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IC h: Report of the first international workshop on C 01 human 14 mapping 1993 S tc rn Prepared by Diane W. Cox D in Research Institute. The Hospital for Sick Children, Toronto, Canada

W dc

The first International Workshop on Human Chromosome Cuticchia and IGD (Integrated Genomic Database), a data 14 mapping was held at Novotel in Toronto, Canada on June base integrating with several other data bases in graphic 9-12, 1993. There were 23 participants from nine countries form, by Otto Ritter. Working groups met on the second day (Australia, Belgium, Canada, France, Germany, Japan, to collate data and prepare reports. Norway, United Kingdom and United States), as listed at the The next workshop will be held in the fall of 1994. end of this report. The goals of the workshop were to compile in physical maps and a consensus linkage map, to consolidate C( available data on disease loci, to catalogue and facilitate Physical maps distribution of resources and to encourage new collaborations te and data sharing. (Michael A. Walter, K. H. Andy Choo. Paul H. Dear) 0 The workshop was funded mainly by CGAT (Canadian fi Genome Analysis and Technology Program). Travel was The following physical maps have been derived by a IF funded by the U.S. Nationid Institutes of Health and number of different approaches. Department of Energy, by the Commission for European Andy Choo used pulsed-field gel electrophoresis (PFGE) Communities, and by individual countries. of a somatic cell hybrid CP43 containing human chromosome All papers were presented on the first full day of the 14 to derive the map order of 8 satellite DNA subset probes workshop and the data from the presentations were posted for covering the p arm and centromeric regions. These probes the duration of the workshop. The abstracts of work presented correspond to the satellite-3 sequences D14S191, Dl423 and and two abstracts submitted by individuals who were unable D14F97S1, and the alpha-satellite sequences D14F93S1, to attend (marked**) are found at the end of the report. Two D14F94S1, D14F95S1, D14F96Sl andsD14F98S1 (Fig. 1). data bases were demonstrated: GDB version 5.2 by Jamie - centromere

