Klug_COG12_Lecture_Accessible_Ch_15-rev

Chapter Overview

• Chapter Title: Gene Mutation, DNA Repair, and Transposition

• Edition: Twelfth Edition

• Copyright: 2021, 2019, 2015 Pearson Education, Inc.

15.1 Gene Mutations Are Classified in Various Ways

• Mutation Definition: An alteration in the DNA sequence, encompassing:

  • Single base-pair substitutions

  • Deletions or insertions of base pairs

  • Major alterations in chromosomal structure

• Occurrence: Mutations can occur in:

  • Somatic cells (non-heritable)

  • Germ cells (heritable)

  • Coding or noncoding regions of the genome

Types of Mutations (by Molecular Change)

• Point Mutation/Base Substitution: Change from one base pair to another.

  • Missense Mutation: New triplet code for a different amino acid.

  • Nonsense Mutation: New triplet code for stop codon, terminating early.

  • Silent Mutation: New triplet code still codes for the same amino acid.

• Transitions: Purine to purine or pyrimidine to pyrimidine substitutions.

• Transversions: Purine and pyrimidine interchanged.

Frameshift Mutations

• Caused by insertions or deletions of base pairs.

• Alters the reading frame during translation.

  • Example:

    • Original: "THE CAT SAW THE DOG"

    • Frameshift due to deletion: "THE ATS AWT HED OG"

    • Frameshift due to insertion: "THE CMA TSA WTH EDO G"

Phenotypic Classification of Mutations

• Loss-of-Function Mutations: Reduce or eliminate function of gene product.

  • Null Mutation: Complete loss of function.

• Gain-of-Function Mutations: Mutant phenotype manifesting novel or excessive activity.

• Visible (Morphological) Mutations: Observable traits.

• Nutritional/Behavioral Mutations: Affect metabolic functions or behavioral traits.

• Regulatory Mutations: Impact gene regulation observed in environmental changes.

• Lethal Mutations: Result in the death of the organism.

• Conditional Mutations: Effect depends on environmental condition, e.g., temperature-sensitive mutations.

Location-Based Classification of Mutations

• Somatic Mutations: Occur in somatic cells; non-heritable.

• Germ-Line Mutations: Occur in gametes; heritable.

• X- and Y-Linked Mutations: Mutations located on sex chromosomes.

15.2 Mutations Occur Spontaneously and Randomly

• Spontaneous Mutations: Natural changes in nucleotide sequences; generally low rates.

• Induced Mutations: Result from external agents such as:

  • Radiation (e.g., UV, X-rays)

  • Chemicals (natural and synthetic)

15.3 Spontaneous Mutations Arise from Replication Errors and Base Modifications

• Replication Errors: Imperfect copying by DNA polymerase can lead to point mutations.

• Replication Slippage: Occurs during replication, especially in repeated sequences, leading to insertions or deletions.

• Tautomeric Shifts: Causes mispairing during DNA replication due to alternate chemical forms of bases.

• DNA Base Damage: Depurination (loss of purine bases) and deamination (conversion of cytosine to uracil) can alter base pairing.

• Oxidative Damage: By-products from cellular processes or radiation can damage DNA leading to mutations.

• Transposable Elements: DNA segments that can move within the genome and can act as mutagens.

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

Mutagens

• Natural or artificial agents that induce mutations.

• Examples include:

  • Fungal toxins

  • UV light

  • Industrial pollutants

  • Medical X-rays

  • Chemicals found in tobacco smoke

Types of Chemical Mutagens

• Base Analogs: Compounds that can substitute for normal bases, altering base-pairing.

• Alkylating Agents: Chemicals that add alkyl groups to DNA bases, affecting pair affinity and increasing mutation rates.

• Intercalating Agents: Chemicals that insert themselves between base pairs, distorting DNA.

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

Radiation Effects

• UV Light: Leads to formation of pyrimidine dimers, distorting DNA structure.

• Ionizing Radiation: Causes direct DNA damage through ionization of molecules, leading to mutations.

• Free Radicals: Reactive molecules that can cause significant alterations to DNA.

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

• Monogenic Diseases: Often resulting from a single base-pair mutation; examples include:

  • Missense: Achondroplasia (mutation in FGFR3 gene)

  • Nonsense: Marfan syndrome (mutation in fibrillin-1 gene)

  • Insertion: Familial hypercholesterolemia (varied insertions in LDLR gene)

  • Deletion: Cystic fibrosis (deletion of phenylalanine in CFTR gene)

  • Trinucleotide Repeat Expansions: Huntington disease (CAG repeats in Huntington gene).

15.6 Organisms Use DNA Repair Systems to Counteract Mutations

• DNA repair systems maintain genetic integrity and counteract damage from both spontaneous and induced mutations.

Repair Mechanisms

• Proofreading: DNA polymerase reviews and corrects synthesis errors.

• Mismatch Repair: Clears and repairs mismatched nucleotides post-replication.

• Excision Repair: Repair mechanism for damage, employing the following:

  • Base Excision Repair (BER): Targets damaged bases.

  • Nucleotide Excision Repair (NER): Handles bulky distortions in DNA.

• Homologous Recombination Repair: Repairs double-strand breaks using sister chromatids as templates.

• Nonhomologous End Joining: Ligates broken ends of DNA strands without a template.

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

• Ames Test: Utilizes strains of Salmonella typhimurium to measure the mutagenic potential of compounds.

• Procedure Summary:

  • Assess frequency of reverse mutations in the presence of test compounds to determine mutagenic effects.

• Implications: Strong correlation between Ames test results and carcinogenic potential; many known carcinogens test positive.