The Biology of the Laboratory Rabbit

THE BIOLOGY OF THE LABORATORY RABBIT

Second Edition

Patrick J. Manning

Division of Comparative Medicine, University of Minnesota Health Sciences Center, Minneapolis, Minnesota

Daniel H. Ringler

Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan

Christian E. Newcomer

Division of Laboratory Animal Medicine, Tufts–New England Medical Center, Boston, Massachusetts

Table of Contents

Cover image

Title page

AMERICAN COLLEGE OF LABORATORY ANIMAL MEDICINE SERIES

Copyright

List of Contributors

Preface

List of Reviewers for Chapters in This Volume

Chapter 1: Taxonomy and Genetics

Publisher Summary

I TAXONOMY AND GEOGRAPHICAL DISTRIBUTION

II ORIGIN AND DOMESTICATION

III GENETICS

IV INBRED STRAINS

Chapter 2: Colony Husbandry

Publisher Summary

I LABORATORY MANAGEMENT

II BREEDING COLONY MANAGEMENT

III COMMERCIAL HERD MANAGEMENT

Chapter 3: Anatomy

Publisher Summary

I INTRODUCTION

II EXTERNAL FEATURES

III OSTEOLOGY

IV ORAL CAVITY

V ABDOMINAL VISCERA

VI UROGENITAL SYSTEM

VII THORACIC VISCERA

VIII BRAIN AND SPINAL CORD

Chapter 4: Physiology

Publisher Summary

I INTRODUCTION

II CARDIOVASCULAR SYSTEM

III RESPIRATORY SYSTEM

IV ALIMENTARY SYSTEM

V METABOLISM

VI THERMOREGULATION

VII WATER METABOLISM

Chapter 5: Basic Biomethodology

Publisher Summary

I INTRODUCTION

II HANDLING AND RESTRAINT

III SAMPLING TECHNIQUES

IV METHODS OF COMPOUND ADMINISTRATION

V SPECIALIZED RESEARCH TECHNIQUES

VI EUTHANASIA

VII NECROPSY PROCEDURES

Chapter 6: Anesthesia and Analgesia

Publisher Summary

I INTRODUCTION

II PREOPERATIVE EVALUATION AND CARE

III METHODS OF ANESTHETIC DELIVERY

IV ENDOTRACHEAL INTUBATION

V PARENTERAL ANESTHETICS

VII ACUTE AND CHRONIC ANALGESIC MANAGEMENT

VIII HYPNOSIS: A SPECIAL ANESTHETIC CONSIDERATION

IX MONITORING OF ANESTHESIA

X INTRAOPERATIVE AND POSTOPERATIVE SUPPORTIVE CARE

Chapter 7: Clinical Biochemistry and Hematology

Publisher Summary

I INTRODUCTION

II CLINICAL BIOCHEMISTRY

III CHEMICAL CONSTITUENTS OF BLOOD

IV URINALYSIS

V HEMATOLOGY

Chapter 8: Bacterial Diseases

Publisher Summary

I INTRODUCTION

II PASTEURELLOSIS

III ENTEROTOXEMIA

IV TYZZER’s DISEASE

V COLIBACILLOSIS

VI SALMONELLOSIS

VII STAPHYLOCOCCOSIS

VIII TREPONEMATOSIS

IX NECROBACILLOSIS

X LISTERIOSIS

XI TUBERCULOSIS

XII TULAREMIA

XIII MISCELLANEOUS BACTERIAL DISEASES

Chapter 9: Viral Diseases

Publisher Summary

I INTRODUCTION

II DNA VIRUS INFECTIONS

III RNA VIRUS INFECTIONS

Chapter 10: Protozoal Diseases

Publisher Summary

I INTRODUCTION

II APICOMPLEXA (SPOROZOA)

