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The chromosome 4 workshop report
SPECIAL FEATURE
D4S187 (mapping to 4q35-4qter) with fascioscapulohumeral muscular dystrophy. The current best order for FSHD with relationship to these markers was established, with FSHD being distal to all the markers in the above group with the order D4S171-Fll-D4S187-D4S163-D4S139-FSHD. One large family exhibiting no evidence for linkage but with a well-defined FSHD phenotype was also presented. Physical resources developed in this area include a number of YACs and cosmids establishing physical maps and/or contigs around all of the above loci.
MEETING REPORT
The Chromosome Report JEFFREY
C.
MURRAY*
4 Workshop
AND KENNETH
H.
BUETOWt
*University of Iowa, Iowa City, Iowa 52242; and tfox Cancer Center, Philadelphia, Pennsylvania 19 111
Chase
KIT, PDGFRA, On June 22 and 23, 1991, a workshop on human chromosome 4 was held in Philadelphia, Pennsylvania. The workshop was hosted by the Fox Chase Cancer Center and the NIH and was divided into three components: a meeting of the CEPH consortium group to develop the genetic linkage map of human chromosome 4; an ad hoc meeting of collaborative groups studying facioscapulohumeral (FSHD) muscular dystrophy, which has been mapped to 4q35; and a meeting of individuals with both general and locus-specific interests in human chromosome 4. This latter group had as its focus not only the presentation of current information about mapping work on chromosome 4, but also the identification and cataloging of available maps and resources for continuing studies of this chromosome. The following is a brief summary of some of the work and information presented at that meeting. CEPH Consortium
Two groups (Bucan and Spritz) presented data on genetic, physical, and comparative map studies on a group of loci containing the KIT and PDGFRA genes in humans and defining the W, patch, and rump white pigment mutations in the mouse as well as piebaldism in the human. YACs encompassing this region were described for the mouse. Two missense mutations and a frameshift mutation for the KIT oncogene in three different human families with piebald&m were presented. HD and 4~16.3 Maja Bucan, Leon Carlock, Margaret Hoehe, Jonathan Haines, Olaf Reiss, Rick Myers, Gert-Jan Van Ommen, Gillian Bates, and Ken Buetow presented data on genetic, physical, and cDNA mapping resources for the 4~16.3 region encompassing the gene for Huntington’s disease (HD). An overlapping pulsed-field map spanning 5.2 Mb of DNA has now been defined for the region from the 4q telomere (D4S142) to D4SlO. Genetic maps of this region have previously demonstrated hot spots of recombination, and regions of linkage disequilibrium have been defined. Current searches for the Huntington gene are based on a variety of strategies making use of data from individual recombinants. Some recombinant data for the localization of HD still appear to be contradictory. Linkage disequilibrium calculations suggest a more proximal location for HD than some of the well-defined recombinants would suggest. Searches for coding sequences within the region are being made by several groups, and a number of cDNAs including both brain- and retina-specific cDNAs have been characterized and were presented at the meeting. Genetic mapping of the ADRABRLB gene was also outlined.
Map
This meeting was attended by eight CEPH collaborators and focused on the development of the CEPH linkage map of chromosome 4 based on the genotypes of 90 loci compiled from over 200 separately characterized genetic systems on human chromosome 4. Both database version four (DB4) from CEPH and information submitted by investigators since the distribution of DB4 were used. The listing included 29 gene-specific loci and 13 sequenced-based polymorphisms on this chromosome. A preliminary 33-10~~s map encompassing 275 CM with odds of 1OOO:l for locus inversion comparisons was presented and discussed. Issues of map construction and order determination, genotyping errors, and time tables for submission of new data were discussed, and final map construction was planned for early in the fall of 1991. The preliminary CEPH linkage map was presented to the entire chromosome 4 community upon the agreement of the individual CEPH collaborators present at that meeting.
Glycophorin
An ad hoc meeting of groups from Lifecodes, Duke University, Cardiff, Collaborative Research, University of Rochester, University of Connecticut, University of Iowa, and Fox Chase Cancer Center was held to discuss the currently available linkage data for the markers D4S171, Fll, D4S139, D4S163, and
12,857-858
(1992)
Genes
Shinichi Kudo presented the physical mapping of three genes in the glycophorin family, GYPA, GYPB, and GYPE. The order, based on hemoglobin Lepore-like fusion genes, is suggested to be A-B-E. A high degree of sequence homology between the genes has also suggested at least two potential pathways for the evolution of this gene family. A physical map of this gene cluster is under development.
