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Human Genome News Archive Edition

Human Genome News, March 1992; 3(6)

First Workshop on Chromosome 2

The First International Workshop on Chromosome 2 was held October 12-13, 1991, in Washington, D.C., to consider the genetic and physical map of human chromosome 2. Twenty-nine participants from six countries attended the conference, which was sponsored by the NIH National Center for Human Genome Research, the European Community, the U.K. Medical Research Council, and the Centre d'Etude du Polymorphisme Humain (CEPH).

Presentation of the CEPH consortium map opened the meeting. Four groups had used genotyping data to produce maps with markers having a ratio of at least 1000:1 in favor of linkage. About 35 markers were ordered along the chromosome, with an average map length of 450 cM in females and 270 cM in males. Attendees largely agreed on marker order and identified markers for haplotyping (determining the particular combination of genetic markers present in a genomic area in an individual). Each group submitting maps for the consortium will meet to decide which markers should be used for the genetic framework map.

Separate sessions were held on genetic and physical maps, specific disease loci, and resources for studying chromosome 2.

Genetic Maps

A discussion of the CEPH consortium map and the mapping data in non-CEPH families by Andrew Pakstis (Yale University) revealed large gaps between markers on the genetic map and only a limited number of highly informative markers. Sean Todd (University of Texas, San Antonio) presented data on a number of new (CA)n repeats at or near genes already mapped to chromosome 2.

Physical Maps

Physical mapping to produce overlapping yeast artificial chromosome (YAC) or cosmid contigs is still at a preliminary stage for chromosome 2. Pieter de Jong [Lawrence Livermore National Laboratory (LLNL)] described chromosome flow sorting and the preparation of phage and cosmid libraries, expected to be completed this spring. The phage library will be distributed through the American Type Culture Collection. Cosmid clones can be obtained by hybridizing high-density filters of the arrayed cosmid library; filters and clones will be available from the Human Genome Center at LLNL. Harvey Mohrenweiser (LLNL) described the success of this approach in screening for gene-and marker-positive cosmids for human chromosome 19.

Fa-Ten Kao (Eleanor Roosevelt Institute) discussed the microdissection of parts of chromosome 2 and the production of three libraries of microclones in the regions 2p23-p25, 2p21-p23, and 2q35-p37. Tom Strachan (St. Mary's Hospital, Manchester, England) described the isolation of YAC contigs from the region 2q35-q37.

Disease Loci

In the past 2 years, at least five major disease genes have been mapped to chromosome 2, including those for induced Waardenberg syndrome (WSI, described below), holoprosencephaly, alveolar rhabdomyosarcoma involving t(2:13) translocation, protein C (PROC) deficiency causing a defect in the coagulation pathway, and the association of the alpha transfusing growth factor (TGFA) with cleft lip and palate.

WSI. Lindsay Farrer (Boston University Medical School) presented data from the WSI consortium group on the latest findings in mapping this locus. WSI, a syndrome characterized by deafness and dystopia conformis, is inherited in an autosomal dominant manner with a high penetrance (95%); a considerable degree of variability exists in phenotypic expression, along with evidence of genetic heterogeneity. The highest LOD score (6.31) has been detected with a marker for placental alkaline phosphatase (ALPP) at a recombination distance of 0.7, which places the WSI gene in the region 2q35-q37. However, no evidence was shown for linkage with other markers in the same region. The gene for fibronectin (FNI) maps about 11.6 cM distal of ALPP and shows no linkage in WSI families.

The biggest challenge in mapping the WSI locus is genetic heterogeneity and the lack of highly informative marker loci in the region. In an estimated 45% of the families studied, WSI was linked to the ALPP locus, and plans are under way to saturate this region with new polymorphic markers.

Other Disease Loci. Pieter Reitsma (University Hospital, Leiden, Netherlands) described the role of PROC in the coagulation pathway. Persons deficient in PROC (homozygotes) are prone to thrombus at birth while heterozygotes are at increased risk in their 30s and 40s. Alterations seen in the PROC gene include missense substitutions, splicing defects, and deletions up to 18 bp in length.

Max Muenke (Children's Hospital of Philadelphia) presented data on mapping the autosomal dominant disease holoprosencephaly, characterized by facial abnormalities and brain defects. Abnormalities have been seen on many chromosomes, including chromosome 2 deletions that overlap on the short arm at 2p21. Marker studies are under way to define the minimal specific-deletion region.

Fred Barr (Children's Hospital of Philadelphia) discussed the incidence of alveolar rhabdomyosarcoma, which involves a (2:13) translocation with a breakpoint in 2q35. Studies will produce a pulsed-field map in this region using material from patients with deletions and translocations.


A number of groups reported progress in preparing panels of hybrids carrying portions of chromosome 2, including irradiation, translocation, and deletion hybrids. By the next meeting, lists of hybrids should be available as a resource to anyone interested in chromosome 2 mapping.

A second workshop, to be held in San Francisco prior to the meeting of the American Society of Human Genetics in November, will be organized by Nigel Spurr [Imperial Cancer Research Fund (ICRF), England] and Susan Naylor (University of Texas Health Science Center, San Antonio).

A more detailed report of the First International Workshop on Chromosome 2 will be published in the April issue of Cytogenetics and Cell Genetics.

Reported by Nigel Spurr, ICRF

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