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Human Genome News, April-June 1996; 7(6)

Santa Fe '96

A Versatile Mapped BAC-PAC Resource

Julie Korenberg (Cedars-Sinai Research Institute) described the practical value of having a single resource of mapped clones for studying human genetics at the sequence, gene, chromosome, and whole-genome levels. She reported on progress toward creating such a resource and its early applications for mapping, sequencing, gene isolation, molecular cytogenetics, and genome-organization analysis.

Ultimately, the Mapped BAC-PAC Resource will represent 0.8 to 1.2x of the human genome (about 18,000 to 20,000 clones, covering over 70%) in a stable framework resource. The Resource will be based on BACs and PACs from Melvin Simon and Pieter de Jong and integrated at 1000 to 5000 loci with the radiation hybrid, genetic, and STS maps. Korenberg chose BACs and PACs because they are relatively stable, easy to use, and useful for sequencing and probes.

By using FISH, almost 4000 BACs and PACs (3638 and 242, respectively) have been assigned to regions of 2 to 6 Mb (average insert sizes, 125 to 150 kb). These BACs and PACs represent 17 to 20% of the human genome. The rate of chimerism is very low (8% for BACs and 2.5% for PACs).

BACs have been obtained for all 24 chromosomes and 17 of the centromeres. Specific BACs for 11 telomeres and nonspecific BACs for 19 telomeres are available, and 100 BACs have been mapped to single bands in the mouse genome.

Tom Hudson (Whitehead-MIT) is screening 5000 markers against the subset of nearly 18,000 BACs; so far, agreement with MIT chromosome and region assignment has been 80% for 216 markers. All common markers are also mapped on STS and radiation hybrid maps.

Applications

• The Cedars-Sinai group's analysis of BACs from a chromosome 7 region usually deleted in Williams syndrome suggests a novel genomic structure involving clustered low-copy repetitive sequences whose arrangement may predispose to deletions. This may be a model for other conditions, such as cancers, characterized by deleted or rearranged regions. People with Williams syndrome have heart disease (due to a lack of elastin) and mental retardation.
• The Resource has been useful for finding areas not covered by STSs, as illustrated by megabase-size regions in a 3- to 4-Mb contig constructed by Korenberg's group for the chromosome 21 Down syndrome region.
• Several collaborative projects are supplying BACs to disease-gene hunters who use them to fill gaps in YAC maps for target regions.
• LANL researchers localized 13% of their unlinked contigs by hybridizing to half the 90 BACs supplied by Korenberg's group. Her team also sent BACs to scientists studying chromosomes 12, 19, and 22.
• Ultimately, the Resource can be used as a framework for genome sequencing or for anchoring end-sequence projects.
• For molecular cytogenetic studies, the Resource can replace chromosomal banding patterns, with a very high resolution of 1 BAC every 700 kb. These can be made into regional paints and used interchangeably to study contigs.

Additional Resource Information: is available at http://www.csmc.edu/csri/korenberg/ and jkorenberg@mailgate.csmc.edu.

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