FSHD Consortium
GENOMICS
and W Locus Studies
857 All
Copyright 0 1992 rights of reproduction
osss-7543/92 $3.00 by Academic Press, Inc. in any form reserved.
SPECIAL FEATURE AGU
(Aspartylglucosaminuria)
Kristiina Gron presented genetic and molecular data for the aspartylglucosaminidase gene (AGA) gene. Linkage of this gene to D4S175, MNS, and the fibrinogen gene cluster has been demonstrated, and a sequence variant in individuals with AGU deficiency that results in a cystine to serine change in the AGA gene has been defined. This missense mutation also alters an EcoRI site and allows for the population genetic characterization of this genetic disorder in the Finnish population. The data suggest that there may be a small amount of heterogeneity present within that population with respect to genotypic abnormalities. Additional RFLPs useful in mapping of the gene were also presented. General
Mapping
Issues
The groups of Buetow, Myers, Van Ommen, Gusella/ Haines, Lehrach/Bates, and Murray presented data relevant to the general mapping on human chromosome 4. Several genetic maps that demonstrated strong intermap consistency were presented, and a complete map of human chromosome 4 based on linkage markers spanning both terminal cytogenetic bands is now available. This map does, however, contain at least three significant areas for which there is a paucity of highly informative markers, and current efforts are directed at filling in these gaps. Physical resources for mapping include the availability of chromosome 4-specific cosmid and phage libraries from Lawrence Livermore and Los Alamos Laboratories and a partial-coverage chromosome 4-specific YAC library developed by Bob Malone at the University of Iowa. Several groups have also converted the phage-specific libraries into plasmid-based libraries. James Weber of the Marshfield Clinic has defined 10 CA repeat markers on chromosome 4, and at least six other sequence-based polymorphic markers are also available. A more detailed summary of the available genetic maps and physical resources of chromosome 4 can be obtained by contacting Jeff Murray at the University of Iowa. Database
Issues
Peter Pearson presented the current genome database version (GDB) as a tool for developing and studying maps on human chromosome 4. Reconstruction of maps from supporting data and the utility of submaps of the chromosome in the database were discussed at length, as was the integration of such maps into GDB. Incorporation of linkage maps as well as contig and physical maps into GDB was outlined and the current versions of such maps were discussed. GDB will serve as both the repository for maps on chromosome 4 and the working framework for future development of such maps.
Summary
Issues
Several groups are continuing to develop resources for human chromosome 4 on a chromosome comprehensive basis. This includes the groups at Cardiff and Leiden that, in addition to disease-based interests, are focusing on CEPH linkage maps and incorporation of further genotypic data into CEPH through EUROGEM. High-resolution genetic maps are also being developed by both the Haines/Gusella and the Buetow/ Murray groups for the entire length of the chromosome. These groups are using the Venezuelan pedigrees and CEPH pedigrees, respectively. The availability of the Venezuelan pedigrees to all members of the user community for the development of high-resolution linkage maps was outlined by Dr. Haines. Physical mapping reagents in addition to those currently available and outlined above through phage and cosmid libraries include the development of YAC libraries on a chromosome-specific basis by the Malone/Murray group at the University of Iowa and the identification of in situ hybridization-based maps using primarily cosmids at Leiden and at UCSF under their Human Genome Center grant. In addition, the Human Genome Center for chromosome 4 at UCSF headed by Rick Myers is developing YAC resources by identifying YACs for existing marker systems on chromosome 4 from the Washington University Library. An excellent somatic cell hybrid panel for chromosome 4 is available through John Wasmuth and Mike Altherr at University of California, Irvine. The UCSF Genome Center is expanding its radiation hybrid map of the 4p region to a radiation hybrid cell panel that will encompass the entire length of human chromosome 4 under the direction of Drs. Myers and Cox. Summary In the concluding session the compilation and availability of available resources on chromosome 4 were discussed. A listing of these resources is available from Jeff Murray at the University of Iowa for anyone with an interest in human chromosome 4. Rick Myers stressed the commitment of the UCSF Genome Center to make resources available to the mapping community as a whole as soon as they have been identified and characterized. There was general agreement that such a philosophy will facilitate the rapid generation and integration of the maps from several groups currently working in this area. The chromosome 4 committee for the Human Gene Mapping workshops was scheduled to meet in August of 1991, and a second chromosome 4-specific meeting is to be held in Leiden on June 13 and 14, 1992 (contact Gert-Jan van Ommen for information). Future venues for the meeting are planned to alternate between countries with groups participating in mapping projects on this chromosome and initially will focus particularly on groups with chromosome wide mapping interests such as EUROGEM and the Human Genome Center.