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distance unknown approx. 100 kh - F or Fig. 1. Pericentric map of . All positions were derived by PFGE analysis except for D14S191 which was placed distal to lin D14Z3 by in situ hybridization and studies on t(14q21q) Robertsonian translocation breakpoints. (K.H.A.Chm) i. . TWO of these probes detected loci both on 14 Main Bernheim, Christine Van Broeckhoven and Pui-ym * and 22, and five probes detected loci on chromosomes 13, 14 Kwok separately reported a series of YAC clones for 14q13, and 21. q21-q22, q22, q22-q23, q24.3, q32, q32.2 and q32.3-qter (see Diane Cox summarized data on probe and Table I). Chromosomal location of these YACs was based on localization based on in situ hybridization and somatic cell in situ hybridization and the known positions of the probes hybrid analyses, many of which are included in Fig. 2. used to isolate the YACs. Gerard Schellenberg presented a >n Christine Van Broeckhoven used PFGE to study the preliminary study of YACs from the 14q24.3 region. He found organization of four loci (D14S43, FOS, HSPA2 IpH2.31 and D14S76 and FOS to be on the Same YAC. Christine Van SPTE3 [pGBS1.3]) in the q24.3 region, which were not found Broeckhoven presented detailed YAC studies on the 14q24.3 to be in close proximity. Patrice Bouvagnet used PFGE to region (see Table I). She described a YAC containing D14S61 map several markers in the 14q32.1 region and found that and FOS. Together these reports are consistent with the D14S1, D14S28 and CKB are within 450 kb. (Alonso, this ordering: D14S76 - FOS - D14S61. YACs are listed in the meeting). Resources section. The use of deletion mapping for order assignment was described by Christophe Beroud, who presented seven Gene Clusters deletion intervals based upon breakpoints in chromosomes Further information on the organization of the IGH region from renal cell carcinoma patients: centromere-(D14S72, has been reported. Paul Dear presented a novel mapping a data D14S64, D14S70)-(D 14S69, D14S75, D14S79, D14S66)- technique which was applied to variable gene segments in the rraphic (D14S63, D 14S77)-(D14S7 1, D 14S76)-(D14S61, D 14S74, IGH locus and this is compared to existing maps in Fig. 3. A nd day D14S68)-D 14S73-(D14S67, D14S8 I, D14S62, D 14S65, physical map of 280 kb spanning four serpin (serine protease D14S78bqter (see Malignancy section). Similarly, Ani1 inhibitor) : al-antiuypsin. al-anti-chymotrypsin. Menon presented the order of two loci based on deletion corticosteroid-binding globulin, and protein C inhibitor, has intervals defined by breakpoints in meningioma patients: also been recently reported within 14q32.1 (Billingsley et ai.. centromere-D14S13-Dl4S23-qter (see Malignancy section). 1993). Michael Walter presented the results of a novel mapping technique, whole genome irradiation and fusion gene transfer New Gene Assignments (WG-IFGT), which was applied to chromosome 14. Thirty New assignments at this workshop are discussed in the five chromosome-I4 STS loci were mapped within 88 WG- disease section. In addition, five new gene assignments have by a 1 IFGT cell lines. recently been reported. Bradykinin B2 receptor (BDKRBZ), has been localized to chromosome 14 by PCR (Powell et al., 1993). PFGE) losome probes probes 13 23 and 12 RNR2 F93S1, P 11.2 ’ ). 11.1 ANG CMAl 11.i 11.2 I TCRA 1rM1 12 FAYH6.7 1014526 13 l~~~&D14S12 CTLAl 21 SSTfll I q PYGL 22 1 23 HSPA2 24.1 I leiomyoma 24.2 I meningioma I f RCC Alzheimer disease( AD3) 24.3 H neuroblastoma : 31 colon carcinoma = : Krabbedisease AACT, PCI 32.1 . I : Machado-Joseph disease CHGA HL - 32.2 ELK2 I I :Usher syndrome(USH 7 A) 8 NHL 32.3 TNFAIP - CLL

Fig. 2. Location of genes and random markers mapped by somatic cell hybrids and in situ hybridization. References are listed in HGM tables distal to or this report. Regions involved in malignancy are indicated by dashed lines. Dotted lines indicate regional assignments of disease loci via linkage.

‘i: 3 Cytogenet Cell Genet. Vol. 66. I994 DISCLAIMER

This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or use- fulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any spe- cific commercial product, process, or service by trade name, trademark, manufac- turer, or otherwise does not necessarily constitute or imply its endorsement, recom- mendation, or favoring by the United States Government or any agency thereof. ?he views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof. DISCLAIMER

Portions of this document may be illegible in eiectronic image products. Images are produced from the best available original document. 14qtf motif VH3-R7 I VH3-Rl7 VH4-Bll VHI-R3 VU1 A1 1 of VH4z V?iS-Bl VHl-RIB d I VH3-Rl8- W3-R25 linka VHZ-62 VH3-Rl9 VH1-RIB VH4-61 VH3-RlO I VH3-R20 VH3-R23 VH4-83 - VH4-65 Seve - VH6 VHPR21 VHl-RE VH5R8 phag VH3-Rl VHl-RZ0 VZB7 from VH1 -R9 VH4-B8 Yan subst VH 141 VHl-R4 VHl-R10 VHl-Rl2 VHI-R16 VHl-RlS VH3-R2 VH3-R4 VH3-R6 VH3-Rl3 VHl-RB VHI-R23 VH1-R25 VH3-RS founi VH3 -R22 VH4-810 VHdBl4 VH3-R7 100 kb pofY auto; .ligat, allel: linka high I I--- - - * ------*--- b) -----* ---- c------I DPSO D;65 DG49 DP78 DP46 DP64 DG6S D;49 DP68DP9 DP26 DPSS DP5 DP47 DP57 DP77(R) 7 33 3 -

