named examples: sickle-cell (missense), cystic fibrosis (in-frame deletion), DMD (frameshift deletion), Huntington's (CAG repeat expansion).
• Mutagens (UV, ionising radiation, chemicals) increase mutation rates and many are carcinogens.
• Somatic mutations affect one cell line; germ-line mutations are inherited.

Reference: OCR A-Level Biology A (H420) specification 6.1.1(a).