D4S187 (mapping to 4q35-4qter) with fascioscapulohumeral muscular dystrophy. The current best order for FSHD with relationship to these markers was established, with FSHD being distal to all the markers in the above group with the order D4S171-Fll-D4S187-D4S163-D4S139-FSHD. One large family exhibiting no evidence for linkage but with a well-defined FSHD phenotype was also presented. Physical resources developed in this area include a number of YACs and cosmids establishing physical maps and/or contigs around all of the above loci.
MEETING REPORT
The Chromosome Report JEFFREY
C.
MURRAY*
4 Workshop
AND KENNETH
H.
BUETOWt
*University of Iowa, Iowa City, Iowa 52242; and tfox Cancer Center, Philadelphia, Pennsylvania 19 111
Chase
KIT, PDGFRA, On June 22 and 23, 1991, a workshop on human chromosome 4 was held in Philadelphia, Pennsylvania. The workshop was hosted by the Fox Chase Cancer Center and the NIH and was divided into three components: a meeting of the CEPH consortium group to develop the genetic linkage map of human chromosome 4; an ad hoc meeting of collaborative groups studying facioscapulohumeral (FSHD) muscular dystrophy, which has been mapped to 4q35; and a meeting of individuals with both general and locus-specific interests in human chromosome 4. This latter group had as its focus not only the presentation of current information about mapping work on chromosome 4, but also the identification and cataloging of available maps and resources for continuing studies of this chromosome. The following is a brief summary of some of the work and information presented at that meeting. CEPH Consortium
Two groups (Bucan and Spritz) presented data on genetic, physical, and comparative map studies on a group of loci containing the KIT and PDGFRA genes in humans and defining the W, patch, and rump white pigment mutations in the mouse as well as piebaldism in the human. YACs encompassing this region were described for the mouse. Two missense mutations and a frameshift mutation for the KIT oncogene in three different human families with piebald&m were presented. HD and 4~16.3 Maja Bucan, Leon Carlock, Margaret Hoehe, Jonathan Haines, Olaf Reiss, Rick Myers, Gert-Jan Van Ommen, Gillian Bates, and Ken Buetow presented data on genetic, physical, and cDNA mapping resources for the 4~16.3 region encompassing the gene for Huntington’s disease (HD). An overlapping pulsed-field map spanning 5.2 Mb of DNA has now been defined for the region from the 4q telomere (D4S142) to D4SlO. Genetic maps of this region have previously demonstrated hot spots of recombination, and regions of linkage disequilibrium have been defined. Current searches for the Huntington gene are based on a variety of strategies making use of data from individual recombinants. Some recombinant data for the localization of HD still appear to be contradictory. Linkage disequilibrium calculations suggest a more proximal location for HD than some of the well-defined recombinants would suggest. Searches for coding sequences within the region are being made by several groups, and a number of cDNAs including both brain- and retina-specific cDNAs have been characterized and were presented at the meeting. Genetic mapping of the ADRABRLB gene was also outlined.
Map
This meeting was attended by eight CEPH collaborators and focused on the development of the CEPH linkage map of chromosome 4 based on the genotypes of 90 loci compiled from over 200 separately characterized genetic systems on human chromosome 4. Both database version four (DB4) from CEPH and information submitted by investigators since the distribution of DB4 were used. The listing included 29 gene-specific loci and 13 sequenced-based polymorphisms on this chromosome. A preliminary 33-10~~s map encompassing 275 CM with odds of 1OOO:l for locus inversion comparisons was presented and discussed. Issues of map construction and order determination, genotyping errors, and time tables for submission of new data were discussed, and final map construction was planned for early in the fall of 1991. The preliminary CEPH linkage map was presented to the entire chromosome 4 community upon the agreement of the individual CEPH collaborators present at that meeting.
Glycophorin
An ad hoc meeting of groups from Lifecodes, Duke University, Cardiff, Collaborative Research, University of Rochester, University of Connecticut, University of Iowa, and Fox Chase Cancer Center was held to discuss the currently available linkage data for the markers D4S171, Fll, D4S139, D4S163, and
12,857-858
(1992)
Genes
Shinichi Kudo presented the physical mapping of three genes in the glycophorin family, GYPA, GYPB, and GYPE. The order, based on hemoglobin Lepore-like fusion genes, is suggested to be A-B-E. A high degree of sequence homology between the genes has also suggested at least two potential pathways for the evolution of this gene family. A physical map of this gene cluster is under development.
