The noncoding regulatory region of polyoma (Py) virus regulates early and late mRNA transcription as well as DNA replication (Tyndall et al., NAR 9, 6231-6250, 1961). This segment of the viral genome also enhances the transcription of heterologous genes in chimeric plasmids (de Villiers and Schaffner, NAR 9,6251-6264, 1961) in a manner analogous to the SV40 enhancer and the LTR region of retroviruses (for review, see Khoury and Gruss, Cell 33, 313-314, 1963). The Py enhancer is of particular interest because sequence rearrangements in this region of the genome have been found frequently among “natural” viral strains (Ruley and Fried, J. Virol. 47 233-237, 1983). Moreover, the activity of the enhancer can be studied in the mouse, the most genetically well characterized mammal. Recently, much attention has been focused on the regulatory region of Py mutants that have a broader host range than wild type (wt) virus strains (such as those growing on embryonal carcinoma or trophoblast undifferentiated cells; Kelly and Condamine, BBA 657, 105-141, 1982; Tanaka et al., EMBO J. 7, 1521-1527, 1982); and Py mutants that grow at a higher rate on differentiated cells which further differentiate in vitro (such as neuroblastoma and Friend erythroleukemic cells; Maione et al., EMBO J. 4, in press; Delli Bovi et al., J. Virol. 49,566-571, 1984; De Simone et al., MCB 5, 2142-2146, 1985). Most of these mutants are characterized by rearrangements of the regulatory region. These rearrangements consist of either duplications or deletions that affect one or both of the two domains involved in the control of DNA replication and mRNA transcription, variously termed a and /I (Muller et al., J. Virol. 47, 586-599, 1983) or A and B (Herbomel et al., Cell 39, 653-662, 1984). The simplest wt Py strain, PyA2, carries a single copy of each of the two domains. Other naturally occurring Py strains (TOR, P16, and CSP) contain a duplication of the A domain, in addition to a few base pair changes (see figure). Sequence analysis of the regulatory region of Py mutants selected for their ability to grow in nonpermissive (undifferentiated) cells indicates that the rearrangements required for viral gene expression and replication in a new environment are host-specific and involve changes that are extensive in some cases and minor in others. The ability of Py mutants to grow on embryonal carcinoma PCC4 cells is always associated with extensive rearrangements (Vasseur et al., PNAS 77; 1068-1072, 1980; Katinka et al., Cell 20, 393-399, 1980; Melin et al., EMBO J. 4, 17991803,1985). Limited base alterations are sufficient for viral growth on the embryonal carcinoma F9 cell line, although Minireview