Myosin heavy chains (MyHCs) are highly conserved ubiquitous actin-based motor proteins that drive a wide range of motile processes in eukaryotic cells. MyHC isoforms expressed in skeletal muscles are encoded by a multigene family that is clustered on syntenic regions of human and mouse chromosomes 17 and 11, respectively. In an effort to gain a better understanding of the genomic organization of the skeletal MyHC genes and its effects on the regulation, function, and molecular genetics of this multigene family, we have constructed high-resolution physical maps of both human and mouse loci using PCR-based marker content mapping of P1-artificial chromosome clones. Genes encoding six MyHC isoforms have been mapped with respect to their linear order and transcriptional orientations within a 350-kb region in both human and mouse. These maps reveal that the order, transcriptional orientation, and relative intergenic distances of these genes are remarkably conserved between these species. Unlike many clustered gene families, this order does not ref lect the known temporal expression patterns of these genes. However, the conservation of gene organization since the estimated divergence of these species (Ϸ75-110 million years ago) suggests that the physical organization of these genes may be significant for their regulation and function.
By sequencing regions flanking the -globin gene complex in mouse (Hbbc) and human (HBBC), we have shown that the -globin gene cluster is surrounded by a larger cluster of olfactory receptor genes (ORGs). To facilitate sequence comparisons and to investigate the regulation of ORG expression, we have mapped 5 sequences of mRNA from olfactory epithelium encoding -globinproximal ORGs. We have found that several of these genes contain multiple noncoding exons that can be alternatively spliced. Surprisingly, the only common motifs found in the promoters of these genes are a ''TATA'' box and a purine-rich motif. Sequence comparisons between human and mouse reveal that most of the conserved regions are confined to the coding regions and transcription units of the genes themselves, but a few blocks of conserved sequence also are found outside of ORG transcription units. The possible influence of -globin regulatory sequences on ORG expression in olfactory epithelium was tested in mice containing a deletion of the endogenous -globin locus control region, but no change in expression of the neighboring ORGs was detected. We evaluate the implications of these results for possible mechanisms of regulation of ORG transcription.O lfactory receptors are a family of seven-transmembrane G protein-coupled receptors expressed in sensory neurons of nasal epithelium, where they bind to odorant epitopes and transduce this primary signal into membrane potential (1-3). These molecules are encoded by a family of up to 1,000 genes in mouse and human, which are grouped into discrete clusters at different chromosomal locations (4-7). Production of a given olfactory receptor is restricted to one of four spatially defined domains within the olfactory epithelium (8,9). Despite the large size of this gene family, each olfactory neuron appears to express only a single olfactory receptor gene (ORG) (10, 11) in an allele-specific manner (12). The mechanisms that underlie any of these regulatory decisions-expression in olfactory neurons, zonal specificity, one receptor per neuron, or allelic exclusionare undefined. In addition, expression of some ORGs has been documented in nonolfactory tissues (13-17), but the significance of such expression is also unknown.The characterization of DNA sequences required for proper gene expression, such as promoters and enhancers, represents a basic approach to such questions. Functional studies of putative ORG regulatory elements, however, are hindered by the lack of a viable cell culture model for olfactory neurons. Although analysis of transgenes in mice provides a suitable model system, the production of mouse lines is time-consuming and expensive. Thus, genomic approaches are particularly relevant to the identification of ORG regulatory sequences, in part to guide the selection of regions to be examined by functional studies in transgenic mice. Candidates for such regions can be recognized as noncoding sequences that are conserved between species (18).Previously, we reported that ORGs surround the complex o...
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