FSHD Consortium
GENOMICS
and W Locus Studies
857 All
Copyright 0 1992 rights of reproduction
osss-7543/92 $3.00 by Academic Press, Inc. in any form reserved.
SPECIAL FEATURE AGU
(Aspartylglucosaminuria)
Kristiina Gron presented genetic and molecular data for the aspartylglucosaminidase gene (AGA) gene. Linkage of this gene to D4S175, MNS, and the fibrinogen gene cluster has been demonstrated, and a sequence variant in individuals with AGU deficiency that results in a cystine to serine change in the AGA gene has been defined. This missense mutation also alters an EcoRI site and allows for the population genetic characterization of this genetic disorder in the Finnish population. The data suggest that there may be a small amount of heterogeneity present within that population with respect to genotypic abnormalities. Additional RFLPs useful in mapping of the gene were also presented. General
Mapping
Issues
The groups of Buetow, Myers, Van Ommen, Gusella/ Haines, Lehrach/Bates, and Murray presented data relevant to the general mapping on human chromosome 4. Several genetic maps that demonstrated strong intermap consistency were presented, and a complete map of human chromosome 4 based on linkage markers spanning both terminal cytogenetic bands is now available. This map does, however, contain at least three significant areas for which there is a paucity of highly informative markers, and current efforts are directed at filling in these gaps. Physical resources for mapping include the availability of chromosome 4-specific cosmid and phage libraries from Lawrence Livermore and Los Alamos Laboratories and a partial-coverage chromosome 4-specific YAC library developed by Bob Malone at the University of Iowa. Several groups have also converted the phage-specific libraries into plasmid-based libraries. James Weber of the Marshfield Clinic has defined 10 CA repeat markers on chromosome 4, and at least six other sequence-based polymorphic markers are also available. A more detailed summary of the available genetic maps and physical resources of chromosome 4 can be obtained by contacting Jeff Murray at the University of Iowa. Database
Issues
Peter Pearson presented the current genome database version (GDB) as a tool for developing and studying maps on human chromosome 4. Reconstruction of maps from supporting data and the utility of submaps of the chromosome in the database were discussed at length, as was the integration of such maps into GDB. Incorporation of linkage maps as well as contig and physical maps into GDB was outlined and the current versions of such maps were discussed. GDB will serve as both the repository for maps on chromosome 4 and the working framework for future development of such maps.
Summary
Issues
Several groups are continuing to develop resources for human chromosome 4 on a chromosome comprehensive basis. This includes the groups at Cardiff and Leiden that, in addition to disease-based interests, are focusing on CEPH linkage maps and incorporation of further genotypic data into CEPH through EUROGEM. High-resolution genetic maps are also being developed by both the Haines/Gusella and the Buetow/ Murray groups for the entire length of the chromosome. These groups are using the Venezuelan pedigrees and CEPH pedigrees, respectively. The availability of the Venezuelan pedigrees to all members of the user community for the development of high-resolution linkage maps was outlined by Dr. Haines. Physical mapping reagents in addition to those currently available and outlined above through phage and cosmid libraries include the development of YAC libraries on a chromosome-specific basis by the Malone/Murray group at the University of Iowa and the identification of in situ hybridization-based maps using primarily cosmids at Leiden and at UCSF under their Human Genome Center grant. In addition, the Human Genome Center for chromosome 4 at UCSF headed by Rick Myers is developing YAC resources by identifying YACs for existing marker systems on chromosome 4 from the Washington University Library. An excellent somatic cell hybrid panel for chromosome 4 is available through John Wasmuth and Mike Altherr at University of California, Irvine. The UCSF Genome Center is expanding its radiation hybrid map of the 4p region to a radiation hybrid cell panel that will encompass the entire length of human chromosome 4 under the direction of Drs. Myers and Cox. Summary In the concluding session the compilation and availability of available resources on chromosome 4 were discussed. A listing of these resources is available from Jeff Murray at the University of Iowa for anyone with an interest in human chromosome 4. Rick Myers stressed the commitment of the UCSF Genome Center to make resources available to the mapping community as a whole as soon as they have been identified and characterized. There was general agreement that such a philosophy will facilitate the rapid generation and integration of the maps from several groups currently working in this area. The chromosome 4 committee for the Human Gene Mapping workshops was scheduled to meet in August of 1991, and a second chromosome 4-specific meeting is to be held in Leiden on June 13 and 14, 1992 (contact Gert-Jan van Ommen for information). Future venues for the meeting are planned to alternate between countries with groups participating in mapping projects on this chromosome and initially will focus particularly on groups with chromosome wide mapping interests such as EUROGEM and the Human Genome Center.