G ENOMIC D ISORDERS

G^ENOMIC D^ISORDERS

Edited by

J

R. L

,

,

P

S

,

,

Department of Molecular and Human Genetics Baylor College of Medicine, Houston, TX

G ^ENOMIC D ^ISORDERS

The Genomic Basis of Disease

/

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Library of Congress Cataloging-in-Publication Data

Genomic disorders : the genomic basis of disease / edited by James R. Lupski, Pawe Stankiewicz.

p. ; cm.

Includes bibliographical references and index.

ISBN 1-58829-559-1 (alk. paper) 1. Genetic disorders--Molecular aspects.

[DNLM: 1. Genetic Diseases, Inborn. 2. Chromosome Aberrations. 3. Genome Components. 4. Genome.

5. Genomics--methods. QZ 50 G3354 2006] I. Lupski, James R., 1957- II. Stankiewicz, Pawe . RB155.5.G465 2006

616'.042--dc22

2005020461

Dedication

To our many mentors who have nurtured our intellectual curiosity and to our dedicated families for their love and support.

—J. R. L. and P. S.

v

In Memorium

In memory of Carlos A. Garcia (1935–2005) and his passion for medicine, science, and the patients and families for whom he cared.

vii

Preface

ix

Uncovering Recurrent Submicroscopic Rearrangements As a Cause of Disease For five decades since Fred Sanger's (1) seminal discovery that proteins have a specific structure, since Linus Pauling's (2) discovery that hemoglobin from patients with sickle cell anemia is molecularly distinct, and since Watson and Crick's (3) elucidation of the chemical basis of heredity, the molecular basis of disease has been addressed in the context of how mutations affect the structure, function, or regulation of a gene or its protein product. Molecular medicine has functioned in the context of a genocentric world.

During the last decade it became apparent, however, that many disease traits are best explained not by how the information content of a single gene is changed, but rather on the basis of genomic alterations. Furthermore, it has become abundantly clear that architec- tural features of the human genome can result in susceptibility to DNA rearrangements that cause disease traits. Such conditions have been referred to as genomic disorders (4,5).

It remains to be determined to what extent genomic changes are responsible for disease traits, common traits (including behavioral traits), or perhaps sometimes represent benign polymorphic variation. The widespread structural variation of the human genome, alter- natively referred to as large-copy number polymorphisms, large-scale copy number varia- tions, or copy number variants has begun only recently to be appreciated (6–9).

High-resolution analysis of the human genome has enabled detection of genome changes heretofore not observed because of technology limitations. Whereas agarose gel electro- phoresis enables detection of changes of the genome up to 25–30 kb in size, and cytoge- netic banding techniques can resolve deletion rearrangements only greater than 2–5 Mb in size, alterations of the genome between more than 30 kb and less than 5 Mb defied detection until pulsed-field gel electrophoresis and fluorescence in situ hybridization became available to resolve changes in the human genome of such magnitude (10–12).

Those methods were limited to detection of specific genomic regions of interest and could not evaluate genomic rearrangements in a global way.

The availability of a “finished” human genome sequence (13) and genomic microarrays (14) have enabled approaches to resolve changes in the genome heretofore impossible to assess on a global genome scale (i.e., simultaneously examining the entire genome rather than discreet segments). Array comparative genome hybridization (aCGH) is one powerful approach to high-resolution analysis of the human genome. The CGH determines differ- ences by comparisons to a reference “normal genome,” whereas the array enables detec- tion of such changes at essentially any resolution that is desired, limited only by imagination and cost. Furthermore, the application of bioinformatic analyses to the finished human genome sequence and comparative genomic analysis enable information technology approaches to identify key architectural features throughout the entire genome that are associated with known recurrent rearrangements causing genomic disorders.

An increasing number of human diseases are recognized to result from recurrent DNA rearrangements involving unstable genomic regions. A combination of high-resolution

genome analysis with informatics capabilities to examine individuals with well- characterized phenotypic traits is a powerful approach to address the question: To what extent are constitutional DNA rearrangements in the human genome responsible for human traits?

