Main types of molecular mutations and their effect on phenotype

Types of Molecular Mutations

Mutations can be broadly classified based on their scale and the type of alteration they induce.

1. Point Mutations

These involve changes at a single nucleotide base pair. They are further categorized as:

• Substitutions: One base is replaced by another.
  • Transitions: Purine replaced by purine (A ↔ G) or pyrimidine replaced by pyrimidine (C ↔ T).
  • Transversions: Purine replaced by pyrimidine or vice versa.
• Insertions: Addition of one or more nucleotide bases.
• Deletions: Removal of one or more nucleotide bases.

Insertions and deletions can cause frameshift mutations, altering the reading frame of the gene and leading to a completely different protein sequence downstream of the mutation.

2. Chromosomal Mutations

These involve larger-scale changes affecting entire chromosomes or large segments of DNA.

• Deletions: Loss of a chromosomal segment.
• Duplications: Repetition of a chromosomal segment.
• Inversions: A segment of a chromosome is reversed end-to-end.
• Translocations: A segment of a chromosome moves to another chromosome.
• Aneuploidy: Abnormal number of chromosomes (e.g., trisomy, monosomy).
• Polyploidy: Having more than two complete sets of chromosomes.

Effects on Phenotype

The phenotypic consequences of mutations vary widely.

1. Loss-of-Function Mutations

These mutations reduce or eliminate the function of the gene product. They are often recessive, meaning that both copies of the gene must be mutated to observe the phenotype.

• Example: Cystic Fibrosis – caused by mutations in the CFTR gene, leading to defective chloride transport and mucus buildup in the lungs.

2. Gain-of-Function Mutations

These mutations increase the activity of the gene product or give it a new function. They are often dominant, meaning that only one copy of the mutated gene is sufficient to produce the phenotype.

• Example: Huntington’s Disease – caused by an expansion of a CAG repeat in the HTT gene, leading to a toxic protein that damages neurons.

3. Dominant Negative Mutations

These mutations produce a protein that interferes with the function of the normal protein.

• Example: Some mutations in collagen genes causing Osteogenesis Imperfecta.

4. Silent Mutations

These mutations do not change the amino acid sequence of the protein due to the degeneracy of the genetic code. They typically have no phenotypic effect.

5. Missense Mutations

These mutations change the amino acid sequence of the protein. The effect on phenotype depends on the importance of the altered amino acid.

Mutation Type	Effect on DNA	Effect on Protein	Phenotypic Consequence
Point Mutation (Substitution)	Single base change	May change amino acid (missense), no change (silent), or create a stop codon (nonsense)	Variable – from no effect to severe disease
Frameshift Mutation	Insertion or deletion not in multiples of three	Altered amino acid sequence downstream of mutation	Usually severe, non-functional protein
Chromosomal Deletion	Loss of a chromosome segment	Loss of genes on the deleted segment	Often lethal or causes severe developmental defects