Generation and Comparative Analysis of ∼3.3 Mb of Mouse Genomic Sequence Orthologous to the Region of Human Chromosome 7q11.23 Implicated in Williams Syndrome

The past decade has brought spectacular advances in our understanding of the contiguous gene deletion disorder Williams syndrome (WS, also known as Williams-Beuren syndrome; OMIM 194050 [see http://www.ncbi.nlm.nih.gov/Omim]). This complex and intriguing developmental disorder is associated with defects in multiple physiological systems, with the classic phenotypic features including cardiovascular disease, dysmorphic facial characteristics, infantile hypercalcemia, and unique cognitive and personality components (Burn 1986; Morris et al. 1988; Bellugi et al. 1990, 1999; Lashkari et al. 1999; Mervis et al. 1999; Donnai and Karmiloff-Smith 2000; Mervis and Klein-Tasman 2000; Morris and Mervis 2000). A key turning point in elucidating the genetic basis of WS came in 1993 with the discovery that the disorder is associated with hemizygous microdeletions within human chromosome 7q11.23 that include the elastin gene (ELN; Ewart et al. 1993). Since that time, there have been numerous studies aiming to map this region of chromosome 7, identify the genes residing within the commonly deleted interval, and associate the phenotypic features of the disorder to the haploinsufficiency of specific genes. These efforts 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. However, significant challenges have been encountered. For example, attempts to establish contiguous and accurate long-range physical maps of the human WS region have been hampered by a number of problems, including unstable yeast artificial chromosome (YAC) clones derived from the region (which are most likely a consequence of the notably high density of repetitive sequences) and the presence of several large (∼300 kb), closely spaced blocks of DNA with near-identical sequence (Gorlach et al. 1997; Osborne et al. 1997a; Hockenhull et al. 1999; Korenberg et al. 2000; Peoples et al. 2000; Valero et al. 2000). The latter genomic segments, which greatly confound conventional mapping and sequencing strategies, are particularly important, both because they contain gene and pseudogene sequences (Gorlach et al. 1997; Osborne et al. 1997a; Perez Jurado et al. 1998) and because they appear to play a central role in mediating the inter- and intrachromosomal recombination events that lead to the WS-associated deletions (Perez Jurado et al. 1996; Robinson et al. 1996; Baumer et al. 1998). Despite the challenges associated with mapping and sequencing the human WS region, numerous genes residing within the commonly deleted interval and the flanking duplicated segments have been identified (Fig. ​(Fig.1;1; Table ​Table1;1; Francke 1999; Osborne 1999; Osborne and Pober 2001). The diverse phenotypic features associated with WS likely result from haploinsufficiency of these and/or yet-to-be-identified genes that reside within the deleted interval. However, with the exception of ELN and cardiovascular/connective tissue disease, correlating individual genes with specific phenotypic features has proven difficult. Figure 1 Long-range organization of human and mouse Williams syndrome (WS) regions. A physical map of the WS regions on human chromosome 7q and mouse chromosome 5G is depicted emphasizing the positions of the known genes residing within and flanking the interval ... Table 1 Known Human/Mouse Genes Residing Within or Near the WS Region As a complement to the above efforts, our interests have focused on the comparative mapping and sequencing of the WS region in the human and mouse genomes. Previously, we established a bacterial clone-based contig map of the mouse genomic region encompassing the Eln and Ncf1 (p47-phox) genes (DeSilva et al. 1999); note that NCF1 gene/pseudogene sequences reside within the duplicated blocks in the human WS region (Fig. ​(Fig.1;1; Table ​Table1).1). Interestingly, we discovered that the mouse WS region is devoid of the large duplicated segments that are characteristic of its human counterpart. To acquire a more detailed view of this important genomic interval, we have now extended our mouse physical mapping efforts as well as sequenced the entire mouse WS region. Here, we report the generation of ∼3.3 Mb of mouse genomic sequence and the results of detailed computational analyses, which included extensive comparisons with the available sequence of the human WS region.