Such approaches may also yield insights into recurrent somatic rearrangements (15).

Genomic Disorders: The Genomic Basis of Disease attempts to survey the subject area of genomic disorders in the beginning of the postgenomic era. After a short historical presentation (Part I) describing the trials and tribulations involved in uncovering the recurrent submicroscopic duplication associated with Charcot-Marie-Tooth disease type 1A, the book is organized into parts on genome structure (II), genome evolution (III), genomic rearrange- ments and disease traits (IV), functional aspects of genome structure (V), and modeling and assays for genomic disorders (VI). Finally, Part VII includes appendices that delineate disease traits and genomic features (listed in tabular form) for well-characterized genomic disorders as well as clinical phenotypes for which chromosome microarray analysis may be used to detect the responsible rearrangement mutation. We believe that the topics chosen for individual chapters illustrate the genomic basis of disease.

James R. Lupski, MD,PhD

Pawel Stankiewicz, MD,PhD

REFERENCES

1. Sanger F. The terminal peptides of insulin. Biochem J 1949;45:563–574.

2. Pauling L, Itamo HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science 1949;110:64–66.

3. Watson DA, Crick FHC. Molecular structure of nucleic acids. A structure for deoxyribose nucleic acids. Nature 1953;171:737–738.

4. Lupski JR. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 1998;14:417–422.

5. Stankiewicz P, Lupski JR. Genome architecture, rearrangements and genomic disorders. Trends Genet 2002;18:74–82.

6. Shaw-Smith C, Redon R, Rickman L, et al. Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J Med Genet 2004;41:241–248.

7. Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in the human genome. Nat Genet 2004;36:949–951.

8. Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome.

Science 2004;305:525–528.

9. Tuzun E, Sharp AJ, Bailey JA, et al. Fine-scale structural variation of the human genome. Nat Genet 2005;37:727–732.

10. Schwartz DC, Cantor CR. Separation of yeast chromosome-sized DNAs by pulsed field gradient gel electrophoresis. Cell 1984;37:67–75.

11. Pinkel D, Straume T, Gray JW. Cytogenetic analysis using quantitative, high-sensitivity, fluorescence hybridization. Proc Natl Acad Sci USA 1986;83:2934–2938.

12. Lupski JR. 2002 Curt Stern Award Address. Genomic disorders: recombination-based disease resulting from genomic architecture. Am J Hum Genet 2003;72:246–252.

13. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 2004;431:931–945.

14. Carter NP, Vetrie D. Applications of genomic microarrays to explore human chromosome structure and function. Hum Mol Genet 2004;13:R297–R302.

15. Barbouti, A., Stankiewicz, P., Birren, B., et al. The breakpoint region of the most common isochro mosome, i(17q), in human neoplasia is characterized by a complex genome architecture with large palindromic low-copy repeats. Am J Hum Genet 2004;74:1–10.

x Preface

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Contents

Dedication ... v

In Memorium ... vii

Preface ... ix

Contributors ... xv

xi PART I INTRODUCTION 1 The CMT1A Duplication: A Historical Perspective Viewed From Two Sides of an Ocean ... 3

James R. Lupski and Vincent Timmerman PART II GENOMIC STRUCTURE 2 Alu Elements ... 21

Prescott Deininger 3 The Impact of LINE-1 Retrotransposition on the Human Genome ... 35

Amy E. Hulme, Deanna A. Kulpa, José Luis Garcia Perez, and John V. Moran 4 Ancient Transposable Elements, Processed Pseudogenes, and Endogenous Retroviruses ... 57

Adam Pavlicek and Jerzy Jurka 5 Segmental Duplications ... 73

Andrew J. Sharp and Evan E. Eichler 6 Non-B DNA and Chromosomal Rearrangements ... 89

Albino Bacolla and Robert D. Wells 7 Genetic Basis of Olfactory Deficits ... 101

Idan Menashe, Ester Feldmesser, and Doron Lancet 8 Genomic Organization and Function of Human Centromeres ... 115

