GENOMIC DISORDERS The Genomic Basis of Disease doc

Genomic

Disorders

The Genomic

Basis of Disease

The Genomic

Basis of Disease

Edited by

James R. Lupski, MD, PhD

Pawel Stankiewicz, MD, PhD

Genomic

Disorders

Edited by

James R. Lupski, MD, PhD

Pawel Stankiewicz, MD, PhD

GENOMIC DISORDERS

Edited by

JAMES R. LUPSKI, MD, PhD

PAWEL STANKIEWICZ, MD, PhD

Department of Molecular and Human Genetics

Baylor College of Medicine, Houston, TX

GENOMIC

DISORDERS

The Genomic Basis of Disease

/

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Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1

eISBN 1-59745-039-1

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 IINTRODUCTION

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

PART III GENOME EVOLUTION

9 Primate Chromosome Evolution .................................................. 133

Stefan Müller

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

Mariano Rocchi and Nicoletta Archidiacono

xii Contents

PART IV GENOMIC REARRANGEMENTS AND DISEASE TRAITS

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

PART VFUNCTIONAL 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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PART VI GENOMIC DISORDERS: MODELING AND ASSAYS

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

PART VII APPENDICES

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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