Molecular Genetics, Gene Transfer, and Therapy
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Advances in Veterinary Medicine
Volume 40
Molecular Genetics, Gene
Transfer, and Therapy
Edited by
W. Jean Dodds
HEMOPET
Santa Monica, California
James E. Womack
Department of Veterinary Pathobiology
College of Veterinary Medicine
Texas A&M University
College Station, Texas
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CONTENTS
From Molecular Genetics to
Diagnosis and Gene Therapy
G. HAUGE
JENS
I . Introduction to Molecular Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
I1. Gene Manipulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
I11. Studies of Metabolic and Gene Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
IV. DiagnosisofGeneticDisease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
V. Therapy of Genetic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
VI . Use of Recombinant DNA Methods to Improve Domestic Animals . . . . . . . 35
VII . Legal and Ethical Aspects of Patenting Biotechnology .................. 39
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Genes Involved in Oncogenesis
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
I1. Detection of Genes Involved in Oncogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
I11. Mapping and Cloning Genes Involved in Oncogenesis . . . . . . . . . . . . . . . . . . . 66
IV. Animal Model Systems Used to Study Gene Function . . . . . . . . . . . . . . . . . . . 69
V. Identity and Function of Genes Involved in Oncogenesis . . . . . . . . . . . . . . . . 73
VI . Applications of Oncogene Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
VII . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Diagnostic Molecular Genetics
H . SACK.JR.
GEORGE
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
I1. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
vi CONTENTS
I11. Linkage Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IV. Single-Gene Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
V. FutureDirections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gene Therapy for the Hemophilias
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I1. Advantages of Gene Therapy as a Treatment for Hemophilia . . . . . . . . . . . .
I11. Advantages of Hemophilia as a Model for Gene Therapy . . . . . . . . . . . . . . . .
n! Choice of Vector . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
V. Factor IX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VI . Factor VIII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VII . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Genes Controlling Retroviral Virulence
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I1. Retrovirus Structure and Replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
111. Additional Retrovirus Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IV. Feline Acquired Immunodeficiency Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .
V. Murine AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VI . Simian AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VII . Murine Leukemia Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VIII . Endogenous Retroviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IX. Lentiviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mapping Animal Genomes
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I1. Why Map Farm Animal Genomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I11. Methods for Animal Genome Mapping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IV. Current Status of Animal Genome Maps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTENTS vii
V. Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
The Canine Genome
CATHRYN
S. MELLERSHAND ELAINEA. OSTRANDER
I.Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
11.Applications of a Canine Genetic Map ................................. 193
111.Organization of the Canine Genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
IV. Development of a Canine Genetic Map ................................ 198
V. Targeted Cloning of Canine Genes
VI. Considerations a
References . . . .
INDEX..................................................................... 217
This Page Intentionally Left Blank
CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors' contributions begin.
JANELLE CORTNER, National Cancer Institute/National Institutes of
Health, Division of Basic Sciences, Bethesda, Maryland 20892 (51)
FREDERICK J. FULLER, Department of Microbiology, Pathology, and
Parasitology, North Carolina State University, College of Veteri-
nary Medicine, Raleigh, North Carolina 27615 (135)
JENS G. HAUGE, Department of Biochemistry, Physiology, and Nutri-
tion, Norwegian College of Veterinary Medicine, Oslo, Norway (1)
KATHERINEA. HIGH, Departments of Pediatrics, Pathology, and Labo-
ratory Medicine, University of Pennsylvania School of Medicine,
and Hematology Division, The Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania 19104 (119)
CATHRYN S. MELLERSH, Clinical Research Division, Fred Hutchinson
Cancer Research Center, Seattle, Washington 98104 (191)
ELAINE A. OSTRANDER, Clinical Research Division, Fred Hutchinson
Cancer Research Center, Seattle, Washington 98104 (191)
GEORGE H. SACK, JR., Departments of Medicine, Pediatrics, and Bio-
logical Chemistry, The Johns Hopkins University School of Medi-
cine, The Johns Hopkins Hospital, Baltimore, Maryland 21287 (103)
SUSAN VANDE WOUDE, Laboratory Animal Resources, Colorado State
University, Fort Collins, Colorado 80523 (51)
GEORGE F. VANDE WOUDE, ABL-Basic Research Program, Frederick
Cancer Research and Development Center, National Cancer Insti-
tute, Frederick, Maryland 21702 (51)
ix
x CONTRIBUTORS
JOHANNESWALTER,Department of Cardiothoracic Surgery, University
of Vienna, Vienna, Austria (119)
JAMES E. WOMACK,Department of Veterinary Pathobiology, College of
Veterinary Medicine, Texas A&M University, College Station, Texas
77843 (157)
PREFACE
The rapid explosion of knowledge relating recombinant DNA tech-
nology to science and medicine has laid the groundwork for its applica-
tion to diagnosis of genetic disease, gene regulation, development of
transgenic animals, and gene therapy. The science of molecular genet-
ics has progressed from an understanding of the basics to manipula-
tions of genes using specific plasmid, viral or shuttle vectors, jet injec-
tion, and particle bombardment to introduce reporter genes and
transfect a variety of microbial, plant, animal, and human cells. These
techniques are now being extended to map the genome of humans and
other species. Early studies focused on developing the linkage map,
and parallel goals include answers to questions about how genes are
regulated and how they interact to control physiology and develop-
ment. These questions involve studying individual genes, as well as
sets of genes-the study of which is now termed "genomics."