Huntington F. Willard and M. Katharine Rudd P^ART III G^ENOME E^VOLUTION 9 Primate Chromosome Evolution ... 133

Stefan Müller 10 Genome Plasticity in Evolution: The Centromere Repositioning .... 153

Mariano Rocchi and Nicoletta Archidiacono

xii Contents

P^ART IV G^ENOMIC REARRANGEMENTS AND D^ISEASE T^RAITS

11 The CMT1A Duplication and HNPP Deletion ... 169 Vincent Timmerman and James R. Lupski

12 Smith-Magenis Syndrome Deletion, Reciprocal Duplication dup(17)(p11.2p11.2), and Other Proximal

17p Rearrangements ... 179 Pawel Stankiewicz, Weimin Bi, and James R. Lupski

13 Chromosome 22q11.2 Rearrangement Disorders ... 193 Bernice E. Morrow

14 Neurofibromatosis 1 ... 207 Karen Stephens

15 Williams-Beuren Syndrome ... 221 Stephen W. Scherer and Lucy R. Osborne

16 Sotos Syndrome ... 237 Naohiro Kurotaki and Naomichi Matsumoto

17 X Chromosome Rearrangements ... 247 Pauline H. Yen

18 Pelizaeus-Merzbacher Disease and Spastic Paraplegia Type 2 ... 263 Ken Inoue

19 Y-Chromosomal Rearrangements and Azoospermia ... 273 Matthew E. Hurles and Chris Tyler-Smith

20 Inversion Chromosomes ... 289 Orsetta Zuffardi, Roberto Ciccone, Sabrina Giglio,

and Tiziano Pramparo

21 Monosomy 1p36 As a Model for the Molecular Basis

of Terminal Deletions ... 301 Blake C. Ballif and Lisa G. Shaffer

22 inv dup(15) and inv dup(22) ... 315 Heather E. McDermid and Rachel Wevrick

23 Mechanisms Underlying Neoplasia-Associated Genomic

Rearrangements ... 327 Thoas Fioretos

PARTV FUNCTIONAL ASPECTS OF GENOME STRUCTURE 24 Recombination Hotspots in Nonallelic Homologous

Recombination ... 341 Matthew E. Hurles and James R. Lupski

25 Position Effects ... 357 Pawel Stankiewicz

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P^ART VI G^ENOMIC D^ISORDERS: MODELING AND A^SSAYS

26 Chromosome-Engineered Mouse Models ... 373 Pentao Liu

27 Array-CGH for the Analysis of Constitutional Genomic

Rearrangements ... 389 Nigel P. Carter, Heike Fiegler, Susan Gribble,

and Richard Redon

P^ART VII A^PPENDICES

Appendix A: Well-Characterized Rearrangement-Based

Diseases and Genome Structural Features at the Locus ... 403 Pawel Stankiewicz and James R. Lupski

Appendix B: Diagnostic Potential for Chromosome

Microarray Analysis ... 407 Pawel Stankiewicz, Sau W. Cheung, and Arthur L. Beaudet Index ... 415 About the Editors ... 427

Contents xiii

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xv

CONTRIBUTORS

NICOLETTA ARCHIDIACONO,PhD• Department of Genetics and Microbiology, University of Bari, Bari, Italy

ALBINO BACOLLA,PhD• Center for Genome Research, Texas A & M University System Health Science Center, Texas Medical Center, Houston, TX

BLAKE C. BALLIF,PhD• Signature Genomic Laboratories, LLC, Spokane, WA ARTHUR L. BEAUDET,MD• Department of Molecular and Human Genetics, Baylor

College of Medicine, Houston, TX

WEIMIN BI,PhD• Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

NIGEL P. CARTER,DPhil• The Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

SAU W. CHEUNG,PhD• Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

ROBERTO CICCONE,PhD• Biologia Generale e Genetica Medica, Universita di Pavia, Pavia, Italy

PRESCOTT DEININGER,PhD• Department of Epidemiology, Tulane Cancer Center, Tulane University Health Sciences Center, New Orleans, LA