XVC: marl info: NIN, micr, Web (41/(41 (01 P (01 3 P 1 with al. hi Fig. 3. Alignment between three maps covering part of the immunoglobulin heavy-chain variable region. a). Long range restriction map and of Walter et al.. (EMBO J. 9:3303-3313, 1990); N = NorI; S = S'; Bs = BssKD; regional assignments of EcoRI or Bgm-fragments containing V, segments are indicated by solid lines above the restriction map; dash-dotted lines delineate region corresponding to (b). b) Map presented datat at workshop by Paul Dear. A YAC clone (IGH2.280kb) was identified by screening the IC1 YAC library for IGH enhancer sequences; sub- used cloning and sequencing showed YAC contains 13 gennline and one rearranged VH segments. Segments on this YAC were mapped by a rapid other method based on an in vitro analogue of classical linkage mapping (paper submitted; see also and Cook (1993)). Nomenclature used is Dear al. 9 from Tomlinson et al. (1992); DP-77(R) is a rearranged and somatically mutated version of the germline segment DP-77. e) From Matsuda et al. (1993). Numbers in italics on (b) give the family to which the segment belongs. Solid lines link equivalent VH segments on (b) and (e);the telor number of nucleotide differences between segments in (e)and their counterparts in (b) are given in brackets. Segments DP-65 and DP-49 (*) TCR are duplicated on (b). Positions given for these are approximate only. Two segments (3-32P and 3-29P) have been omitted from (c); these are highly degenerate pseudogenes lying between 3-33/4-31 and 3-30/4-26 respectively. Dotted lines delineate an insertion on map (b) relative to pubf (c) representing an alternative haplotype of this region; both haplotypes have roughly equal frequencies. On all maps, the centromere iies to whic the right and the 14q telomere to the left. t meei on ti the $ D14,' et al., 1993). Transglutaminase 1 (TGMl), involved in The mast-cell chymase (CMAI), a major secretory protein D14,' of a subset of mast cells, was localized to 14q11.2 as part of envelope formation in cultured keratinocytes, has been D14.' the serine protease cluster (Caughey et al., 1993). The gene localized to 14q11.2 (Yaminishi et al., 1992). and was localized by its presence on the Same YACs as related D14! serine proteases. Their order is granzyme B (CGLI) - New Anonymous DNA Segmenls D14! granzyme H (CGL2) - cathepsin G (CTSG) - CMAI, within a One hundred and three new PCR-based probes were order region of 110 to 210 kb. One of the somatostatin receptor reponed for chromosome 14. Twenty-four STSs (D14S117 - genes (SSTRl) mapped to 14q13 (Yamada et al., 1993). D14S140) detecting simple sequence repeats were developed D14! was not I The PCR primers amplify a polymorphic (CA)n repeat. One by screening a human genomic DNA library with simple di,- fami of the calmodulin genes (CALMl), involved in calcium ai., this ui- and tetranycleotide repeat motifs (Gerkin et IOCa! regulation, has been mapped to chromosome 14 using PCR, meeting). Heterozygosity estimates for these loci ranged from and localized by in situ hybridization to 14q24-q31 (Berchtold 0.50 to 1.00. One STS (D14S82) was isolated by screening a -