III MICROSPORIDA

IV FLAGELLATES AND AMOEBAE

V ORGANISMS OF UNCERTAIN CLASSIFICATION

Chapter 11: Arthropod and Helminth Parasites

Publisher Summary

I INTRODUCTION

II ARTHROPOD PARASITES

III HELMINTH PARASITES

TRICHOSTRONGYLIDEA

TRICHURIDS

FILARIOIDIDEA

METASTRONGYLOIDEA

OXYUROIDEA

ASCAROIDEA

LAGOMORPH AS DEFINITIVE HOST

LAGOMORPH AS INTERMEDIATE HOST

Chapter 12: Neoplastic Diseases

Publisher Summary

I INTRODUCTION

II NEOPLASMS OF Oryctolagus cuniculus

III NEOPLASMS OF Sylvilagus

IV NEOPLASMS OF Lepus

V NEOPLASMS ASSOCIATED WITH ONCOGENIC VIRUSES

VI TRANSPLANTABLE NEOPLASMS AND NEOPLASTIC PROCESSES USED AS MODEL SYSTEMS

Chapter 13: Inherited Diseases and Variations

Publisher Summary

I INTRODUCTION

II CONDITIONS CONTROLLED BY SINGLE (MUTANT) GENES

III FAMILIAL OR POLYGENIC CONDITIONS

IV SOURCES OF RABBITS WITH INHERITED DISEASE AND VARIATIONS

Chapter 14: Nutrition and Nutritional Diseases

Publisher Summary

I INTRODUCTION

II FEEDING BEHAVIOR AND DIGESTIVE TRACT PHYSIOLOGY

III NUTRITIONAL REQUIREMENTS

IV DIETARY FACTORS AND DISEASE

V FEEDSTUFFS FOR RABBITS

VI COMPOSITION OF DIETS AND FEEDING PRACTICES

Chapter 15: Metabolic, Traumatic, Mycotic, and Miscellaneous Diseases

Publisher Summary

I INTRODUCTION

II MUCOID ENTEROPATHY

III GASTRIC TRICHOBEZOARS (HAIR BALLS)

