Typical-azaguanine-resistant (AGr) and diaminopurine-resistant (DAPr) variants of cultured human fibroblasts are being analyzed by means of somatic cell hybridization, karyotype analysis and enzymological characterization. Twin objectives of this work are to understand basic mechanisms of somatic cell variation in humans and to genetically validate methods being developed for detecting mutagens and carcinogens. The results indicate that ARr and DAPr variants of human cells originate by means of stable changes in cell heredity. We will use the information obtained with cultured cells to develop methods of quantitatively detecting AGr and DAPr variants among cells directly upon their removal from the bodies of humans or experimental animals. Hybridized somatic cells are being used to study the differentiation of human X-chromosomes into active and inactive forms. Hybrids that have only an active X or only an inactive X in a background of mouse chromosomes are being used to isolate human X-chromosomal DNA by means of nucleic acid hybridization. The DNA's of the two functional forms of the X will then be compared chemically. The hybrids with inactive X chromosomes are also being used to discover kinds of mutagenic treatments that will derepress X-chromosomal genes. BIBLIOGRAPHIC REFERENCES: Held, K.R., Kahan, B. and DeMars, R. Adenine phosphoribosyltransferase and hypoxanthine-guanine phosphoribosyltransferase immunoprecipitation reactions in human-mouse and human-hamster cell hybrids. Humangenetik 30 (1975) 23-34. Kahan, B. and DeMars, R. Localized derepression on the human inactive X chromosome in mouse-human cell hybrids. Proc. Nat. Acad. Sci. 72 (1975) 1510-1514.