ATTEMPTS TO LOCATE COMPLEMENTARITY‐DETERMINING RESIDUES IN THE VARIABLE POSITIONS OF LIGHT AND HEAVY CHAINS *

Examination of the sequences of Bence-Jones proteins and myeloma immunoglobulin light chains from humans and from mice has led to the recognition of the variable and constant regions, and the accumulation of data on heavy chains indicates that they too contain a variable and a constant regi0n.I-j The variable region comprises approximately the amino terminal half of the light chain and the amino terminal quarter of the heavy chain, and it is these regions which are generally believed to be responsible for antibody complementarity. The genetic control of the constant regions of both chains is readily explainable on classical genetic principles, but the genetics of the variable regions is far from clear and no generally agreed upon concept of the genetic determination of antibody complementarity has as yet been formulated. The recognition of subgroups in the variable regions of human (Reference 2, p. 133) ,8* and mouse l1 from sequence analyses, mainly of the first 20-25 amino terminal residues, has led to the designation of genes for these subgroups. It is generally accepted that the light chain and the heavy chain are each under the control of two genes, one for the variable and one for the constant region, and that a translocation results in the joining of these two genes.12 These conclusions, however, do not account for antibody complementarity nor do they localize the combining site to any specific portions of the variable region. When the subgroups of the variable regions were first recognized, it was noted 7 1 that certain positions, notably those near 30 and 91-96, showed greater variability than could be accounted for by the subgroups. As further sequences accumulated, it became clearer that there were two regions of hypervariability, one following cysteine 23 and the other following cysteine 88 and comprising residues 24-34 and 89-96 respectively, and it was of special interest that these two regions were brought into close proximity by the disulfide bond Iz3-1Is8, and that insertions or deletions occurred in these regions.13~ 4 A more detailed analysis indicated the presence of three hypervariable regions. FranEk (Reference 5, p. 311) tabulated the positions showing nonhomologous replacements and recognized a region from residues 50-55 in light chains and in human heavy

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