Question

please answer the following regarding Mutation

Why do methylated cytosines produce hotspots for mutation?

What happens if an insertion or deletion mutation does not consist of a multiple of three nucleotides? What is this called?

What is “polarity” in relation to these gene mutations?

Mutations outside the coding sequence can speed up or slow down transcription. What are these mutations called and which is which? What is a “position effect”?

Answer 1

1. 5-Methylcytosine in DNA is genetically unstable. Methylated CpG (mCpG) sequences frequently undergo mutation resulting in a general depletion of this dinucleotide sequence in mammalian genomes. Unmethylated C deaminates to uracil spontaneously and this is corrected by the mismatch repair machinery because uracil is not a DNA nucleotide.
   Methylated C deaminates to thymidine, here the mismatch repair machinery would not be able to tell which base is the mistake on complementary strands thus you have higher mutation rates of C in the context of CG outside of an island, assumed to be methylated, mutating to T resulting in a G/T mismatch.
2. If an insertion or deletion mutation does not consist of a multiple of three nucleotides, it can lead to frameshift mutation. The outcome of a frameshift mutation is complete alteration of the amino acid sequence of a protein. This alteration occurs during translation because ribosomes read the mRNA strand in terms of codons, or groups of three nucleotides.  Thus, if the number of bases removed from or inserted into a segment of DNA is not a multiple of three, the reading frame transcribed to the mRNA will be completely changed.
3. "Polarity" refers to: Having an effect on downstream products. A polar mutation somewhere in a polycistronic mRNA will introduce changes to the genes further down the chain. This could mean that the other genes are just switched off. Polar mutation tends to have rather broad reaching effects because entire sections of genetic code are as a result transcribed differently.
4. “Silent” mutation: does not change an amino acid, but in some cases can still have a phenotypic effect, e.g., by speeding up or slowing down protein synthesis, or by affecting splicing. Position effect is used to explain why genes in some spots on a chromosome seem to be harder or easier to access - and transposition will sometimes change a gene's accessibility.
   Insertion and deletion can cause polar mutations, as can frameshifts.