C\ 1 4 Cnogenet Cell Genet. Vol 66. 1994 Ijqter-associated YAC with a dinucleotide d(CA)n repeat motif (Sunil Pandit, this meeting). Two-point linkage analysis of these microsatellite repeats shows strong support for 12 6 D 1 4872' linkage to loci previously mapped on chromosome 14. --TCAA Seventy-eight STSs (D14S141 - D14S 190), derived from 11.2 5 -- MYH7 phage and cosmid libraries of flow-sorted chromosome 14 and 11.1 6 from chromosome 14-specific YACs, were reported by Piu- 3 11.1 4 yan Kwok and Deborah Nickerson. Single nucleotide --Dl4854 substitutions, Or Small insertion/deletion polymorphisms are 11.2 8 found in 37 of these STSs and genotyping of these 7 -414S49 polymorphisms (pSTSs) can be performed using a semi- -- 12 5 D14870 automated method combining with an oligonucleotide PCR 6 --Dl 4847 ligation assay. Heterozygosity estimates for most of these di- --PYGL allelic loci ranged from 0.20 to 0.37; haplotypes of loci in 13 --Dl4852 linkage equilibrium resulted in heterozygosity estimates as high aS 0.73. 21 -2PTB - -D 1 4877 Genetic Mapping 6 22 - D 1 4843 (Tobias Gedde-Dah1Jr., Steven Gerken) "Dl4853 23 --Dl 4855 Testing of the CEPH families has been expanded by 24.1 -1)14S48 several groups, and, for short regions of the chromosome, markets tested on disease families have provided additional 24.2 -91 information. Sunil Pandit et al. have supplemented the 24.3 J' NIWCEPH map (Donis-Keller et al., 1992) with further -a14845 microsatellite markers (Weissenbach et al., 1992; Wang and -4314551 Weber, 1992). In total, 28 microsatellites and seven RFLPs 31 with minimum 0.70 heterozygosity were used. Diane Cox et - -01 4S13 al. have compiled a map of loci (14 markers tested by them 32.1 tion map 40 --CKB ontaining and 26 other highly polymorphic markers from the CEPH 32.2 4 ?resented on CEPH families. A BsrEII polymorphism was 32.3 --01451 database) -414S23 =s; sub- used for the IGH constant region, replacing IGHJ used by 'y a rapid e used is others. Gene order differs from previous maps (Nakamura et tatsuda et al., 1989; NIWCEPH 1992) in placing the IGH cfuster -IGH (c); the telomeric to D14S23 at 14q32 and D14S50 centromeric to -49 (*) TCRA at 14qll. Fig. 4 shows a consensus of all maps Fig. 4 Consensus linkage map of maps published to date and ese are presented at this workshop. Reference markers are in bold itive to published to date and presented at this workshop. Markers for type. lies to which the position is inconsistent have ken omitted. Of 24 of the new polymorphic STSs (Steve Gerken, this meeting), I6 have been typed in four CEPH families. Based on the consensus map in Fig. 4, two-point lod scores suggest the following map order and locations: D14S122 (close to dved in D14S72); D14S121 and D14S123 (between MYH7 and :s been D14S49); D14S139; D14S129 (between D14S49 and PYGL); Disease Genes D14S125 and D14S119; D14S130; D14S120 (between SPTB and D14S55); D14S126 (close to D14S68); D14S124; (Christine Van Broeckhoven, Patrice Bouvagnet) D14S128 and D14S127; D14S140 (between D14S48 and PI); -+sere D14S117; D14S118 (between D14S51 and D14S1). Marker Since the CCM92 report, one new disease has been .i7 - orders from disease families (Alonso et al.: D14S13, D14S1. mapped to chromosome 14. two others have been confumed D14S23, D14S20; Nishizawa et al.: 14q24.2-q32.1 region) are ioped and a search has been carried out for one due to prediction ;:le di,- not consistent with the CEPH maps. The Alzheimer disease from the mouse map. i.,this families of Van Broeckhoven et al. (1992) allowed regional Machado-Joseph disease (MJD) (MIM 109150) is a ;ed from localization of D14S57 and D14S59 close to D14S43. dominant multisystem newodegenerative disorder involving eening a predominantly cerebellar, motor neuron, pyramidal.

Cytogenet Cell Genet, Vol. 66. I994 5 e \.

