Gene Mutations (OCR A-Level Biology A): Revision Notes
Gene Mutations
What are gene mutations?
A gene mutation refers to a change in the DNA nucleotide sequence within a gene. These alterations occur when errors are made during DNA replication. When the base sequence is modified, a new variant of the gene forms – this represents a new mutation.
Gene mutations can be classified into two main categories:
- Chromosome mutations – affect chromosome number or structure
- Gene mutations – changes to the DNA base sequence of individual genes
The outcome of a mutation depends on several factors, including where it occurs in the DNA and how it affects the protein produced.
Why some mutations have no effect
Many mutations do not alter the final protein product. This occurs because the genetic code is degenerate – most amino acids are encoded by more than one triplet codon. Only methionine and tryptophan have single codons.
For example, if a mutation changes one base but the new triplet still codes for the same amino acid, no change occurs in the protein. Additionally, mutations in non-coding regions of DNA have no impact on the amino acid sequence.
Even when mutations do change the amino acid sequence, they may not produce observable effects because:
- The mutant allele may be recessive, masked by a dominant allele
- The gene may be one of several controlling a characteristic, diluting the effect
- Epistasis may occur, where one gene suppresses the expression of others
Types of gene mutations
Substitution mutations
A substitution mutation occurs when one base is replaced by a different base, altering a single triplet codon.
The table above shows a normal sequence from the β-globin gene of haemoglobin. The codons CTG, ACT, CCT, GAG, GAG, AAG code for leucine, threonine, proline, glutamic acid, glutamic acid, and lysine respectively.
Silent mutations
When a substitution changes a base but the new codon still specifies the same amino acid, this is a silent mutation. This occurs because of the degenerate nature of the genetic code.
Worked Example: Silent Mutation in β-globin
In this example, the fourth codon has changed from GAG to GAA. However, both triplets code for glutamic acid, so the protein sequence remains completely unchanged despite the DNA mutation.
Missense mutations
When substitution produces a different amino acid, this is a missense mutation. The altered amino acid may affect protein structure and function.
Worked Example: Sickle Cell Mutation
Here, the fourth codon has changed from GAG to GTG, replacing glutamic acid with valine. This single amino acid change causes sickle cell anaemia when an individual inherits two copies of this mutant allele (HbS). The altered haemoglobin affects red blood cell shape and oxygen transport.
Insertion and deletion mutations (frameshift)
Insertion involves adding one or more extra bases to the DNA sequence, while deletion removes bases. Both cause a frameshift – the reading frame shifts, altering every triplet downstream from the mutation point.
Deletion example
Worked Example: Deletion Causing Frameshift
When the G base is deleted from the first triplet (CTG becomes CTA), all subsequent codons change:
Original sequence: CTG-ACT-CCT-GAG-GAG-AAG
Amino acids: leucine-threonine-proline-glutamic acid-glutamic acid-lysine
After deletion: CTA-CTC-CTG-AGG-AGA-AG
Amino acids: leucine-leucine-leucine-arginine-arginine
This frameshift dramatically alters the entire polypeptide chain downstream from the mutation.
Insertion example
Worked Example: Insertion Creating Premature Stop Codon
Adding an extra base creates a similar frameshift effect. In this case, the sequence becomes CTC-GAC-TCC-TGA-GGA-GAA, producing leucine-aspartate-serine followed by a stop codon (TGA).
The stop codon terminates translation prematurely, producing a truncated, non-functional protein.
Critical Point About Frameshifts:
If three bases (or a multiple of three) are inserted or deleted, no frameshift occurs because complete codons are added or removed. The reading frame remains intact.
Stutter mutations
Stutter mutations involve the repetition of a triplet sequence many times. Huntington's disease results from the triplet CAG being repeated excessively. CAG codes for glutamine, creating a long polyglutamine sequence in the protein. When repeats exceed , the disease typically manifests later in life, causing progressive neurodegeneration in the brain.
