Mutations Genotype Versus Phenotype

Genetic information exists in the form of nucleic acids known as the genotype. In contrast, the encoded proteins function to create a phenotype, an outwardly observable characteristic. Genotypic alterations may or may not cause phenotypic alterations. For instance, missense mutations refer to genetic changes that result in the incorporation of a different amino acid at a specific codon location. These changes may not dramatically alter the protein if the replacement amino acid is similar to the original amino acid (for example, a hydrophobic amino acid replaces another hydrophobic amino acid). However, replacement of an amino acid with a different type of amino acid may significantly change the conformation of the protein and thus change its function. For example, in sickle cell anemia, a valine replaces a glutamic acid at a single position and permits the polymerization of the beta globin molecules to cause stiffening and sickling of the red blood under low oxygen conditions. Different forms of proteins (known as conformers) provide the mechanism for diseases ranging from Creutzfeldt-Jacob disease to Huntington disease. Nonsense mutations describe base changes that replace an amino-acid-encoding codon with a stop codon, which causes premature termination of translation and results in a truncated protein.35 Truncation may result from the addition or deletion of one or two nucleotide bases, resulting in a shift in the reading frame. Frameshifts often result in premature termination when stop codons are formed downstream from the mutation. Alterations in splice donor or acceptor sites may either erroneously generate or prevent appropriate splicing of the 1° transcript, resulting in a frameshift mutation.36 Genetic changes in the untranslated portions of the gene affecting the promoter, enhancer, or polyadenylation signals may affect the expression of the gene product and result in a phenotypic change. Not all genotypic changes affect the phenotype. Genetic changes affecting the third base of the codon rarely alter the gene code and would therefore be less likely to cause incorporation of a different amino acid.

With the sequencing of the human genome, numerous single nucleotide polymorphisms have been identified, demonstrating the individual nature of human beings. Numerous studies currently target correlating genotype variations to disease phenotypes. These efforts, in combination with improved understanding of gene structure and function, hold the promise of improved diagnosis, treatment, and patient outcomes in the future.

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