EVAN E. EICHLER,PhD• Department of Genome Sciences, University of Washington, Seattle, WA

ESTER FELDMESSER,MSc• Department of Molecular Genetics and the Crown Human Genome Center Weizmann Institute of Science, Rehovot, Israel

HEIKE FIEGLER,PhD• The Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

THOAS FIORETOS,MD,PhD• Department of Clinical Genetics, Lund University Hospital, Lund, Sweden

SABRINA GIGLIO,MD,PhD• Ospedale San Raffaele, Milano, Italy

SUSAN GRIBBLE,PhD• The Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

AMY E. HULME,BS,MS• Department of Human Genetics, The University of Michigan Medical School, Ann Arbor, MI

MATTHEW E. HURLES,PhD• The Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

KEN INOUE,MD,PhD• Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

JERZY JURKA,PhD• Genetic Information Research Institute, Mountain View, CA DEANNA A. KULPA,BS,MS• Department of Human Genetics, The University of Michigan

Medical School, Ann Arbor, MI

NAOHIRO KUROTAKI,MD,PhD• Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

DORON LANCET,PhD• Department of Molecular Genetics and the Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel

xvi Contributors PENTAO LIU,PhD• The Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK JAMES R. LUPSKI,MD,PhD• Department of Molecular and Human Genetics, Department

of Pediatrics, Baylor College of Medicine, Houston, TX

NAOMICHI MATSUMOTO,MD,PhD• Department of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura, Yokohama, Japan

HEATHER E. MCDERMID,PhD• Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada

IDAN MENASHE,MSc• Department of Molecular Genetics and the Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel

JOHN V. MORAN,PhD• Department of Human Genetics and Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI

BERNICE E. MORROW,PhD• Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY

STEFAN MÜLLER,PhD• Department of Biology II, Ludwig, Maximilians University, Munich, Germany

LUCY R. OSBORNE,PhD• Departments of Medicine and Molecular & Medical Genetics, University of Toronto, Toronto, Canada

ADAM PAVLICEK,PhD• Genetic Information Research Institute, Mountain View, CA JOSÉ LUIS GARCIA PEREZ,PhD• Department of Human Genetics, The University

of Michigan Medical School, Ann Arbor, MI

TIZIANO PRAMPARO,PhD• Biologia Generale e Genetica Medica, Universita di Pavia, Pavia, Italy

RICHARD REDON,PhD• The Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

MARIANO ROCCHI,PhD• Department of Genetics and Microbiology, University of Bari, Bari, Italy

M. KATHARINE RUDD,PhD• Institute for Genome Sciences & Policy, Duke University, Durham, NC

STEPHEN W. SCHERER,PhD• Program in Genetics & Genomic Biology, Sick Kids Hospital, Toronto, Canada; Department of Molecular & Medical Genetics, University of Toronto, Toronto, Canada

LISA G. SHAFFER,PhD• Signature Genomic Laboratories, LLC, Spokane, WA; Sacred Heart Medical Center, Spokane, WA; Health Research and Education Center, Washington State University, Spokane, WA

ANDREW J. SHARP,PhD• Department of Genome Sciences, University of Washington, Seattle, WA

PAWEL STANKIEWICZ,MD,PhD• Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

KAREN STEPHENS,PhD• Departments of Medicine and Laboratory Medicine, University of Washington, Seattle, WA

VINCENT TIMMERMAN,PhD• Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium

CHRIS TYLER-SMITH,PhD• The Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

ROBERT D. WELLS,PhD• Center for Genome Research, Texas A & M University Sys- tem Health Science Center, Texas Medical Center, Houston, Texas

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RACHEL WEVRICK,PhD• Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada

HUNTINGTON F. WILLARD,PhD• Institute for Genome Sciences & Policy, Duke University, Durham, NC

PAULINE H. YEN,PhD• Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan ORSETTA ZUFFARDI,PhD• Biologia Generale e Genetica Medica, Universita di Pavia,

Pavia, Italy

Contributors xvii