Human Chromosome 7: Sequencing, Comparative Genomics, and Study of Disease Genes

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A central activity of the ongoing Human Genome Project is the construction of maps for all human chromosomes en route to the elucidating 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 mammalian 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. Following the recent completion of a YAC-based physical map depicting the relative positions of 2150 chromosome 7 STSs, our efforts have shifted to the construction of a BAC-based contig map suitable for systematic sequencing 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 resulted in our recent identification of the Pendred syndrome gene, which has opened up numerous new avenues of biological study relating to the structure and function of this interesting gene. Similar searches continue for the genes implicated in a number of other important diseases, including cerebral cavernous malformations (CCM1), Charcot-Marie -Tooth syndrome (CMT2D), and Williams syndrome.