Mutations and Diseases
What is a genetic mutation?
A mutation is a permanent change in the DNA. Mutations in germ cells are transmitted to progeny (and cause heritable disease) while mutations in somatic cells are not transmissible but can affect cell behaviour (e.g., malignant transformation). Mutations can involve changes in coding or non-coding regions of the genome. In addition, mutations can affect just one or a few nucleotides, or they can cause complete deletion of a gene.
Categories of Genetic Mutations:
- Point mutations in coding sequences
- Missense mutation: Single nucleotide substitutions can change the triplet base code and yield a different amino acid in the final protein product. This can be a conservative mutation if the new amino acid is not significantly different from the original, with minimal (if any) consequences. However, non-conservative mutations (e.g., substituting amino acids of different size or charge) can lead to loss of function, misfolding and degradation of the protein, or gain of function.
- Nonsense mutation: Single nucleotide substitutions can potentially result in the formation of an inappropriate “stop” codon; the resulting protein may then be truncated with loss of normal activity.
- Mutations within noncoding regions: Point mutations or deletions in enhancer or promoter regions can significantly affect the regulation or level of gene transcription. Point mutations can lead to defective splicing and thus failure to form mature mRNA species.
- Frameshift mutations: Loss of one or more nucleotides can alter the reading frame of the DNA. Insertions or deletions of multiples of three nucleotides may have no effect other than adding or deleting an amino acid. Frameshifts of other numbers of nucleotides lead to defective protein products (missense or nonsense).
- Trinucleotide repeat mutations: This special category of mutations is characterized by amplification of triple-nucleotide sequences (e.g., fragile X syndrome or Huntington disease). Trinucleotide repeats are a common feature of many normal genetic sequences; however, mutations involving these repeats can see a 10-fold to 200-fold amplification of the normal number, leading to abnormal gene expression. This type of mutation is also dynamic, with the length of the trinucleotide repeat sequences frequently expanding during gametogenesis.