IV PYLORIC STENOSIS/PYLOROSPASM

V LIVER LOBE TORSION

VI PREGNANCY TOXEMIA

VII EXTRAUTERINE PREGNANCY

VIII HYDROMETRA

IX PROLAPSED VAGINA

X MASTITIS

XI CORNEAL DISORDERS

XII UROLITHIASIS

XIII SUPERFICIAL MYCOSIS

XIV DEEP MYCOSES

XV MOIST DERMATITIS

XVI ULCERATIVE PODODERMATITIS

XVII TRAUMATIC VERTEBRAL FRACTURE

XVIII HEAT PROSTRATION

XIX SHOCK DISEASE

XX PLANT TOXICOSIS

XXI PULMONARY EMPHYSEMA

Chapter 16: Zoonoses and Occupational Health Considerations

Publisher Summary

I OCCUPATIONAL HEALTH CONSIDERATIONS

II BACTERIAL ZOONOSES

III MYCOTIC ZOONOSES

IV VIRAL ZOONOSES

V RICKETTSIAL ZOONOSES

VI PROTOZOAL ZOONOSES

VII HELMINTHIC ZOONOSES

VIII ARTHROPOD INFESTATIONS

Chapter 17: Atherosclerosis Research

Publisher Summary

I INTRODUCTION

II ATHEROSCLEROSIS OF RABBITS

III WHOLE-BODY CHOLESTEROL METABOLISM

IV ARTERIAL METABOLISM AND FUNCTION

Chapter 18: Models in Infectious Disease Research

Publisher Summary

I INTRODUCTION

II VIRUSES

III BACTERIA

IV FUNGI

V CONCLUSIONS

Chapter 19: Models in Ophthalmology and Vision Research

Publisher Summary

I INTRODUCTION

II ANATOMY AND PHYSIOLOGY OF THE VISUAL SYSTEM

III SPONTANEOUS OCULAR DISEASE

IV EXPERIMENTALLY INDUCED OCULAR DISEASE

V MODELS IN VISION RESEARCH

VI CONCLUSIONS

Chapter 20: Polyclonal Antibody Production

Publisher Summary

I INTRODUCTION

II HUMORAL ANTIBODY RESPONSE

III ROUTES OF INJECTION

IV ADJUVANTS

Chapter 21: Toxicity and Safety Testing

Publisher Summary

I INTRODUCTION

II LOCAL TOLERANCE TESTING

III DEVELOPMENTAL TOXICITY TESTING

IV TOXICOKINETICS

V PYROGEN TESTING

VI INTRACUTANEOUS/IMPLANTATION TESTS

VII NEUROTOXICITY

VIII NEPHROTOXICITY

IX IMMUNOTOXICITY

Selected Drug Dosages and Clinical Reference Data

Index

AMERICAN COLLEGE OF LABORATORY ANIMAL MEDICINE SERIES

Steven H. Weisbroth, Ronald E. Flatt, and Alan L. Kraus, eds.:

The Biology of the Laboratory Rabbit, 1974

Joseph E. Wagner and Patrick J. Manning, eds.:

The Biology of the Guinea Pig, 1976

Edwin J. Andrews, Billy C. Ward, and Norman H. Altman, eds.:

Spontaneous Animal Models of Human Disease, Volume I, 1979; Volume II, 1979

Henry J. Baker, J. Russell Lindsey, and Steven H. Weisbroth, eds.:

The Laboratory Rat, Volume I: Biology and Diseases, 1979; Volume II: Research Applications, 1980

Henry L. Foster, J. David Small, and James G. Fox, eds.:

The Mouse in Biomedical Research, Volume I: History, Genetics, and Wild Mice, 1981; Volume II: Diseases, 1982; Volume III: Normative Biology, Immunology, and Husbandry, 1983; Volume IV: Experimental Biology and Oncology, 1982

James G. Fox, Bennett J. Cohen, and Franklin M. Loew, eds.:

Laboratory Animal Medicine, 1984

G. L. Van Hoosier, Jr., and Charles W. McPherson, eds.:

Laboratory Hamsters, 1987

Patrick J. Manning, Daniel H. Ringler, and Christian E. Newcomer, eds.:

The Biology of the Laboratory Rabbit, 2nd Edition, 1994

Copyright

Copyright © 1994, 1974 by ACADEMIC PRESS, INC.

All Rights Reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher.

Academic Press, Inc.

A Division of Harcourt Brace & Company

525 B Street, Suite 1900, San Diego, California 92101

United Kingdom Edition published by

Academic Press Limited

24–28 Oval Road, London NW1 7DX

Library of Congress Cataloging-in-Publication Data

The Biology of the laboratory rabbit / edited by Patrick J. Manning, Daniel H. Ringler, Christian E. Newcomer, -- 2nd ed.

p. cm. -- (American College of Laboratory Animal Medicine series)

Includes bibliographical references and index.

ISBN 0-12-469235-4

1. Rabbits--Diseases. 2. Rabbits as laboratory animals. 3. Rabbits. I. Manning, Patrick J. II. Ringler, Daniel H. III. Newcomer, Christian E. IV. Series.

SF966¨5.B56 1994

636′.9322--dc20 93-39577

CIP

PRINTED IN THE UNITED STATES OF AMERICA

94 95 96 97 98 99 QW 9 8 7 6 5 4 3 2 1

List of Contributors

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

JOHN A. ANDERSON,     (449), Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105

VALERIE K. BERGDALL,     (335), Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109

W. SHELDON BIVIN,     (71), Division of Laboratory Animal Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803

NATHAN R. BREWER,     (47, 63), Animal Resources Center, University of Chicago, Chicago, Illinois 60637

J. ROGER BRODERSON,     (355), Boyd Graduate Studies Research Center, University of Georgia, Athens, Georgia 30602

PETER R. CHEEKE,     (321), Department of Animal Sciences, Oregon State University, Corvallis, Oregon 97331

THOMAS B. CLARKSON,     (367), Department of Comparative Medicine, and the Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157

KELLY CORCORAN,     (409), Departments of Ophthalmology and Pathology, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599