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extrapyramidal, and oculomotor systems. The UD gene was 14. The minimum region containing a putative tumor assigned by linkage analysis of five Japanese pedigrees (2= suppresser gene was defined using partial deletions that were 5.66, 6 = 0.00) with D14S48 (14q24.3-q32.1; Takiyama et al.. seen in six tumom. This region is located between D14S76 and D14S73 in the cytogenetic band 14q24.3. 1993; Nishizawa et al., this meeting). Suggestive lod scores were also obtained in four Canadian families (2= 2.28, 8 = 14q24q32. Anil Menon reported studies of LOH of 0.05) with D14S68 (14q24.3-qter) (Peter St.George-Hyslop, chromosome 14 markers in meningiomas (Gmndy, this this meeting). meeting). A total of 70 tumours, including 57 benign Recently a gene for familial eariy-onset Alzheimer meningiomas and 13 atypical and malignant tumours were analyzed. Analysis of showed a high frequency of disease (AD3) was mapped to 14q24.3 in an interval of 23.2 LOH cM between the markers D14S52 and D14S53 by four groups, chromosomal loss (40%) for markers on chromosome 14 in and additional data were presented (Schellenberg et al., Van atypical and malignant tumors. Using the markers D14S43, Broeckhoven et al., and St.George-Hyslop et al., this D14S16, D14S13 and D14S23, the putative tumour meeting). Eight markers located in this interval showed a hvo- progression gene in these tumours was assigned to the region between D14S43 and D14S23 in the cytogenetic region point lod score of >3 in at least one AD pedigree, i.e. D14S63, D14S57, D14S77, D14S71, D14S43, D14S76. D14S61 and 14q24-q32. LOH of markers in this region of chromosome 14 D14S59. No recombinants were seen with D14S77, D14S71 in neuroblastoma and colon adenoma, and the overlap of this and D14S76. region with the region implicated in RCC suggests that a The group that previously mapped French type I Usher common tumour suppresser locus might be involved in these disease (USHlA) has added seven new families and added neoplasias. markers AFM120xg5 (Gknkthon) and D14S78, which flank 14q24. A t(12;14) translocation involving 14q24 has been D14S13. The lod score with D14S13 is now 5.12 at 8 = 0.00 described in uterine leiomyoma (Pandis et al., 1990). (Kaplan et ai., this, meeting). Krabbe disease, GALC, shows a 14q32. Translocations involving the IGH locus at 14q32 lod score with D14S48 of 13.7 at 8 = 0.00 (Oehlmann et al., are commonly associated with B-cell leukemia (Jonveaux et 1993). Based on phenotype similarity between mice al., 1992; Lorenzen et al., 1992), Hodgkin's lymphoma homozygous for the iv (situs inversus) mutation and humans (Poppema et al., 1992) and non-Hodgkin's lymphoma (Offit e: with recessive situs inversus syndrome with heart defect, ai., 1992). D14S13, D14S1, D14S23 and D14S20 were tested on 30 families with multiple cases. In some instances, use was made of solitary cases of consanguineous parentage. Total lod scores Homology with the Mouse Map with each of the four markers were negative, suggesting either absence of linkage or heterogeneity (Alonso et al., this (Peter DEustachio, Roy Riblet) meeting). The same group mapped iv in the mouse 22 CM telomeric to Zgh-C. The distal half of human chromosome 14q (about 45 Mb) is homologous to mouse chromosome 12. A small portion of the proximal region is homologous to mouse Malignancy chromosome 14. The boundary between the regions has not been established. The maps are shown in Fig. 5. (Anil Menon. Christophe Beroud)

