Question

What effect does mutation at nucleotides within a silencer element have on the expression of the gene associated with the silencer? Why does it have this effect?

Answer 1

Genetic mutations occur when nucleotide sequences in an organism are altered. These mutations lead to not only observable phenotypic influences in an individual, but also alterations that are undetectable phenotypically. The sources for these mutations can be errors during replication, spontaneous mutations, and chemical and physical mutagens (UV and ionizing radiation, heat). Silencers, being encoded in the genome, are susceptible to such alterations which, in many cases, can lead to severe phenotypical and functional abnormalities. In general terms, mutations in silencer elements or regions could lead to either the inhibition of the silencer’s action or to the persisting repression of a necessary gene. This can then lead to the expression or suppression of an undesired phenotype which may affect the normal functionality of certain systems in the organism.

for example

At the molecular level, Huntington's disease results from a mutation in the huntingtin protein (Htt). More specifically, there is an abnormal repetition of a CAG sequence towards the 5’-end of the gene, which then leads to the development of a toxic polyglutamine (polyQ) stretch in the protein. The mutated Htt protein affects an individual’s proper neural functions by inhibiting the action of REST/NRSF.

REST/NRSF is an important silencer element that binds to regulatory regions to control the expression of certain proteins involved in neural functions. The mechanistic actions of huntingtin are still not fully understood, but a correlation between Htt and REST/NRSF exists in HD development. By attaching to the REST/NRSF, the mutated huntingtin protein inhibits the action of the silencer element, and retains it in the cytosol.

other example is Mutation of gene-proximal regulatory elements disrupts human gamma and beta-globin expression in yeast artificial chromosome transgenic mice.