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CHROMOSOR/IE 14 LONG ARM SUBTELOMERIC REGION at 14Q32.33+ 1Sqter

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CHROMOSOR/IE 14 LONG ARM SUBTELOMERIC REGION at 14Q32.33+ 1Sqter PHYSICAL AND GENETIC ANALYSIS OF THE HUPIAN CHROMOSOR/IE 14 LONG ARM SUBTELOMERIC REGION AT 14q32.33+ 1Sqter RICHARD F. WINTLE A thesis subrnitted in conformity with the requirements for the degree of Doctor of Philosophy, Graduate Department of Molecular and Medical Genetics, University of Toronto O 1997 by Richard F. Wintle National: Library Bibliothèque nationale du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Sbest 395. rue Wellington Otrawa ON K1A ON4 ûttawaON K1AON4 Canada canada The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/film, de reproduction sw papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantid extracts fiom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Physical and genetic analysis of the human chromosome 14 long arm subtelomeric region at 14q32.33- 14qter. Ph.D.. 1997, Richard Francis Wintle. Graduate Department of Molecular and Medical Genetics, University of Toronto- ABSTRACT The human immunoglobulin heavy chain gene cluster (IGH) is located at 14q32.33. near the long arm telomere of chromosome 14. Physicd maps suggested that Mqter might be some distance from IGH. Human subtelomeric regions are the sites of increased recombinaiion and have a mde to fernale recombination ratio that is higher than elsewhere in the genome. My goal was to complete the map of distal 14q, to develop genetic markers for Mqter. and to examine recombination in this subtelomeric region. Initially, 13 DNA markers were used to characterize naturally occurring terminal deletions. to refine the physical rnap and determine if deletion breakpoints were near 14qter. Two markers. previously mapped disial to IGH. were mapped proximal to IGH. The breakpoint of a ring chromosome was rnapped to a 350 kb interval within IGH. representing the smallest region of distal monosomy 14q reported to date. Somatic ce11 hybrid lines were next used to map IGH variable region (.VH) segments that previously were not placed within IGH. Four Nor1 DNA fragments. representing eleven VH segments, mapped to chromosomes 15 and 16. Two yeast artificial chromosomes (YAC) contiiining functional hurnan telorneres were mapped to the telomeric end of IGH. A VH segment at the distal ends of the YACs was sensitive to nuclease Bu13 1 digestion of human DNA. demonstrating that these represent the llq telomere. The physical rnap of IGH ivas completed and extends to within 25 kb of the telornere. Polymorphic markers were cloncd from the distd part of IGH. approximately 90 and 200 kb from the telomere. Haplotypes of these rnarkers were constructed for use as a highly polymoryhic genetic marker which will be useful for anchoring genetic rnaps. Linkspe analysis using the 40 pedigree CEPH reference panel revealed increased recombination within this region. Recombination was not significantly higher in males than in fernales, indicating that this region differs from other human subtelomeric regions. ACKNOWLEDGEMENTS This thesis would not have been possible without constant support and encouragement from my supervisor. Diane Cox. Special thanks are also extended to the two other mernbers of my permanent supervisory cornmittee. Gillian Wu and Lap-Chee Tsui. I thank rny collaborators, Drs. Robert Haslarn. Teresa Costa, Ikuko Teshima, Toby Nygaard and Kirsti Kvaley. Some results were supplied by other collaborators: Catherine Duff (NCE somatic hybrid mapping facility), Lin Anderson and Alessandra Duncan (NCE in sitrl hybridization facility). Ikuko Teshima (HSC cytogenetics [ab). 1 am particularly indebted ro lo- Anne Herbrick, who worked for one surnmer under my guidance. I thank the following for providing reagents: Drs. William Brown, Harold Riethman. Steve Reeders. Ad Guerts van Kessel and Ian Tornlinson. I am grateful to Dr. Celia Greenwood for her assistance with the statisticd analyses. I am indebted to Drs. -Wke Wdter and Steve Scherer for their insights and suggestions. Ihave been pnvilrged to work in a lab filled with people who over the years have hrlprd me in müny wnys. Particular mention goes to Gai1 Billingsley. Babs Byth. Mary Grace Bnibacher. and of course to my fellow students Gord Thomas and John Forbes. Numerous members of othcr labs in and around the HSC Genetics department and the U. of T. Department of Molecular and Medical Genetics have helped to make this a more pleasant experience: thanks to all. My persona1 thanks to Louise for putting up with my years of graduate school. to Alessandra Duncan for giving me a push in the right direction. to Dijen and Boomerang for biting me when it was necess'q. and to rny parents for bankrolling the entire operation. TABLE OF CONTENTS page ABSTRACT U .