Recent experiments with transgenic mice have led to the prediction
that animal agriculture would undergo an immediate revolution. One
could envision "super cows, pigs, and other species," which carry trans-
genes that would make them particularly productive and healthy.
There remains a large knowledge gap, however, in applying this tech-
nology in a scientific and ethically acceptable manner to farm animals
and other species. The latest breakthrough whereby the lamb "Dolly"
was successfully cloned from the cells of an adult sheep has catapulted
these issues to the forefront of world debate.
Recent publications of specific genetic defects of large animals have
demonstrated the applicability of molecular genetics to the improve-
ment of animal health. Examples are the studies of the leukocyte adhe-
sion deficiency (LAD) of Holstein cattle; hyperkalemic periodic paraly-
sis (HPP) of quarterhorses; malignant hyperthermia of swine; and
canine progressive retinal atrophy, copper storage disease, pyruvate
kinase deficiency, phosphofructokinase deficiency, and von Wille-
brand's disease (vWD).
Development of genetic techniques including sequencing of specific
normal and mutant genes has permitted positive identification of car-
rier animals for effective genetic screening. For example, the frequency
xii PREFACE
of carriers for bovine LAD varies from 6 to 15%,whereas equine HPP
has a major impact on the genotype of the quarterhorse. Similarly,
breeds of dogs that carry a high freqency of vWD can be affected to the
extent of 15 to 80% of current bloodlines.
Not all genetic defects have undesirable consequences, for evolution
of some abnormalities may have a potential beneficial effect in the
carrier state. Very little is currrently known about the potential physi-
ological or other benefits associated with certain genotypes and their
observed phenotype. Identification of genetic markers permits their
selection to segregate economically important animals for beneficial
traits and allows for selective breeding and even positional cloning of
the genes involved. The future for marker-assisted selection of the
genetic loci responsible for economically valuable traits is potentially
large and can involve a variety of domestic farm animals including
cattle, pigs, and chickens. How these tools will be used appropriately
and responsibly by the animal industry has yet to be determined.
Application of these techniques to the diagnosis and control of infec-
tious disease is also important. For example, understanding the genet-
ic basis of various animal and human retroviruses leads to ways to
control their respective diseases. Recent work on studying the equine
infectious anemia virus indicated that exchange of the envelope region
of a highly virulent strain of the virus with the same region of an
avirulent viral strain can make the avirulent strain now become viru-
lent. This research has opened a wide range of possibilities for viral
manipulation in controlling the disease in infected horses and also for
the development of other antiinflammatory and antipyretic drugs for
therapy of the disease.
These recent developments in biotechnology have led to an increas-
ing plethora of related patents. The idea of patenting genes, partic-
ularly human genes, has raised a series of ethical dilemmas. While
patents have become crucial to the biotechnology business, scientists
and businessmen are concerned about how patents they file for por-
tions of a gene (i.e., copies of gene fragments) could potentially prevent
patenting the useful genes themselves. In other words, having a patent
on a part of a gene could prevent the patenting of discoveries that
affect the whole gene. Thus, the actual useful genes or gene products
may now be protected by patents. A more utilitarian approach could be
adopted in order to solve this problem plaguing the commercial bio-
technology industry. Linked hand-in-hand with the commercial con-
cerns are the ethical problems of holding a monopoly on patented tech-
nology which could provide lifesaving therapeutic products. The
...
PREFACE xlll
ethical issues are particularly relevant to the application of this tech-
nology to veterinary medicine.
The present volume addresses various perspectives on these exciting
and challenging times. We thank the authors Jens Hauge, Janelle
Cortner, Susan Vande Woude, George F. Vande Woude, George H.
Sack, Johannes Walter, Katherine A. High, Frederick J. Fuller, Cath-
ryn S. Mellersh, and Elaine A. Ostrander for their scholarly contribu-
tions.
W. JEAN DODDS
JAMES E. WOMACK
This Page Intentionally Left Blank
ADVANCESIN VETERINARYMEDICINE,VOL.40
From Molecular Genetics
to Diagnosis and Gene Therapy
JENS G. HAUGE
Department of Biochemistry, Physiology, and Nutrition,
Norwegian College of Veterinary Medicine, Oslo, Norway
I. Introduction to Molecular Genetics
A. Structure and Replication of Genes
B. From Gene to Gene Product
II. Gene Manipulation
A. Basic Features
B. Methods and Tools
C. Vectors
D. Studies of Gene Structure
III. Studies of Metabolic and Gene Regulation
A. Tissue Culture Studies
B. Regulation in Transgenic Animals
IV. Diagnosis of Genetic Disease
A. Gene Changes in Hereditary Disease
B. Detection of Gene Changes with DNA Probes
C. DNA Probes and Disease Susceptibility
D. Application to Domestic Animals
E. Gene Changes in Cancer
V. Therapy of Genetic Diseases
A. Germ Line Gene Therapy
B. Somatic Gene Therapy
VI. Use of Recombinant DNA Methods to Improve Domestic Animals
A. Markers and Maps
B. Parentage Identification
C. Transgenic Animals
VII. Legal and Ethical Aspects of Patenting Biotechnology
References
Copyright 9 1997by AcademicPress.
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1093-975X/97 $25.00