Several regions of chromosome 14 are involved in Resources malignancy and recent publications were reviewed for the workshop. 14q11. The T-cell receptor locus at 14qll is involved in (Pui-Yan Kwok. Debbie Nickerson) translocations in T-cell leukemias, and more cases have been documented (Bernard et al., 1992). A new B-cell acute The reagent resources available on chromosome 14 and lymphocytic leukemia involving translocation in the T-cell presented at the workshop include 8 satellite DNA probes (see receptor at 14qll has been reported (Cigudosa et al., 1992; Fig. 2), 103 newly generated STSs (described under new Xia et al.. 1992) and suggests that association between 14qll assignments). 91 YACs from the CEPH and St. Louis rearrangements and neoplasia is not T-cell specific. libraries, radiation hybrid cell lines Containing chromosome 14q24. Christophe Btroud reported the analysis of 14 fragments (Walter), and humadrodent Somatic cell hybrid recunent cytogenetic rearrangements of chromosome 14 in lines, established by Paul Goodfellow. Karl-Heinz Gneschik, renal cell carcinoma (RCC). These include monosomy in 30- and Hunt Willard (Cox, this meeting) (Fig. 6). New STSs were 45% of tumours. Analysis of loss of heterozygosity &OH) presented for several mapped genes on chromosome 14, was performed using 20 polymorphic (CA), repeats. The including TCRA, PIL, FOS, SPm. ELK, IGH, MYH6, study revealed 21 tumours that showed LOH on chromosome SSTRl, BKRl and AACT.

6 Cytogenet Cell Genet. VO~.66.1994 Mouse chromosome 14 Human l4 and Van Broeckhoven, this meeting); five to the T-cell Homologues receptor a/d locus at 14q11.2 (Nickerson, this meeting); two to ANG 14q12, two to 14q24, one to 14q32 (Kwok,this meeting); and two to the telomeric region at 14q32.3 (Pandit Dear, this NP,TCRD meeting). The YACs that are available from the CEPH and St MYH6, MYH7 Louis CGM libraries are listed in Table I. Also available on chromsome 14, but not presented at the meeting, are an TCRA arrayed cosmid library &any Deaven, Los Alamos National CTLA 1 Laboratory, New Mexico, USA) and a radiation hybrid panel (David Cox, Stanford University, California, USA), and additional whole chromosome 14 somatic cell hybrid lines Mouse Chromosome 12 CP43 (Frank Ruddle, Yale) and GM10479 (Camden Cell Repository).

?

PYGL HSPA2, KUP. SPTB l3 FOS 12 TGFB3 =

TSm. P 11.1 CHGA 11.1 Serpin cluster 11*2R11.2) 1 ? CKB. D14S17.? 131 I

Flg. 5 This is a mouse-centric view of human chromosome 14. The left column is a linkage map of the portions of mouse chromosomes 12 and 14, with markers ordered and spaced on the basis of linkage data pooled from analyses of recombinant inbred strains and backcross and intercross progenies. Distances are 23 shown in units of centimorgans from the centromere. Markeis that 24.1 can only be regionally localized in the mouse linkage map are not associated with a linkage distance. Two additional markers with 24.2 known human homologues. Nkr2-1 and Mar, cannot be placed in 24.3 the genetic map, but can be provisionally ordered by in situ hybridization studies: (centromere) - Nh2-1 - Max - Aat Known human homologues, are listed in the order suggested(PI). by the mouse linkage map. Question marks indicate positions of genes known in the mouse and not yet described in the human, and may represent positions for human homologues. Mouse: linkage data are reviewed in detail in the Chromosome 12 32.3 Conimittee Report in Mammalian Genome (In press.1993) and in the CCM92 Report. ::::ti Twenty-seven of 91 YACs have been localized by fluorescent in situ hybridization (FISH) to specific chromosomal bands (Bemheim, Schellenberg, Kwok, Pandit, this meeting). Sixty YACs are localized to the Familial Rg. 6 Chromosome 14 somatic cell hybrid panel. (D. W. COX). Alzheimer's Disease locus at 14q24.3 (AD3) (Schellenberg, Dark lines indicate the chromosome 14 contents of each of the lines.