LEON J. CRUISE,     (47, 63), Veterinary Services, School of Medicine, Howard University, Washington, D.C. 20059

DAVID DELONG,     (131), Division of Comparative Medicine, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455

RONALD F. DIGIACOMO,     (171), Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington 98195

ROBERT C. DYSKO,     (335), Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109

RICHARD E. FISH,     (111), Office of Laboratory Animal Medicine, University of Missouri, Columbia, Missouri 65212

JAMES G. FOX,     (381), Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

RICHARD R. FOX,     (1, 293), The Jackson Laboratory, Bar Harbor, Maine 04609

LAURETTA W. GERRITY,     (205), Division of Comparative Medicine, The University of Texas Southwest Medical Center, Dallas, Texas 75235

CYNTHIA S. GILLETT,     (467), Division of Comparative Medicine, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455

FRITZ P. GLUCKSTEIN,     (355), National Library of Medicine, Bethesda, Maryland 20892

JUDITH W. HENCK,     (449), Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105

GARY L. HOFING,     (231), Department of Laboratory Animal Resources, Warner Lambert/Parke-Davis, Ann Arbor, Michigan 48105

JEANNE M. JAYO,     (367), Department of Comparative Medicine, and the Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157

ALAN L. KRAUS,     (231), Division of Laboratory Animal Medicine, University of Rochester Medical Center, Rochester, New York 14627

J. RUSSELL LINDSEY,     (293), Department of Comparative Medicine, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama 35294

NEIL S. LIPMAN,     (381), Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

PATRICK J. MANNING,     (131), Division of Comparative Medicine, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455

C. JOHN MARÉ,     (171), Department of Veterinary Science, University of Arizona, Tucson, Arizona 85721

RONALD M. MCLAUGHLIN,     (111), Office of Laboratory Animal Medicine, University of Missouri, Columbia, Missouri 65212

CHRISTIAN E. NEWCOMER,     (381), Division of Laboratory Animal Medicine, Tufts–New England Medical Center, Boston, Massachusetts 02111

STEVEN P. PAKES,     (205), Division of Comparative Medicine, The University of Texas Southwest Medical Center, Dallas, Texas 75235

NEPHI M. PATTON,     (27), Laboratory Animal Resources Center, Oregon State University, Corvallis, Oregon 97331

ROBERT L. PEIFFER, JR.,     (409), Departments of Ophthalmology and Pathology, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599

LAURIE POHM-THORSEN,     (409), Departments of Ophthalmology and Pathology, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599

DAWN C. SCHWENKE,     (367), Department of Pathology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157

HAROLD F. STILLS, JR.,     (435), Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210

STEVEN H. WEISBROTH,     (259), Anmed/Biosafe Incorporated, Rockville, Maryland 20855

SALLY K. WIXSON,     (87), Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822

Preface

Since its founding in 1957 as a veterinary specialty, the American College of Laboratory Animal Medicine (ACLAM) has advocated and sponsored programs of continuing education for its diplomates and has kept the broader scientific community informed of the advances in laboratory animal science and medicine. An outstanding achievement of this program has been the publication of a series of texts on laboratory animals through the collaborative efforts of the College, scientists in other disciplines, and Academic Press. This series includes books on the rabbit, guinea pig, rat, mouse, hamster, and spontaneous animal models of human diseases. It was launched in 1974 with the publication of the first edition of The Biology of the Laboratory Rabbit. After twenty years, the publication of this second edition attests to its popularity within the scientific community as well as to the need to update an expanding database on the rabbit as a major species in laboratory investigation. The principal aim of this text is to provide a comprehensive and authoritative source of scientifically based information on a major species of laboratory animal. We have been fortunate in enlisting the contributions of thirty-six experts as authors. Although the subjects covered are likely to be of greatest interest to veterinarians and veterinary students, the editors and authors have strived to cover the material in a manner that will stimulate interest and be of practical value to a broader audience of researchers, technicians, life sciences students, and colony managers. The text continues to emphasize the normal biology as well as diseases of the European (domestic) rabbit, Orytolagus cuniculus, especially the New Zealand White breed, with occasional reference to other rabbit species (Sylvilagus sp.) and hares (Lepus sp.) as appropriate. New topics have been added to this second edition in response to changing trends in biomedical research and product testing as well as to suggestions from readers. They include chapters on anesthesia and analgesia, models in infectious disease research, models in ophthalmology and vision research, polyclonal antibody production, toxicity and safety testing, and an appendix on drug dosages and clinical reference data.

