Mutations are genetic changes that can alter an organism's DNA. They come in various types, from tiny point mutations affecting single nucleotides to large chromosomal rearrangements. Understanding these changes is key to grasping how genetic information can be modified.

Mutations can occur spontaneously or be induced by external factors like chemicals or radiation. Their effects range from harmless to beneficial or detrimental, potentially altering gene function and an organism's traits. This diversity in mutations plays a crucial role in genetic variation and evolution.

Types of Mutations

Identify the different types of mutations, including point mutations, insertions, deletions, and chromosomal rearrangements

• Point mutations involve changes to a single nucleotide
  • Substitution mutations replace one nucleotide with another
    • Transition exchanges a purine for a purine (A↔G) or a pyrimidine for a pyrimidine (C↔T)
    • Transversion exchanges a purine for a pyrimidine or vice versa (A↔C, A↔T, G↔C, G↔T)
  • Silent mutation changes a codon but does not alter the amino acid it codes for (GGA→GGC, both code for glycine)
  • Missense mutation changes a codon resulting in a different amino acid (GAG→GUG, changes glutamic acid to valine)
  • Nonsense mutation changes a codon to a premature stop codon (UAA, UAG, or UGA), truncating the protein
• Insertions and deletions (indels) add or remove nucleotides from the DNA sequence
  • Frameshift mutation inserts or deletes a number of nucleotides not divisible by three, shifting the reading frame and altering all subsequent codons (insertion of AU in AUGCCC→AUAUCGCC)
  • In-frame insertion or deletion adds or removes a number of nucleotides divisible by three, maintaining the reading frame but adding or removing amino acids (deletion of AUG in AUGCCCAUG→CCCAUG)
• Chromosomal rearrangements involve changes to large segments of DNA
  • Translocation exchanges genetic material between non-homologous chromosomes (reciprocal translocation between chromosomes 9 and 22 in chronic myeloid leukemia)
  • Inversion reverses the orientation of a chromosomal segment (pericentric inversion includes the centromere, paracentric inversion does not)
  • Duplication creates extra copies of a chromosomal segment (Charcot-Marie-Tooth disease type 1A involves a duplication in the PMP22 gene)
  • Deletion results in the loss of a chromosomal segment (Cri-du-chat syndrome involves a deletion in the short arm of chromosome 5)

Causes and Types of Mutations

Explain the causes of mutations, such as replication errors, chemical mutagens, and radiation

• Replication errors can occur during DNA synthesis
  • DNA polymerase slippage may cause insertions or deletions, especially in repetitive sequences (microsatellites)
  • Misincorporation of nucleotides by DNA polymerase can lead to substitution mutations (incorporation of dATP instead of dGTP)
• Chemical mutagens are substances that alter DNA structure
  • Alkylating agents add alkyl groups to bases, causing mispairing (ethyl methanesulfonate adds ethyl groups to guanine)
  • Base analogs are incorporated into DNA in place of normal bases, causing mispairing (5-bromouracil is incorporated instead of thymine and pairs with guanine)
  • Intercalating agents insert between base pairs, distorting the DNA helix and causing insertions or deletions (ethidium bromide)
• Radiation can damage DNA directly or indirectly
  • Ionizing radiation has high energy and can break chemical bonds
    • Causes double-strand breaks and oxidative damage to bases (X-rays and gamma rays)
  • Non-ionizing radiation has lower energy but can still damage DNA
    • Causes the formation of pyrimidine dimers, typically thymine dimers (UV light)

Differentiate between spontaneous and induced mutations and their relative frequencies

• Spontaneous mutations arise naturally without exposure to mutagens
  • Result from inherent errors in DNA replication, tautomeric shifts in bases, or depurination (loss of a purine base)
  • Occur at a relatively low rate, estimated at $10^{-10}$ to $10^{-8}$ mutations per nucleotide per cell division (1 mutation per billion to 100 million nucleotides)
• Induced mutations are caused by exposure to mutagens
  • Mutagens can be chemical (alkylating agents) or physical (radiation)
  • Occur at a higher frequency than spontaneous mutations, depending on the type and dose of the mutagen (UV light can increase mutation rate by 100-fold)

Describe the potential effects of mutations on gene function and phenotype

• Loss-of-function mutations reduce or eliminate the activity of the gene product
  • Often result from nonsense mutations, frameshift mutations, or deletions
  • Typically recessive, as one functional copy of the gene is sufficient in diploid organisms (cystic fibrosis caused by mutations in the CFTR gene)
• Gain-of-function mutations increase the activity of the gene product or confer novel functions
  • Can result from missense mutations, in-frame insertions, or gene duplications
  • Often dominant, as the mutant gene product has an effect even in the presence of the wild-type gene product (Huntington's disease caused by an expanded CAG repeat in the HTT gene)
• Dominant-negative mutations produce a gene product that interferes with the function of the wild-type gene product
  • Mutant gene product may form non-functional complexes with the wild-type gene product
  • Dominant phenotype, as the mutant gene product disrupts the function of the wild-type gene product (some forms of epidermolysis bullosa caused by mutations in the KRT5 or KRT14 genes)
• Neutral mutations have no significant effect on gene function or phenotype
  • Include silent mutations that do not change the amino acid sequence
  • Some missense mutations in non-critical regions of the gene product may also be neutral (substitution of valine for isoleucine in a hydrophobic region of a protein)