Cytogenet Cell Genet 90:285–290 (2000) Divergent human and mouse orthologs of a novel gene (WBSCR15/Wbscr15 ) reside within the genomic interval commonly deleted in Williams syndrome J.L. Doyle, a U. DeSilva, a W. Miller, b and E.D. Green a a Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD (USA), and b Department of Computer Science and Engineering, Pennsylvania State University, University Park, PA (USA) Supported in part by grant LM05110 to W.M. from the National Library of Medicine. U.D.’s present address is CSIRO, Division of Animal Production, Blacktown, NSW 2148 (Australia). Received 6 July 2000; accepted 25 July 2000. Request reprints from Dr. Eric Green, National Human Genome Research Institute, 49 Convent Drive, Building 49, Room 2A08, Bethesda, MD 20892; telephone: 301-402-0201; fax: 301-402-4735; e-mail: egreen@nhgri.nih.gov. ABC Fax + 41 61 306 12 34 E-mail karger@karger.ch www.karger.com © 2000 S. Karger AG, Basel Accessible online at: www.karger.com/journals/ccg Abstract. Williams syndrome (WS) is a contiguous gene deletion disorder resulting in complex and intriguing clinical features. Detailed molecular characterization studies of the genomic segment on human chromosome 7q11.23 commonly deleted in WS have uncovered numerous genes, each of which is being actively studied for its possible role in the etiology of the syndrome. Our efforts have focused on the comparative mapping and sequencing of the WS region in human and mouse. In previous studies, we uncovered important differ- ences in the long-range organization of these human and mouse genomic regions; in particular, the notable absence of large duplicated blocks of DNA in mouse that are present in human. Aided by available genomic sequence data, we have used a combination of gene-prediction programs and cDNA isolation to identify the human and mouse orthologs of a novel gene (WBSCR15 and Wbscr15, respectively) residing within the genomic segment commonly deleted in WS. Unlike the flank- ing genes, which are closely related in human and mouse, WBSCR15 and Wbscr15 are strikingly different with respect to their cDNA and corresponding protein sequences as well as tis- sue-expression pattern. Neither the WBSCR15- nor Wbscr15- encoded amino acid sequence shows a statistically significant similarity to any characterized protein. These findings reveal another interesting evolutionary difference between the human and mouse WS regions and provide an additional candidate gene to evaluate with respect to its possible role in the patho- genesis of WS. Copyright © 2000 S. Karger AG, Basel Williams syndrome (WS; also known as Williams-Beuren syndrome; OMIM 194050 [see http://www.ncbi.nlm.nih.gov/ Omim]) is a complex, multisystem developmental disorder associated with cardiovascular disease, dysmorphic facial fea- tures, infantile hypercalcemia, and unusual cognitive and per- sonality components (Burn, 1986; Morris et al., 1988; Bellugi et al., 1990; Keating, 1997). Following the key finding that WS is caused by hemizygous microdeletions within human chromo- some 7q11.23 that include the elastin gene (ELN) (Ewart et al., 1993), numerous other genes have been identified within the commonly deleted genomic interval (see Fig. 1; Francke, 1999; Hockenhull et al., 1999; Osborne, 1999). The broad range of phenotypic features associated with WS likely results from haploinsufficiency of these and/or other yet-to-be-identified genes that reside within the deleted segment. Efforts to construct a long-range physical map of the human WS region have been plagued by problems relating to its com- plex genomic structure, namely, the presence of several large, closely spaced blocks of DNA with near-identical sequence (Gorlach et al., 1997; Osborne et al., 1997). These duplicated segments contain gene and pseudogene sequences of several genes (Francke et al., 1990; Gorlach et al., 1997; Osborne et al., 1997; Perez Jurado et al., 1998; Hockenhull et al., 1999; also reviewed by Francke, 1999, and Osborne, 1999). Many of these studies have been aided by a joint effort between our group and the Washington University Genome Sequencing Center (http: //genome.wustl.edu/gsc) to map and sequence the human WS region (unpublished data).