A central activity of the ongoing Human Genome Project is the construction of maps for all human chromosomes en route to the eventual elucidation of their complete DNA sequence. The major aims of the Physical Mapping Section are to establish and implement approaches for developing integrated and annotated physical maps of human chromosomes and to utilize the resulting information for studying important biological problems. Our general mapping paradigm involves the detection of PCR-based landmarks called sequence-tagged sites (STSs) within large segments of DNA cloned into yeast artificial chromosomes (YACs) and bacterial artificial chromosomes (BACs). We have focused our attention on the 170-megabase human chromosome 7. This year we reached an important milestone in the project, with the completion of a YAC-based physical map depicting the relative positions of 2150 chromosome 7 STSs. Our map thus provides a mapped STS, on average, every 79 kb across the chromosome, surpassing the goal of 100-kb verage STS spacing established for the Human Genome Project. The map has also been rigorously integrated with the cytogenetic, genetic, and radiation hybrid maps of the chromosome. Our recent efforts have increasingly shifted into two important directions. First, we are actively using our YAC-based map to derive a suitable 'sequence-ready map' of the chromosome. This effort, being performed in collaboration with two extramural genome centers (at Washington University and the University of Washington), represents the central focus of the current phase of the Human Genome Project. It is our expectation that chromosome 7 will be among the first few human chromosomes to be completely sequenced. Second, we are actively using our integrated maps and (increasingly) sequence data to study regions of chromosome 7 associated with human genetic disease. These efforts involve searching for the genes implicated in a number of interesting diseases, including cerebral cavernous malformations (CCM1), Pendred syndrome, Charcot-Marie -Tooth syndrome (CMT2D), and Williams syndrome.
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