Spontaneous mutations arise naturally during normal cellular processes. DNA replication isn't perfect - DNA polymerases occasionally insert the wrong nucleotide, creating mismatches. While proofreading mechanisms catch most errors, some slip through. Additionally, DNA bases can undergo spontaneous chemical changes, like cytosine spontaneously converting to uracil through deamination.

Induced mutations result from external factors. Chemical mutagens can directly modify DNA bases or interfere with replication. For example, alkylating agents add chemical groups to bases, while base analogs get incorporated during DNA synthesis but pair incorrectly. Radiation causes mutations differently - UV light creates thymine dimers that distort the DNA helix, while ionizing radiation breaks chemical bonds and creates reactive molecules that damage DNA.

Replication errors beyond simple mispairing include slippage events. When repetitive DNA sequences cause the template and new strand to misalign temporarily, it can lead to insertions or deletions. This is particularly common in microsatellites - short repeated sequences.

Recombination errors can occur during crossing over in meiosis. If chromosomes don't align perfectly, unequal crossing over can result in duplications in one chromosome and deletions in another.

The cellular environment also influences mutation rates. Oxidative stress from metabolism produces reactive oxygen species that damage DNA bases. Heat can cause depurination, where bases detach from the DNA backbone.

Mutations are permanent changes in the DNA sequence. They can be classified in several useful ways—by scale, mechanism, effect on protein function, and origin.

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1. By Scale of Genetic Change

A. Point (Gene) Mutations

Affect one or a few nucleotides.

1. Substitution

One base is replaced by another.

• Silent mutation

  • Codon changes but amino acid stays the same

  • Example: GAA → GAG (both code for glutamate)

• Missense mutation

  • Codon change → different amino acid

  • Example: Sickle cell disease (Glu → Val in β-globin)

• Nonsense mutation

  • Codon becomes a stop codon

  • Leads to truncated protein

  • Example: Duchenne muscular dystrophy (many cases)

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B. Insertion and Deletion (Indels)

• Insertion: addition of nucleotides

• Deletion: removal of nucleotides

Frameshift Mutation

• Occurs if insertion/deletion is not a multiple of 3

• Alters the reading frame

• Usually produces a severely abnormal protein

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2. By Effect on Reading Frame

• Frameshift mutation

  • Changes downstream amino acids

  • Often introduces premature stop codon

• In-frame mutation

  • Insertion/deletion in multiples of 3

  • Reading frame preserved

  • Protein shorter or longer but partially functional

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3. By Chromosomal Level (Large-Scale Mutations)

A. Structural Chromosomal Mutations

• Deletion – loss of a chromosome segment

• Duplication – repeated segment

• Inversion – segment reversed

• Translocation – segment moved to another chromosome

  • Example: Philadelphia chromosome (t(9;22)) in CML

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B. Numerical Chromosomal Mutations

• Aneuploidy – abnormal number of chromosomes

  • Example: Trisomy 21 (Down syndrome)

• Polyploidy – extra complete sets (common in plants)

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4. By Functional Consequence

• Loss-of-function

  • Reduced or absent protein activity

  • Usually recessive

  • Example: CFTR mutation in cystic fibrosis

• Gain-of-function

  • Increased or new function

  • Usually dominant

  • Example: Achondroplasia

• Dominant negative

  • Mutant protein interferes with normal protein

  • Example: Some p53 mutations

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5. By Origin

• Germline mutations

  • Occur in sperm or egg

  • Heritable

• Somatic mutations

  • Occur in body cells

  • Not inherited

  • Common in cancer

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6. Special Types

• Repeat expansion

  • Expansion of trinucleotide repeats

  • Example:

    • Huntington disease (CAG)

    • Fragile X syndrome (CGG)

• Splice-site mutations

  • Affect RNA splicing

  • Can cause exon skipping or intron retention

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High-Yield Summary Table

Type	Key Feature
Silent	No amino acid change
Missense	Different amino acid
Nonsense	Premature stop
Frameshift	Reading frame altered
In-frame	Reading frame preserved
Gain-of-function	Increased activity
Loss-of-function	Decreased activity
Germline	Inherited
Somatic	Acquired

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