The paternal allele of H19 is silenced; maternal allele active in a wide array of mesenchymal and epithelial tissues, both in mice and humans (Bartolomei et al., 1991; Zhang and Tycko, 1992). H19 encodes an abundant spliced and polyadenylated RNA that has a conserved exon–intron structure among mammals, but that lacks conserved open reading frames. H19 RNA accumulates in the cytoplasm (Brannan et al., 1990; Li et al., 1998). H19 and Igf2 (see above) are inversely regulated in cis through shared insulator and enhancer sequences (Leighton et al., 1995a; Bell and Felsenfeld, 2000; Hark et al., 2000). Accordingly, net expression of H19 generally parallels that of Igf2 (Pachnis et al., 1988; Ohlsson et al., 1994; Leighton et al., 1995b; Drewell et al., 2000), but the two genes are expressed from opposite alleles. Somatic overgrowth was observed in knockout mice lacking the H19 gene and its immediate upstream sequences (Leighton et al., 1995b). Igf2 showed loss of imprinting (i.e., activation of the maternal allele) in these mice and crossing of H19-minus females with Igf2-minus males abrogated the overgrowth of the conceptuses (Leighton et al., 1995). This implied that the biological function of the H19 locus, with its 5′ flanking DNA, may be restricted to controlling Igf2 in cis. However, in another study, deletion of a smaller sequence element upstream of H19 led to activation of the paternal H19 allele, and these mice were growth-retarded, without a measurable effect on Igf2 expression (Drewell et al., 2000). Expression of H19 RNA also inhibited soft agar growth and tumorigenicity in some, but not all, transfected cancer cells (Hao et al., 1993; Isfort et al., 1997), so a possible trans-acting function of the RNA deserves future scrutiny. H19 is silenced, either by de novo DNA hypermethylation of the maternal allele and immediate upstream DNA, or by loss of this allele, in most Wilms' tumors and in several other embryonal neoplasms (Moulton et al., 1994; Steenman et al., 1994; Liu et al., 1995; Taniguchi et al., 1995; Casola et al., 1997; Fukuzawa et al., 1999). Biallelic methylation of H19, associated with relaxation of IGF2 imprinting, is also observed in a specific subset of cases of classical BWS (Catchpoole et al., 1997) with a high predisposition to Wilms' tumor (Engel et al., 2000; Weksberg et al., 2001; DeBaun et al., 2002), and in a related BWS-like overgrowth disorder, also with a predisposition to Wilms' tumor (Morison et al., 1996). In summary, while the physiological role of H19 RNA is not yet known, by several criteria, the H19 locus satisfies the predictions of the conflict hypothesis.