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Human Genome News Archive Edition

Human Genome News, September 1994; 6(3):12

Chromosome 16 Mappers Review Status

The Third International Workshop on Human Chromosome 16 was held May 7-9 at the Pittsburgh Supercomputing Center at Carnegie Mellon University. Workshop goals were to review the status of physical, genetic, and comparative mapping on chromosome 16, construct consensus physical and genetic maps, on solidate data on disease loci, review and deposit data into the Genome Data Base (GDB), and facilitate data sharing and collaborations. Some 29 participants from Australia, Great Britain, Netherlands, and the United States presented 19 abstracts. The workshop was sponsored by DOE, and travel for international participants was funded by the Human Genome Organisation.

Genetic Maps

Helen Kozman [Adelaide Women's and Children's Hospital (AWCH), Australia] and Anne Black [University of Iowa, Cooperative Human Linkage Center (CHLC)] reported the merger of chromosome 16 genetic linkage maps from the CEPH consortium and CHLC into a high-quality consensus linkage map. Loci chosen for the consensus map were highly informative polymorphisms detectable by the polymerase chain reaction (PCR). These polymorphisms included dinucleotide, trinucleotide, and tetranucleotide repeats spaced about 5 to 10 cM apart with odds of an alternative locus placement at 1000:1 or greater. The map extends from the hypervariable locus D16S85 at 16pter to D16S303 at qter. Genetic linkage information on loci generated by the CEPH consortium is available from the CEPH database, and information on loci generated by CHLC can be obtained via ftp (

Comparative Maps

Michael Siciliano and Zuoming Deng (University of Texas M.D. Anderson Cancer Center) summarized all available data on conserved homology, synteny, and linkage of human chromosome 16 with the mouse. The most significant new findings were the identification of regions of (1) conserved linkage involving five loci from p13.12 to p13.3 and mouse chromosome 16 and (2) conserved synteny involving two loci between p12.3 and p12.2 and mouse chromosome 11.

Physical Maps

Three working groups were responsible for summarizing physical mapping data for pter to p13.3, p13.2 to the centromere, and centromere to 16qter. Peter Harris (John Radcliffe Hospital, U.K.) reported on the terminal short-arm band 16p13.3, which contains four genetic-disease loci: PKD1 (polycystic kidney disease), TSC2 (tuberous sclerosis), MEF (familial Mediterranean fever), and RSTS (Rubenstein-Taybi syndrome). Efforts to map and clone these genes have made this one of the best characterized regions of chromosome 16. Isolation of the TSC2 gene by a positional-cloning approach was reported in December 1993 by the European Chromosome 16 TSC consortium. Positional cloning of the PKD1 gene was reported soon after the workshop by the European polycystic kidney disease consortium. Harris's working group presented a consensus physical map, assembled at the workshop, that contained 35 ordered markers spanning 9 cytogenetic breakpoints in 16p13.3.

Sara Mole (University College London) summarized physical-mapping data for 16p13.2 to the centromere. This region is divided into 30 intervals by somatic cell hybrids and fragile sites. A yeast artificial chromosome (YAC) contig was constructed across the folate-sensitive fragile site FRA16A at p13.11. This fragile site was later cloned and found to be the expansion of a CCG repeat (Nancarrow et al., 1994). The Batten disease gene CLN3 location has been substantially refined in p11.2 with new markers that display allelic association. Several candidate genes and sequences identified by exon amplification are being characterized for this region.

David Callen (AWCH) summarized physical-mapping data for the centromere to 16qter, a region divided into 39 intervals by hybrid breakpoints and fragile sites. A number of new genes, expressed sequence tags (ESTs), and DNA markers have been mapped to these intervals and entered in GDB. Bardet-Biedl and Townes-Brocks syndromes have been mapped to the long arm. Bardet-Biedl was reported to be heterogeneous, with relatively few families showing linkage to this chromosome. Genetic mapping is narrowing the search area for this gene; in general, gene density is increased in the 16q22.1 and 16q24.3 bands. Construction of high-density cosmid maps for the 16q24.3 region is progressing as researchers probe high-density cosmid grid filters with Alu-PCR products from somatic cell hybrids that contain only restricted regions of this chromosome.

Norman Doggett [Los Alamos National Laboratory (LANL)] reported construction of an integrated physical-genetic-cytogenetic map of human chromosome 16 based on the high-resolution cytogenetic breakpoint map. The physical map consists of both a low-resolution YAC contig map and a high-resolution cosmid contig map. The YAC contig map is composed of 450 CEPH mega-YACs and 200 flow-sorted, chromosome 16-specific YACs that are anchored to the breakpoint map with ESTs and 300 sequence tagged sites (STSs) from cosmid contigs, genetic markers, and genes. This YAC map provides nearly complete coverage of the euchromatic arms of the chromosome.

LANL has produced a high-resolution, "sequence-ready" map consisting of 4000 fingerprinted cosmids assembled into contigs covering 60% of the chromosome. This map was integrated with the YAC and cytogenetic breakpoint maps by mapping STSs from cosmid contigs and by detecting hybridizations between YACs and cosmids. A highly informative microsatellite-based genetic map of PCR-typable markers was integrated with the cytogenetic and physical map by placing markers on the breakpoint map and screening against the YAC and cosmid maps. All these data were assembled into an integrated map using SIGMA software developed at LANL.

Discussions were held on coordinating efforts to complete the cosmid contig map, develop an EST map, and begin large-scale sequencing. Martijn Breuning (Leiden University) agreed to host the next Chromosome 16 Workshop in November 1995.

Daniel Drell (DOE), Norman Doggett (LANL), and David Callen (AWCH)

Norman A. Doggett; LANL Life Sciences Division, MS M88; Los Alamos, NM 87545 (505/665-4007, Fax: -3024, Internet:

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