WK3 LEC PR

• A mutation is any heritable change in the amount or structure of genetic material
• Classification of mutations based on

  • Origin
  • Cell type
  • Expression
  • Effect on function
  • Molecular change and its effects on protein products
• Based on the origin

  • Spontaneous
  • Induced
• Spontaneous mutations occur in the absence of known mutagen and are statistically random, unpredictable events
• Induced mutations occur in the presence of known mutagen
• Each gene has its rate of mutation which can increase by treatment with a mutagen or radiation
• Based on cell type

  • Somatic
  • Germ line
• Somatic mutations occur in nonreproductive cells and can yield a genotypic mixture of normal and mutant tissue, common in most cancers
• Germ line mutations occur in reproductive cells and are inherited
• Based on expression


  • Conditional
  • Unconditional
• Conditional mutations are expressed only under restrictive conditions, while unconditional mutations are expressed under permissive conditions as well as restrictive conditions
• Based on function and effects

  • Loss of function (Knockout or null mutations)
  • Hypomorphic (Leaky mutations)
  • Hypermorphic
  • Gain of function (Ectopic expression)
• Substitutions, deletions, insertions, duplications, inversions, and translocations are types of mutations
• Base-pair substitutions in molecular genetics are also termed point mutations
• Substitutions involve the replacement of a single nucleotide by another, either as transition or transversion
• Deletions involve the loss of one or more nucleotides, with patterns including multiple of 3 nucleotide (codon) deletions and not multiple of 3 deletions
• LARGE DELETION


  1. May arise through unequal crossover between repeat sequences

  2. Either: Partial gene deletion or Whole gene deletion
• INSERTIONS


  1. Involves the addition of one or more nucleotides into a gene

  2. Insertion patterns: MULTIPLE OF 3 NUCLEOTIDE (CODON), NOT MULTIPLE OF 3
• LARGE DELETION


  1. Results from unequal crossover or the insertion of transposable elements

  2. Either: Partial gene duplication or Whole gene duplication
• EXPANSION OF TRINUCLEOTIDE REPEAT (most contain C and/or G)

  1. Amplification of a sequence of three nucleotides, which prevents normal expression of the gene

  2. Involves dynamic mutations wherein the repeat sequence becomes more unstable as it expands in size

  3. POSSIBLE CAUSES: Unequal sister chromatid exchange on non-replicating DNA, Slipped-strand mispairing and polymerase slippage in replicating DNA

  4. EXAMPLE OF DISORDERS: Fragile X syndrome (FMR1 gene) – CGG repeats, Huntington disease (HTT gene) – CAG repeats, Myotonic dystrophy (DMPK gene) – CTG repeats, Friedreich ataxia (FXN1 gene) – GAA repeats
• DUPLICATIONS


  1. Involves the production of one or more copies of a gene or region of a chromosome

  2. In a disease process, extra copies of the gene can contribute to cancer

  3. Important mechanism for the developmental evolution of various organisms
• INVERSIONS


  1. Formed by two break events in a chromosome in which the middle segment is reversed in orientation before the breaks are healed

  2. No change in the amount of genetic material – no particular abnormalities at the phenotypic level

  3. However, when chromosome breaks are within a gene of essential function – results in lethal gene mutation

  4. Inversion patterns: PARACENTRIC INVERSION, PERICENTRIC INVERSION
• TRANSLOCATIONS


  1. Occurs when a portion of the chromosome attaches to another nonhomologous chromosome during cell division

  2. Can be due to abnormal synapsis event at Meiosis I caused by incorrect chromosomes coming together

  3. Examples: t(9;22) – Philadelphia chromosome (CML), t(8;14) – Burkitt’s Lymphoma
• EFFECTS OF MUTATIONS ON PROTEIN PRODUCTS

  SYNONYMOUS MUTATIONS, SILENT MUTATIONS, NONSYNONYMOUS MUTATIONS, MISSENSE MUTATIONS, NONSENSE MUTATIONS, FRAMESHIFT MUTATIONS
• SYNONYMOUS MUTATIONS


  Mutation does not alter the polypeptide product of the gene
• SILENT MUTATIONS


  Mutation does not alter the polypeptide product of the gene
• Mutations


  Mal function, usually associated with disease or lethality
• Types of Mutations


  • MISSENSE MUTATIONS
  • NONSENSE MUTATIONS
  • FRAMESHIFT MUTATIONS
  • SILENT MUTATIONS
• MISSENSE MUTATIONS


  1. Base-pair substitutions that produce a change in a single amino acid

  2. Change in amino acid may affect the protein structure
• SICKLE CELL ANEMIA affects the β-globin chain of hemoglobin
• NONSENSE MUTATIONS


  1. Base-pair substitutions that produce a stop codon in the mRNA

  2. Result in a premature termination of the polypeptide chain

  3. Unlikely to retain normal biological activity, especially when there is a loss of an important functional domain(s) of the protein
• β 0 -thalassemia affects the β-globin chain of hemoglobin. The codon for glutamine (CAG) creates a stop codon (UAG) as U is substituted for C
• FRAMESHIFT MUTATIONS


  1. When a mutation involves the insertion or deletion of nucleotides that are not a multiple of three, it will disrupt the reading frame

  2. Resulting amino acid sequence bears no resemblance to the normal sequence and may have an adverse effect on its function
• Single-base deletion at the ABO (glycosyltransferase) locus leads to a frameshift mutation responsible for the O allele
• Tay-Sachs disease: Four-base insertion in the hexosaminidase A gene
• Summary of Mutation Types

  • Substitution
  • Deletion
  • Insertion
  • Duplication
  • Dynamic Mutation
• Effects on Protein Product

  • Same amino acid
  • Altered amino acid —may affect protein function or stability
  • Stop codon-loss of function or expression due to degradation of mRNA
  • Aberrant splicing-exon skipping or intron retention
  • Altered gene expression