We isolated and sequenced a human genomic-DNA segment that is homologous to a portion of v-rel, the transforming gene of reticuloendotheliosis virus (strain T). We also localized the human rel sequences to human chromosome 2 by screening a panel of rodent x human somatic-cell hybrids with the newly described human rel segment. Cellular homologs of retroviral transforming genes have been identified in birds and mammals, in which these homologs are thought to perform important roles in regulating cell proliferation and differentiation (for a review, see reference 2). Recent studies suggest, however, that specific alterations in normal cellular oncogene structure and expression may themselves initiate cellular transformation in the absence of retroviral infection (e.g., see references 7, 15, 24, and 30). Such observations have prompted investigators to clone cellular oncogene homologs to study their normal biological properties and to determine whether alterations in these properties are consistently associated with naturally occurring, nonvirally induced malignancies. In this study, we determined the nucleotide sequence and chromosomal localization of a cloned human DNA segment carrying two putative exons homologous to the transforming gene (v-rel) of reticuloendotheliosis virus strain T (REV-T). The human c-rel sequences may provide a useful tool for studying the structure and function of this cellular oncogene in mammals.REV-T is a replication-defective (11) type C retrovirus (3,12,25,36) that induces acute leukemia in young chickens and turkeys (32). It is the only known acutely transforming member (9, 10) of a retroviral family that includes spleen necrosis virus, chick syncytial virus, duck infectious anemia virus, and the REV-T helper reticuloendotheliosisassociated virus (REV-A) (11,14). The REV-T genome carries a genomic substitution of approximately 1.42 kilobases (kb) near its 3' end (4, 6, 29) that is required for cellular transformation (5). This sequence, termed v-rel, is believed to have been derived from several exons of a turkey cellular gene (4,27,35), and recent molecular analyses of the turkey c-rel locus support this hypothesis (33). We began our investigation by performing Southern transfer and hybridization experiments to determine whether v-rel homologies could also be detected in humans and other mammals. The results of one such experiment in which cellular DNAs of hamsters, mice, humans, and chickens were hybridized with Sst v-rel, a 514-base-pair (bp) subclone of v-rel, are shown in Fig. le. After a 3-day exposure, one or two rel-homologous DNA bands were noted in all of the lanes, including those containing human DNA (see also reference 4).We next used Sst v-rel to screen (1) a human partial HaeIII-AluI genomic-DNA library (18) This fragment (pPHHSrel-1) was subcloned for further sequence analysis. Additional Sst v-rel homologies could not be identified, leading us to speculate either that the phage clone carried only a small portion of the human c-rel gene or that HSrel-1 and Sst v-r...