-. ACKNOWLEDGEMENTS U1 LIST OF TABLES ix LIST OF FIGURES .Y LIST OF APPENDICES xii .. LIST OF ABBREVIATIONS .Ull Chapter 1. INTRODUCTION AND LITERATURE REVIEW 1 1.1 MAPPING OF HUMAN CHROMOSOME 14 3 1.1 .a Physical and genetic maps of chromosome 14q32-qter 2 1.1 .b The human irnmunoglobulin heavy chain gene cluster 4 1.2 TELOMERE STRUCTURE AND FUNCTION 6 1 2. Telonieres 6 1.3. b Telomeric DNA 7 1 2.c Unusud telorneres of Drusophilr 9 1-3.d Interstitial telorneric DNA repeats in humans 10 1.2.r interstitial telomrric DN.4 repeüts in other specirs 11 1 2.E Protein components of telorneres 15 1.3 TELOMERASE 17 1.4 SUBTELOMERIC DNA 20 1 -4.a Subtelomeric DIVA sequences 20 1 -4.b Methods of cloning subtelomeric DNA 23 1 -4.c Transcription repression in subtelomeric regions 29 1.5 PHYSICAL MAPPING OF HUMAN SUBTELOMERIC REGIONS 30 1 -5.a Humnn subtelomeric regions 30 1 .5.b Terminal deletions 3 1 T.4BLE OF CONTENTS (continuedl 1.6 RECOMBINATION IN SUBTELOMEWC REGIONS 1-6.a Genetic linkage andysis and genetic maps 1 -6.b Recombination in subtelomenc regions 1.7 OBJECTIVES Chapter 2. PHYSICAL MAPPING OF THE TELOMERIC REGION 14q32.33-t Irlqter: THE USE OF CHROMOSOMAL DELETIONS 3.1 INTRODUCTION 2.1 .a The map of subte!amrric 1Jq 2.1 .b Chromosome drletions for mapping within distal 14q 2.1 .c Terminal deletions of ilq 2.1 .d Ring chromosome 14 2.2 MATERIALS AND METHODS 2.3.a Patient materiais 2.2.b Genomic DNA and probes 3.2.c Poiymorphic CA repeats 2.3 RESULTS 2.4 DISCUSSIOI\J 2.4.a Marker order ciarified by moleculm deletion analysis 2.J.b The smallest region of distal monosorny 14q 2.4.c Ring chromosome 14 syndrome 2.l.d Differrnt deletions undrrlying similiu cytogenetic findings 2.4.e P henotypes of terminal deletions of Ilq TABLE OF CONTENTS (continuedl page Chapter 3. PHYSICAL MAPPING OF THE IGH GENE 62 CLUSTER NEAR THE TELOMERE OF 14q: THE USE OF TELONIERIC YACS AND SOMATIC CELL HYBRIDS 3.1 INTRODUCTION 3.1 .a The physical map ncar I-lqter 3.1. b The human immunoglobulin heavy chain prne cluster 3.1 .c Human VH segments at other genomic locations 3.1 .d Telomenc YACs from distal Mq 3.2 MATEMALS AiiD METHODS 3.2.a Somatic ce11 hybrids 3.2.b Genomic DNA and probes 3 2.c Physical mapping of telomeric YACs 3.2.d Alri-PCR generation of probes from telomeric YACs 3.7.e VH segment nomenclature 3 -2.f Nuclrase Ba13 1 digestion of genomic DNA 3.2.g Two-dimensionri1 DNA electrophoresis 3 2.h Chromosomal NI sitlr mappinp of VHI probe 3.3 RESULTS 3.3.a Itz sirri hybridization of VH2 probe to metaphase chromosomes 3.3.b The VH region of chromosome 14 hybrid ce11 tines 3.3.c VH segments on chromosomes 15 and 16 3.3.d The IGHV4B7.5 gene segment on chromosome 14 3 .? .e ID-DE mapping of the VH 1 f probe 3.3. f du-PCR clone grneration TABLE OF CONTENTS (continuedl page 3.3 .g VH segments within telomenc YAC yRM206 52 3 -3.h PFGE mapping of two telorneric YACs 82 3.3. i Nuclease Ba13 1 sensitivity 88 3.4 DISCUSSION 94 3-42 IGH segments located nrar the 14q telomere 94 3 -4.b VH segments on chromosomes 1 5 and 16 95 3.4.c Two VH segments detected by the VH lf probe 98 3 -4.d YACs representing the tdomere of 14q 99 3 -4.e The IGH gene cluster at 14qter 1O0 Chapter 4. GENETIC RECOMBtNATION AND POLYMORPHIC MARKERS IN THE 14qter SUBTELOMERIC REGION 4.1 INTRODUCTION 4.1 .a Recombination in human subtelomeric regions 4.1 .b Linkage maps of chromosome 14 4.2 .MATERIALS .&ND METHODS 4.2. a Isolation of microsatellite markers 4.2. b PCR amplification of microsatellite markers 4.3.~ Linkase analyses 4.î.d Typing of IGH constant region markers 4.3 RESULTS 4.3.a Polymorphic CA repeats at the telomere of 14q 4.3.b Analysis and physicd mapping of CA repeat clones at the telomere of 14q 4.3 .c Linkage Analyses 4.3.d Re-typing of known IGH recombinant families vii TABLE OF CONTENTS (continuedl page 4.4 DISCUSSION 123 4.4.a tncreased recornbination near 14qter 4.4. b The recombination hotspot within the IGH constant region IL+ 4.4.c CA repeat polymorphisms near 14qter 125 Chapter 5.
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