Effects of mutations on protein structure and function
Beneficial mutations
Mutations can provide selective advantages depending on environmental conditions. A clear example involves human skin pigmentation and vitamin D synthesis.
Early humans in Africa had dark skin due to high melanin production. This protected against harmful UV radiation while still allowing vitamin D synthesis in the intense sunlight. Pale-skinned individuals would have suffered increased skin cancer risk.
When humans migrated to temperate regions with lower UV intensity, dark skin became disadvantageous. Darker skin reduces vitamin D synthesis efficiency, leading to:
- Rickets – bone deformities, particularly dangerous for females during childbirth
- Reduced protection against heart disease and cancer
Paler-skinned individuals gained a selective advantage in these environments through more efficient vitamin D production. This demonstrates how a mutation's effect depends on environmental context – the same trait can be beneficial or harmful in different conditions.
Harmful mutations
Many genetic diseases result from gene mutations that produce harmful effects:
Sickle cell anaemia: A substitution mutation changes glutamic acid to valine in β-globin (shown earlier). This alters haemoglobin structure, causing red blood cells to become sickle-shaped, reducing oxygen transport capacity.
Cystic fibrosis: In of cases, deletion of three base pairs removes phenylalanine at position in the CFTR protein. This causes abnormally thick mucus, particularly affecting lungs and pancreas.
Huntington's disease: A stutter mutation where CAG repeats exceed critical levels (usually ), causing neurodegeneration.
Phenylketonuria (PKU): A mutation prevents production of the enzyme needed to metabolise phenylalanine. Phenylalanine accumulates, causing serious medical problems including mental impairment.
Cancer-related mutations
Proto-oncogenes are normal genes promoting controlled cell division. They encode:
- Growth factors and their receptors
- Regulatory enzymes that can be switched off after cell division
- Proteins restricting progress through the G stage of the cell cycle
Proto-oncogenes to Oncogenes:
A single mutation can convert a proto-oncogene (e.g. ras) into an oncogene (e.g. rasD). The oncogene cannot be switched off, leading to unregulated cell division and tumour formation.
Tumour suppressor genes normally prevent excessive cell division. The TP53 gene encodes the p protein, which halts cell division at G when DNA damage or copying errors occur. Chemicals in cigarette smoke can mutate TP53, inactivating p and preventing the cell cycle checkpoint from functioning. This increases lung cancer risk. When modified by human papilloma virus (HPV), mutated TP53 is linked to cervical cancer.
Critical Concept: Tumour Suppressor Gene Dominance
Tumour suppressor genes are dominant in their normal form – only one functional copy is needed. Both copies must be lost or inactivated for tumours to develop.
Neutral mutations
Neutral mutations provide neither advantage nor disadvantage to survival. They may:
- Change a base without altering the amino acid (silent mutation)
- Change the amino acid without affecting protein function
- Alter function in ways irrelevant to survival
The TAS2R38 gene controls the ability to taste PTC (phenylthiocarbamide), a bitter chemical. A mutant allele prevents tasting this compound. Since PTC rarely occurs naturally in food, this ability offers no survival advantage. However, people with the tasting variant also detect bitter compounds in Brussels sprouts and avoid eating them. This may have provided some historical advantage, as many poisons taste bitter, but remains neutral in modern environments.
Key Points to Remember:
- Gene mutations are changes to DNA base sequences caused by replication errors
- The degenerate genetic code allows some mutations to be silent, producing no change in the protein
- Substitution mutations change single codons and may be silent or alter one amino acid
- Insertion and deletion mutations cause frameshifts, altering all downstream codons and often producing stop codons
- Mutations can be beneficial (e.g. pale skin in low-UV environments), harmful (e.g. sickle cell anaemia, cancer-related genes), or neutral (e.g. PTC tasting ability)
- Proto-oncogenes promote controlled cell division; mutations convert them to oncogenes causing uncontrolled division
- Tumour suppressor genes like TP53 prevent damaged cells from dividing; their inactivation increases cancer risk