Cytogenet Cell Genet. Vol. 66. 1994 7 1 ' .> a i L > -'

Acknowledgments support was provided by Phil Romkey, funded by HSC. Phannacia Biotech Inc., Perkin Elmer Cetus, and Amersham The workshop was organized by Diane W. Cox with the Canada Limited, conuibuted. Computers and other equipment assistance of Wesley McBride (U.S.A.) and, from The were provided by Sun Microsystems of Canada Inc., Apple Hospital for Sick Children, Valerie Selander, Gail Billingsley, Canada and Gestetner/Calcan. Barbara Byth assisted in and Barbara Byth. Assistance at the workshop was also preparing the report for publication. provided by Kristina Gals and Richard Wintle. Computer

Table 1. YACs on chromosome 14

Region Locus Yac No. Origin Size (kb). type1

14q13 D14S162 Yi405C ST. LOUIS CGM IO00 kb 14q21-q22 D14S187 Y1401A ST. LOUIS CGM 640 kb; L,R 14q22 262E12 CEPH C 14q22-q23 D14S168 Y1402B ST. LOUIS CGM 525 kb; L,R Y1402A 295 kb; L,R 14q24.3 D14S52 777m CEPH MWjAYAC 14q24.3 D14S57 89C12 14q24.3 D14S42 932C7 L, R 14q24.3 D14S43 74183 783F2 1 964E2 R 14q24.3 D14S61 737H 10 746B4 749A2 14q24.3 D14S59 74G11 803E1 8788 12 892C 11 93OC12 14q24.3 D14S48 756A4 807F10 82806 87s1 964B5 924E8 14q24.3 FOS 746B4 797D 1 1 14q32.1 D14S 151 Y 14030 ST.LOUIS CGM 490 kb 14q32.2 632E8 CEPH C 14q32.3-qter IGHV 14GG2(IGH2) 1c1 280 kb Note: "L - left end sequenced; "R- right end sequenced: "C"-chimeric. Sizes of YACs are indicated where known.

8 Cpogenet Cell Genet. VoI. 66. I994 Participants

Alain Bernheim. New York. NY USA. Roy Riblet Laboratoie de Cytogenique and John Edwards Medical Biology Institute Genetique Oncologiques - IGR, Dept. of Biochemisuy . Genetics Lab La Jolla, CA USA. Villejuif, France. Oxford University Otto Ritter Christophe BCroud Oxford, UK. Deutches Krebsforschungszentm INSERM U73, Tobias Gedde-Dah1 Heidelberg, Germany. Paris, France. Institute of Forensic Medicine Peter St. George-Hyslop Gail Billingsley Rikshospitalet Div. of Neurology (Medicine) Dep.of Genetics Oslo, Norway. Univ. of Toronto Steven Gexken Toronto, Canada The Hospital for Sick Children. Toronto, Canada Eccles Institute of Human Genetics University Gerard Schellenberg MceBouvagnet of Utah Dept. of Neurology RG-27 CRBWNRS-INSERM Salt Lake City, UT USA. Univ. of Washington Montpellier. France. hi-Yan Kwok Seaule, WA USA K. H. Andy Choo, Div. Dermatology Karl Tibelius Murdoch Institute Washington Univ. Medical Center Medical Research Council Royal Children’s Hospital SLLouis, MO USA. Ottawa. Canada Victoria Australia. Bronwen Loder Shoji Tsuji Diane W. Cox Joint Research Centre, DG XIYE4 Brain Research Institute Dept. of Genetics Analysis Niigata University The Hospital for Sick Children Brussels, Belgium. Niigata, Japan. Toronto, Canada Ani1 G. Menon Chnstine Van Broeckhoven Jamie Cuticchia University of Cincinnati Medical Center Neurogenetics Laboratory GDB. Medical School of Cincinnati. OH USA. University of Antwerp Deborah Nickerson Antwerpen, Belgium. Johns Hopkins University Baltime. MD USA. Dep. of Molecular Biotechnology Michael Walter Paul Dear University of Washington Department of Genetics Laboratmy of Molecular Biology Seaale, WA USA. University of Cambridge. University Medical School Sunil Pandit Cambridge. UK Cambridge, UK. Human Molearlar Genetics Paul Watkins Peter DEustachio Washington Univ. School of Medicine. Genome Analysis Laboratory, LTI NYU Medical Center St Louis, MO USA. Gaithersburg MD, USA

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Cytogenet Cell Genet. Vol. 66. I994