Genotype-Phenotype Interactions

Genotype-Phenotype interactions - how factors can influence the phenotype of a certain genotype:factors include:Mutation TypeWhat type of mutation is it? e.g. missense, nonsense, does it cause a frameshift?EXAMPLE - DMD and BMD - same gene, one mutation causes frameshift, one doesn'tMutation LocationMutations can affect the protein product differently according to their location. At one position they may render the protein non-functional (null mutation), whereas others may reduce the activity of the protein (loss of function).EXAMPLE -Haemoglobinopathy - genetic defect leading to alteration in the structure of haemoglobin - e.g. sickle cell diseaseOf the mutations in the haemoglobin gene: One mutation (missense mutation at 6th aa position) leads to sickle cell anaemia Others can lead to thalassaemia (weakening and destruction of red blood cells) Others can lead to polycythaemia - a benign condition that can cause a 50% increase in the oxygen carrying capacity of the blood. This can be beneficial to athletes, giving them advantage in endurance events.     Genetic Background Common variants (polymorphisms) can form an additive risk/protective factor for certain conditions and thus this interacts with the effect of the mutant allele. EXAMPLE - Sick Sinus Syndrome - arrhythmias caused by malfunction of the sinus node SSS is caused by a mutation in the gene SCN5A A common SNP in this gene H558R has been shown to modulate the effect of the mutation  Gui et al 2010 found that 558R was able to rescue some of the loss of function defect in certain mutant ion channels.   X-inactivationSkewed x-inactivation can occur - for example, phenotype of x-linked disorder may be expressed in a femaleAdrenoleukodystrophy - female may show earlier onset of neurological symptoms/more severeGenomic ImprintingSee epigenetics - Prader-Willi vs Angelman SyndromeEnvironmente.g. lifestyle, diet, stress

Introduction