Gene Mutation, DNA Repair, and Transposition: Study Guide

Gene Mutation, DNA Repair, and Transposition

15.1 Gene Mutations Are Classified in Various Ways

Gene mutations are fundamental changes in the DNA sequence that can affect genetic function and phenotype. They are classified by molecular change, phenotypic effect, and location within the genome.

• Mutation: Any alteration in DNA sequence, including base-pair changes, insertions, deletions, or major chromosomal alterations.

• Point Mutation: A single base-pair substitution.

• Missense Mutation: Changes a codon to encode a different amino acid.

• Nonsense Mutation: Converts a codon to a stop codon, terminating translation prematurely.

• Silent Mutation: Alters a codon but does not change the encoded amino acid.

• Frameshift Mutation: Insertions or deletions that shift the reading frame, altering downstream amino acid sequence.

Base Substitutions: Can be classified as transitions (purine to purine or pyrimidine to pyrimidine) or transversions (purine to pyrimidine or vice versa).

Mutations by Phenotype: Loss-of-function, gain-of-function, visible, nutritional, biochemical, behavioral, regulatory, lethal, and conditional mutations.

• Loss-of-function: Reduces or eliminates gene product function.

• Null mutation: Complete loss of function.

• Dominant negative mutation: Inactive product interferes with wild-type allele.

• Haploinsufficiency: One functional allele is insufficient for normal phenotype (e.g., Marfan syndrome).

• Gain-of-function: Enhanced, negative, or new function.

• Suppressor mutation: Second mutation relieves effects of a previous mutation.

Mutations by Location: Somatic (non-heritable), germ-line (heritable), autosomal, X-linked, and Y-linked mutations.

15.2 Mutations Occur Spontaneously and Randomly

Mutations can arise naturally (spontaneous) or be induced by external factors. Spontaneous mutations result from normal cellular processes, while induced mutations are caused by radiation, chemicals, or other environmental agents.

• Spontaneous Mutation: Occurs naturally, rates are low but variable.

• Induced Mutation: Caused by external agents such as UV light, chemicals, or radiation.

• Luria–Delbrück fluctuation test: Demonstrated that mutations arise randomly, not adaptively.

15.3 Spontaneous Mutations Arise from Replication Errors and Base Modifications

Spontaneous mutations often result from errors during DNA replication or chemical changes to DNA bases.

• Replication Errors: DNA polymerase may insert incorrect nucleotides, leading to point mutations.

• Replication Slippage: Loops in template strand cause insertions/deletions, especially in repeated sequences (e.g., Fragile-X, Huntington disease).

• Tautomeric Shifts: Alternate chemical forms of bases increase mispairing probability.

• DNA Base Damage: Depurination (loss of purine base) and deamination (conversion of cytosine to uracil, adenine to hypoxanthine) cause mutations.

• Oxidative Damage: Caused by cellular by-products and radiation (superoxides, hydroxyl radicals, hydrogen peroxide).

• Transposable Elements: DNA segments that move within or between genomes, causing chromosomal damage.

15.4 Induced Mutations Arise from DNA Damage Caused by Chemicals and Radiation

Induced mutations are caused by mutagens—agents that increase mutation rates. These include chemicals and various forms of radiation.

• Base Analogs: Chemicals that mimic DNA bases and increase mutation rates (e.g., 5-bromouracil).

• Alkylating Agents: Donate alkyl groups to DNA bases, altering pairing and causing transitions (e.g., mustard gas).

• Intercalating Agents: Wedge between DNA bases, causing distortions and unwinding (e.g., ethidium bromide).

• Adduct-Forming Agents: Covalently bind to DNA, altering conformation and interfering with replication (e.g., acetaldehyde, heterocyclic amines).

• UV Light: Causes pyrimidine dimers, distorting DNA and leading to replication errors.

• Ionizing Radiation: Includes X-rays, gamma rays, and cosmic rays; penetrates tissues and causes ionization, leading to DNA damage.

