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BACs, PACs and the Structure of the Human Genome

J. R. Korenberg, X-N. Chen, S. Mitchell, Z. Sun, E. Vataru, U-J. Kim[1], P. de Jong[3], M. Simon[1], T. J. Hudson[2], B. Birren[2], E. Lander[2], J. Silva[2], X. Wu[2].

Cedars-Sinai Research Institute, Los Angeles, CA.

Not all that glitters is single copy sequence. In order to study genome organization and to provide an integrated, genomic framework for gene isolation, sequencing and mapping, we have established a Mapped BAC/PAC Resource. The goal is to represent unequivocally, 0.8-1.2X of the human genome in a stable framework resource, integrated at 1-5,000 loci with the RH, genetic and STS maps.

Current Resource: Human
The current Mapped BAC/PAC Resource now defines 4,300 sites, and represents about 18% of the human genome. We have assigned 4,000 of 17,000 BAC/PAC clones, including 3750 BACs and 250 PACs, to regions of 2-6 Mb by using fluorescence in situ hybridization, and have integrated 91 BACs with the genetic, YAC/STS, and radiation hybrid (RH) maps by using PCR of 1,000 markers to screen the 17,000 BACs. More than 250 sites are non-tandem repetitive sequence sites; 264 BAC/PACs recognize alpha satellite sites, of which 143 were selected with a consensus alpha oligonucleotide, 102 are specific to a single chromosome and the totality of all alpha-BACs now recognize all chromosomes except 10 and the Y. Finally, BACs selected by a TTAGGG consensus oligonucleotide recognize 18 telomeres, 5 of which are specific to a single chromosome.

Information on the Resource, is available on the WWW site http://www.csmc.edu/genetics/korenberg/korenberg.html that includes request forms and agreements. To facilitate distribution, screening, and aneuploidy applications, 2,902 BACs were rearrayed to reflect the true chromosomal organization, from chromosome 1p through 22q.

Using high resolution techniques, 100 BACs have been mapped to single bands in the mouse genome.

Human Disease and Genome Organization
Analysis of the 227 BACs on chromosome 7 suggests a novel genomic structure involving clustered low-copy repetitive sequences whose arrangement likely predisposes to the deletions responsible for Williams syndrome. Similar clustering of other subsets of BACs suggests that this structure may be a model for the existence of additional subsets of low copy interspersed repeated sequences that account not only for deletions responsible for human disease syndromes but also for a subset of somatic deletions and rearrangements responsible for cancers.

The Mapped BAC /PAC Resource now provides rapid approaches to genome organization and a rapidly integrated and flexible framework for mapping and sequencing the human genome.

[1] Caltech, Pasadena, CA;

[2] Whitehead Institute/MIT, Boston, MA;

[3] Roswell Park Cancer Institute. Buffalo. NY.

Abstract scanned from text submitted for January 1996 DOE Human Genome Program Contractor-Grantee Workshop.

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Last modified: Wednesday, October 22, 2003

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