SUBDECK

• Gene Mutation


  Alteration in DNA sequence, including single base-pair substitutions, insertions, deletions, or major chromosome structural changes
• Types of Mutations


  • Point Mutation: Single base-pair substitution
  • Insertion: Addition of one or more base pairs
  • Deletion: Removal of one or more base pairs
  • Chromosome Alteration: Structural changes affecting whole chromosomes
• Mutation Locations


  • Coding Regions: Impact protein structure and function
  • Noncoding Regions: Include introns and regulatory sequences, affecting gene expression
• Effects on Phenotype


  Mutations may or may not lead to observable changes in the organism's traits. Impact depends on where the mutation occurs and its effect on gene function or regulation
• Heritability


  • Germ Cell Mutations: Heritable, passed on to offspring, affecting genetic diversity and potentially causing genetic diseases
  • Somatic Cell Mutations: Not heritable, may lead to altered cell function or tumors within the individual
• Classification Schemes


  • Geneticists categorize mutations based on various criteria, such as molecular impact, phenotypic effect, or their role in disease
• Spontaneous Mutations


  Occur without known external cause, often during normal biological processes like DNA replication
• Induced Mutations


  Result from external factors, natural or artificial agents
• Spontaneous Mutation Rate is extremely low across all organisms, but varies significantly between species and even within the same species and among different genes
• Factors Affecting Mutation Rates include genomic hotspots and differences in DNA proofreading and repair efficiencies between organisms
• Single-Gene Mutations in Humans

  • Base-pair changes: Point mutations alter a single nucleotide base, leading to missense, nonsense, or silent mutations
  • Insertions and Deletions: These mutations can disrupt the reading frame of a gene, leading to frameshift mutations and potentially truncated or non-functional proteins
  • Expanded DNA Repeats: These mutations involve expansions of repetitive DNA sequences within genes, leading to disorders such as Huntington disease and various types of ataxias
• Types and Mechanisms of Multiple Gene Mutations

  • Compound Heterozygosity: Two different mutations present in the two alleles of a single gene
  • Polygenic Mutations: Mutations in several genes contribute to a single trait or disease
  • Epistatic Interactions: Mutation in one gene can mask or modify the effect of mutations in another gene
  • Genetic Modifiers: Certain genes can alter the phenotypic expression of mutations in other genes
• Effects and Implications of Multiple Gene Mutations

  • Disease Phenotypes: Wide range of phenotypic outcomes, from mild to severe
  • Therapeutic Challenges and Approaches: Require comprehensive approaches targeting all involved pathways
  • Evolutionary Impact: Contribute to genetic diversity and evolution
• DNA Repair Systems


  • Proofreading
  • Mismatch Repair
  • Postreplication Repair
  • Photoreactivation Repair
  • SOS Repair
  • Base Excision Repair
  • Nucleotide Excision Repair
  • Double-Strand Break Repair
• Detection and Analysis of Gene Mutations

  • High-Throughput Sequencing: Whole-genome sequencing (WGS) and whole-exome sequencing (WES)
  • Bioinformatics Tools: Computational tools and algorithms to analyze interactions between multiple gene mutations
• Examples of Multiple Gene Mutations in Humans

  • Cancer: Mutations in genes like BRCA1, BRCA2, TP53
  • Neurodegenerative Diseases: Mutations in genes like APP, PSEN1, PSEN2, APOE
  • Cardiovascular Diseases: Mutations in genes regulating blood pressure, lipid metabolism, and vascular function
• Ames Test


  Widely used assay to assess the mutagenicity and potential carcinogenicity of chemical agents
• Techniques used to detect and analyze gene mutations

  • Sequencing Technologies: Next-generation sequencing (NGS)
  • PCR-Based Methods: Allele-specific PCR or real-time PCR
  • Genome Editing Tools: CRISPR/Cas9 systems
• Effects of Gene Mutations

  • Loss-of-Function Mutations: Reduced or absent gene product activity
  • Gain-of-Function Mutations: Altered or enhanced gene product activity
  • Conditional Mutations: Phenotypic effects depend on environmental conditions
• The Luria-Delbrück Fluctuation Test demonstrated that mutations occur randomly, not in response to selective pressure
• Classification Based on Location of Mutation

  • Somatic Mutations: Occur in any cell of the body except germ cells
  • Autosomal Mutations: Mutations within genes located on autosomes
  • X-linked Mutations: Mutations within genes located on the X chromosome
  • Y-linked Mutations: Mutations within genes located on the Y chromosome
  • Germ Cell Mutations: Occur in cells that give rise to gametes
• Classification Based on Type of Molecular Change


  • Point Mutation (Base Substitution): Missense, Nonsense, Silent
  • Insertion or Deletion Mutations: Frameshift Mutation
• Tumor Suppressor Genes


  Genes that encode proteins that normally inhibit cell division, thereby preventing uncontrolled cell proliferation. Mutations in these genes result in the loss of their function, leading to uncontrolled cell division and tumor formation.
• Severe consequences


  If occurring early in the gene sequence, potentially leading to premature termination of protein synthesis due to introduction of stop codons
• Cancer


  A group of diseases characterized by the rapid, uncontrolled proliferation of cells within a tissue, leading to the formation of a tumor
• Although cancer has many causes and manifests in various phenotypes, the fundamental mechanism underlying all cancers is genetic
• Tumor Suppressor Genes


  Genes that encode proteins that normally inhibit cell division, thereby preventing uncontrolled cell proliferation
• Mutations in tumor suppressor genes


  Result in the loss of their function, leading to uncontrolled cell division and tumor formation
• Tumor Suppressor Genes


  • Rb Gene (Retinoblastoma)
  • BRCA1 (Hereditary Breast Cancer Gene)
  • p53 Gene
• Proto-oncogenes


  Genes that encode proteins that normally promote cell division in a controlled manner, acting like an on/off switch for cell proliferation
• Mutations in proto-oncogenes


  Convert them into oncogenes, which are permanently activated, leading to uncontrolled cell division and tumor formation
• Proto-oncogenes


  • N-ras
  • N-myc
  • HER2 (Human Epidermal Growth Factor Receptor 2)
• Mutagens


  Agents that increase the mutation rate beyond the spontaneous mutation rate
• Types of Mutagens


  • Chemical Mutagens
  • Physical Mutagens
  • Biological Mutagens
• Chemical Mutagens


  Compounds that interact with DNA to cause mutations
• Chemical Mutagens


  • Base Analogues (e.g. 5-bromouracil)
  • Intercalating Agents (e.g. Ethidium bromide)
  • Alkylating Agents (e.g. Mustard gas, nitrosamines)
  • Deaminating Agents (e.g. Nitrous acid)
  • Reactive Oxygen Species (e.g. Hydrogen peroxide)
• Physical Mutagens


  Physical factors that cause DNA damage
• Physical Mutagens


  • Ionizing Radiation (e.g. X-rays, gamma rays, alpha particles)
  • Ultraviolet (UV) Radiation (e.g. UV rays from the sun)
• Biological Mutagens


  Organisms or biological processes that cause mutations
• Biological Mutagens


  • Viruses (e.g. Human papillomavirus (HPV))
  • Transposable Elements (e.g. LINEs and SINEs)