Comparative genome mapping in the sequence-based era: Early experience with human chromosome 7

The success of the ongoing Human Genome Project has resulted in accelerated plans for completing the human genome sequence and the earlier-than-antici pated initiation of efforts to sequence the mouse genome. As a complement t o these efforts, we are utilizing the available human sequence to refine hu man-mouse comparative maps and to assemble sequence-ready mouse physical ma ps. Here we describe how rile First glimpses of genomic sequence from human chromosome 7 are directly facilitating these activities. Specifically, we are actively enhancing the available human-mouse comparative map by analyzi ng human chromosome 7 sequence For the presence of orthologs of mapped mous e genes. Such orthologs can then be precisely positioned relative to mapped human STSs and other genes. The chromosome 7 sequence generated to date ha s allowed us to more than double the number of genes that can be placed on the comparative map. The latter effort reveals that human chromosome 7 is r epresented by at least 20 orthologous segments of DNA in the mouse genome. A second component of our program involves systematically analyzing the evo lving human chromosome 7 sequence for the presence of matching mouse genes and expresses-sequence tags (ESTs). Mouse-specific hybridization probes are designed from such sequences and used to screen a mouse bacterial artifici al chromosome (BAC) library, with the resulting data used to assemble BAC c ontigs based on probe-content data. Nascent contigs are then expanded using probes derived from newly generated BAG-end sequences. This approach produ ces BAG-based sequence-ready maps that are known to contain a gene(s) and a re homologous to segments of the human genome for which sequence is already available. Our ongoing efforts have thus far resulted in the isolation and mapping of >3,800 mouse BACs, which have been assembled into >100 contigs. These contigs include >250 genes and represent similar to 40% of the mouse genome that is homologous to human chromosome 7. Together, these approache s illustrate how the availability of,of genomic sequence directly Facilitat es studies in comparative genomics and genome evolution.