Molecular Evolutionary analysis of Genetic Variation in Skeletal Muscle Sodium-Channel Gene (SCN4A)

Discovering the mysteries of human genetic variation is an essential precursor for the development of personalized medicine where the aim is to relate the genotype with the phenotype in improved understanding of an individual’s susceptibility to diseases .Each individual carries thousands of amino acid altering nucleotide mutations. Genetic defects in voltage-gated sodium channels are responsible for several hereditary diseases. Because of the lack of information available for the association of phenotype effects with these mutations, computational methods are useful in lieu of time consuming wet lab sequencing. Using available information from online database, we conducted a study to directly evaluate interspecific sequence alignments that reveal common attributes of deleterious mutations observed in humans using the Skeletal-muscle sodium-channel gene SCN4A. This gene is in charge of making sodium channels, which transport sodium ions into cells to generate and transmit electrical signals. Mutations on this gene are associated with Myotonia or periodic paralysis and in rare cases fatigable weakness; these disorders are inherited in an autosomal dominant fashion. Our objective was to determine if there existed a difference in rate of disease- associated mutation between highly conserved sites and less conserved sites. Biochemical differences of disease-associated amino acid changes are more radical than the commonly encountered polymorphic amino acid variation permitted by natural selection throughout evolutionary history. We hypothesized that disease mutations occur more frequently in sites that are highly conserved. This research supported our hypothesis showing that disease-associated mutations are more likely to occur at highly conserved sites.