Studies in histocompatibility.

The major histocompatibility complex (MHC) is a group of closely linked loci present in remarkably similar form in all mammals and perhaps in all vertebrates. It plays a still imperfectly understood but clearly important role in immune phenomena. Because of the unusual concentration of similar genes, I referred to it in 1968 as a supergene (1). Bodmer (2) has gone me one better, calling it a super supergene. The term is not inappropriate, because we now , know that the MHC contains at least four gene clusters, each with its own type of end product and its own specific effects on the immune response. The MHC was originally discovered because of its role in the rejection of transplants made between incompatible individuals. Genes competent to play this role in the appropriate experimental or surgical context are called histocompatibility or H genes. An influence on transplants probably is entirely irrelevant to the true function of such genes, but the influence does give the geneticist a handle by which to study them. It was by this route that, over a period of a good many years, I became involved first in immunogenetics and then in the new and fascinating area of cellular immunity. That susceptibility and resistance to transplants are influenced by multiple genes showing Mendelian inheritance was demonstrated in the pioneering studies of Little and coworkers (3, 4, 5). Dr. Little became interested in this subject as a graduate student at Harvard because of experiments with tumor transplants in mice carried out by Tyzzer at the Harvard Medical School. Little suggested (3) a Mendelian interpretation of Tyzzer’s data, and worked jointly with him in experiments to test this hypothesis. After he founded the Jackson Laboratory, he and his associates returned again to an investigation of transplant genetics. While these studies revealed the existence of multiple histocompatibility genes, they did not provide any means of identifying the individual loci. Any individuality was masked by the non-discriminatory nature of a test based on only one variablethe success of transplant growth. Were there any methods by which the individuality of these genes could be revealed? A project in radiation genetics which I had pursued during my first few years at the Jackson Laboratory was winding down in the late 1930’s, and in examining histocompatibility genetics as one of several potential new undertakings, I thought I saw possibilities for new openings. Two methods of locus identification appeared possible. The first was the use of visible marker genes to