• Free Radicals: Unpaired electrons break DNA bonds, causing deletions, translocations, and fragmentation.

15.5 Single-Gene Mutations Cause a Wide Range of Human Diseases

Single-gene mutations can lead to inherited disorders, though most human genetic diseases are polygenic. Examples include beta thalassemia, Fragile-X syndrome, Huntington disease, and myotonic dystrophy.

• Monogenic Diseases: Caused by single base-pair changes or small insertions/deletions.

• Trinucleotide Repeat Sequences: Expanded repeats in genes cause disorders (e.g., Fragile-X, Huntington disease).

15.6 Organisms Use DNA Repair Systems to Counteract Mutations

DNA repair systems maintain genetic integrity by correcting spontaneous and induced DNA damage. Multiple mechanisms exist to repair different types of errors.

• Proofreading and Mismatch Repair: DNA polymerase removes and replaces incorrect nucleotides; mismatch repair detects and corrects errors.

• Strand Discrimination: Based on DNA methylation; newly synthesized strands are unmethylated and targeted for repair.

• Postreplication Repair: RecA protein mediates recombination with undamaged parental strand to fill gaps.

• SOS Repair System: Error-prone repair in bacteria; allows survival with DNA damage but may introduce mutations.

• Photoreactivation Repair: Enzyme cleaves thymine dimers using light; absent in humans.

• Base and Nucleotide Excision Repair: Exonuclease removes damaged bases or bulky lesions; DNA polymerase and ligase restore DNA.

• Base Excision Repair (BER): Corrects single damaged bases.

• Nucleotide Excision Repair (NER): Repairs bulky lesions that distort the double helix.

• Xeroderma Pigmentosum: Genetic disorder due to NER defects; high cancer risk, severe skin and neurological symptoms.

• Cockayne Syndrome and Trichothiodystrophy: Autosomal recessive diseases with NER defects; developmental and neurological issues, sunlight sensitivity, but no increased cancer risk.

• Double-Strand Break Repair: Repairs dangerous breaks via homologous recombination or nonhomologous end joining.

15.7 The Ames Test Is Used to Assess the Mutagenicity of Compounds

The Ames test uses strains of Salmonella typhimurium to detect mutagenic compounds by measuring the frequency of reverse mutations. It is widely used in industrial and pharmaceutical safety testing.

• Many carcinogens are mutagens: Ames test identifies compounds that cause cancer in animals.

15.8 Transposable Elements Move within the Genome and May Create Mutations

Transposable elements (transposons) are DNA segments that move within and between chromosomes, potentially causing mutations and chromosomal rearrangements.

• Ac–Ds System in Maize: Mobile genetic elements in corn; movement of Ds gene depends on Ac gene.

• Retrotransposons: Transposable elements that use RNA intermediates; include LTR and non-LTR types.

• Copia Elements in Drosophila: Retrotransposons dispersed throughout the genome; cause mutations such as white-apricot eye color.

• Human Transposable Elements: LINEs and SINEs make up 34% of the human genome.

Summary Table: Types of Mutations by Phenotypic Effects

Type	Effect
Loss-of-function	Reduces/eliminates gene product function
Gain-of-function	Enhances or creates new function
Null mutation	Complete loss of function
Dominant negative	Inactive product interferes with wild-type
Suppressor mutation	Relieves effects of previous mutation
Conditional	Expressed only under certain conditions

Summary Table: DNA Repair Mechanisms

Repair Type	Mechanism	Example
Proofreading	DNA polymerase removes incorrect nucleotides	During replication
Mismatch repair	Detects and corrects mismatches	Strand discrimination
Photoreactivation	Cleaves thymine dimers with light	PRE enzyme
Base excision repair	Removes damaged bases	DNA glycosylase
Nucleotide excision repair	Removes bulky lesions	NER pathway
Double-strand break repair	Reattaches broken strands	Homologous recombination, NHEJ