In an attempt to develop a genetic model consistent with the known findings about the structure of immunoglobulins, W. Dreyer and J. Bennett suggested, in their classic theoretical paper of 1965, that two separate genes encode a single immunoglobulin heavy or light chain, one gene for the V region (variable region) and the other for the C region (constant region). They suggested that these two genes must somehow come together at the DNA level to form a continuous message that can be transcribed and translated into a single Ig heavy or light chain. Moreover, they proposed that hundreds or thousands of V-region genes were carried in the germ line, whereas only single copies of C-region class and subclass genes need exist.
The strength of this type of recombinational model (which combined elements of the germ-line and somatic-variation theories) was that it could account for those im-munoglobulins in which a single V region was combined with various C regions. By postulating a single constant-region gene for each immunoglobulin class and subclass, the model also could account for the conservation of necessary biological effector functions while allowing for evolutionary diversification of variable-region genes.
At first, support for the Dreyer and Bennett hypothesis was indirect. Early studies of DNA hybridization kinetics using a radioactive constant-region DNA probe indicated that the probe hybridized with only one or two genes, confirming the model's prediction that only one or two copies of each constant-region class and subclass gene existed. However, indirect evidence was not enough to overcome stubborn resistance in the scientific community to the hypothesis of Dreyer and Bennet. The suggestion that two genes encoded a single polypeptide contradicted the existing one gene-one polypeptide principle and was without precedent in any known biological system.
As so often is the case in science, theoretical and intellectual understanding of Ig-gene organization progressed ahead of the available methodology. Although the Dreyer and Bennett model provided a theoretical framework for reconciling the dilemma between Ig-sequence data and gene organization, actual validation of their hypothesis had to wait for several major technological advances in the field of molecular biology.
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