Long-range comparison of human and mouse SCL loci: Localized regions of sensitivity to restriction endonucleases correspond precisely with peaks of conserved noncoding sequences

Long-range comparative sequence analysis provides a powerful strategy for i dentifying conserved regulatory elements. The stem cell leukemia [SCL] gene encodes a bHLH transcription factor with a pivotal role in hemopoiesis and vasculogenesis, and it displays a highly conserved expression pattern. We present here a detailed sequence comparison of 193 kb of the human SCL locu s to 234 kb of the mouse SCL locus. Four new genes have been identified tog ether with an ancient mitochondrial insertion in the human locus. The SCL g ene is flanked upstream by the SIL gene and downstream by the MAP17 gene in both species, but the gene order is not collinear downstream from MAP17. T o facilitate rapid identification of candidate regulatory elements, we have developed a new sequence analysis tool (SynPlot) that automates the graphi cal display of large-scale sequence alignments. Unlike existing programs, S ynPlot can display the locus Features of more than one sequence, thereby in dicating the position of homology peaks relative to the structure of all se quences in the alignment. In addition, high-resolution analysis of the chro matin structure of the mouse SCL gene permitted the accurate positioning of localized zones accessible to restriction endonucleases. Zones known to be associated with functional regulatory regions were found to correspond pre cisely with peaks of human/mouse homology, thus demonstrating that long-ran ge human/mouse sequence comparisons allow accurate prediction of the extent of accessible DNA associated with active regulatory regions.