Phenotypic variation in the structure of proteins

The concept of one gene-one polypeptide implies that the synthesis of each polypeptide chain of a given protein is controlled by a single gene. Thus, the structure (phenotype) of a protein is directly under genetic control. In protein structural studies, the term phenotype often refers to genetically controlled different structural forms of a protein. Analysis of genetically determined phenotypic variability in protein structure became possible with the advent of various electrophoretic techniques. Early work on protein polymorphism focused mainly on enzymes in humans (Harris) and Drosophila, a fruit fly (Lewontin and Hubby). Using these conventional methods of electrophoresis, Harris estimated that approximately one-third of all possible amino acid substitutions in the polypeptide chain of proteins could be detected. However, the early methods were not sensitive enough to detect phenotypic differences in molecules having similar or identical molecular size and conformation but different isoelectric points (a point at which protein carries no net electrical charge).

In the early 1980s, the application of the isoelectric focusing (IEF) technique made it possible to detect minute differences of isoelectric points between various protein isoforms, thus allowing the observation of previously undetectable phenotypic variation. In addition to the charged amino acid substitutions, the IEF technique can also detect some neutral amino acid substitutions in the protein structure. Approximately 40% of mutations resulting from single-base substitution would lead to electro-phoretically detectable changes in charged amino acids, while another 40-60% would involve neutral-to-neutral amino acid substitutions. In addition to the progress in separating proteins, advanced protein detection methods have also played a major role in observing protein phenotypes. The development of immunoblotting or western blotting techniques has replaced most other detection methods because of their sensitivity and versatility. Today, there are about 100 plasma proteins and red cell enzymes that show electrophoretically detectable polymorphisms in humans.

Alleles coding for protein phenotypes are expressed in a codominant fashion because both the homozygous and heterozygous forms are distinguishable and both pairs of alleles are fully expressed in heterozygotes. In such cases, the genotype can be inferred directly from the visible phenotypic patterns on the electrophoretic gels. Most of these protein polymorphisms are neutral because they do not appear to have drastic effects on an individual's physical or biological functions.

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