The number, chromosomal distribution, and insertional polymorphisms of endogenous feline leukemia viruses (enFeLVs) were determined in four domestic cats (Burmese, Egyptian Mau, Persian, and nonbreed) using fluorescent in situ hybridization and radiation hybrid mapping. Twenty-nine distinct enFeLV loci were detected across 12 of the 18 autosomes. Each cat carried enFeLV at only 9 to 16 of the loci, and many loci were heterozygous for presence of the provirus. Thus, an average of 19 autosomal copies of enFeLV were present per cat diploid genome. Only five of the autosomal enFeLV sites were present in all four cats, and at only one autosomal locus, B4q15, was enFeLV present in both homologues of all four cats. A single enFeLV occurred in the X chromosome of the Burmese cat, while three to five enFeLV proviruses occurred in each Y chromosome. The X chromosome and nine autosomal enFeLV loci were telomeric, suggesting that ectopic recombination between nonhomologous subtelomeres may contribute to enFeLV distribution. Since endogenous FeLVs may affect the infectiousness or pathogenicity of exogenous FeLVs, genomic variation in enFeLVs represents a candidate for genetic influences on FeLV leukemogenesis in cats.Endogenous feline leukemia virus (enFeLV) sequences are present in the genome of the domestic cat, Felis catus. They are homologous to exogenous feline leukemia viruses, which are oncogenic retroviruses capable of inducing both proliferative and degenerative diseases (15, 34). Whereas exogenous FeLVs are transmitted horizontally, endogenous feline leukemia proviruses are part of the germ line and are transmitted from parent to offspring as integral components of chromosomes (5,20). Endogenous FeLVs are found in wild species of the genus Felis closely related to the domestic cat, although they are not present in species from other lineages within the Felidae (4, 56-58). Thus, enFeLVs are believed to have entered the germ line after the initial radiation of lineages in the cat family but before the radiation of domestic cat lineage species (3,23,25), although subsequent additional integrations into the germ line may also have occurred (50).Endogenous FeLV sequences do not by themselves produce infectious virus but readily recombine with exogenous feline leukemia viruses, notably in the env region that codes for the viral coat, producing recombinant viruses with altered biological activity and pathogenicity (4,17,21,43,44,51,53,54,60). For example, the recombinant subgroup C viruses have been found to induce aplastic anemia (18). Furthermore, portions of the enFeLV env region are transcribed and translated in lymphoma and other cell lines (26), producing a truncated envelope protein that inhibits infection by exogenous subgroup B feline leukemia viruses (26). Transcription and translation of enFeLVs have also been demonstrated in tissues from healthy cats, including lymphoid tissue, suggesting a protective role for enFeLVs in vivo (7, 26). Likewise, inoculation with recombinant subgroup B exogenous FeLV attenuates ...