We are indebted to the authors for their expertise and selfless generosity in lending their talent to this effort, to the reviewers whose constructive comments were especially valuable in enhancing the quality and continuity of the text, and to ACLAM for an unflagging commitment to an exemplary program of continuing education. All royalties from this text are paid to ACLAM for use in continuing education programs in laboratory animal science and medicine. We also acknowledge the generous support of our respective institutions in providing the resources and environment necessary to pursue scholarly activities and the staff of Academic Press for bringing this volume to fruition.

PATRICK J. MANNING, DANIEL H. RINGLER and CHRISTIAN E. NEWCOMER

List of Reviewers for Chapters in This Volume

Norman H. Altman,     School of Medicine, University of Miami, Miami, FL

J. Roger Broderson,     University of Georgia, Athens, GA

Peggy J. Danneman,     University of Michigan, Ann Arbor, MI

Thomas M. Donnelly,     Rockefeller University, New York, NY

Jitender P. Dubey,     United States Department of Agriculture, Beltsville, MD

Pamela H. Eisele,     University of California, Davis, CA

Mary A. Ellenberger,     Tufts-New England Medical Center, Boston, MA

Craig S. Frisk,     Mayo Clinic, Rochester, MN

Michael J. Huerkamp,     Emory University, Atlanta, GA

Matthew J. Kluger,     University of Michigan, Ann Arbor, MI

William P. Porter,     Marion Merrell Dow Inc., Cincinnati, OH

George G. Pucak,     Hazelton Research Products Inc., Denver, PA

Howard G. Rush,     University of Michigan, Ann Arbor, MI

James L. Schardine,     International Research and Development Corp., Mattawan, MI

Stephen P. Schiffer,     Georgetown University Medical Center, Washington, D.C.

Damon C. Shelton,     St. Louis, MO

John D. Strandberg,     The Johns Hopkins University, Baltimore, MD

Joseph E. Wagner,     University of Missouri, Columbia, MO

Steven H. Weisbroth,     Anmed/Biosafe Inc., Rockville, MD

Robert B. Wilson,     Washington State University, Pullman, WA

Peter T. Zacharia,     New England Medical Center, Boston, MA

Donald B. Zilversmit,     Cornell University, Ithaca, NY

CHAPTER 1

Taxonomy and Genetics*

Richard R. Fox

Publisher Summary

Laboratory rabbits, descendents of the European wild rabbit, Oryctolagus cuniculus, along with other rabbits, hares, and pikas, are classified as the members of the order Rodentia or rodents. However, instead of the four incisor or chisel teeth characteristic of rodents, rabbits have six. The additional pair is reduced in size and placed directly behind the large pair in the upper jaw. These little teeth are rounded and lack a cutting edge. The order Lagomorpha comprises two major families, the Ochotonidae and Leporidae, with many genera and species native to all parts of the world. The pikas, sometimes called rock rabbits or mouse hares, are small, tailless members with short, broad, rounded ears, chunky bodies, and short legs. The front pair of legs is a little shorter than the rear pair. This chapter discusses the genetic features of rabbits. Rabbits could produce hemolysins and agglutinins against red blood cells of other rabbits. On the basis of this work, rabbits are classified into four blood types. Rabbits may be inbred by a number of different breeding systems; the simplest is the brother–sister inbreeding. In this system, it is possible to intersperse father–daughter or mother–son matings with no change in the theoretical rate of inbreeding provided that no one animal is used more than two generations and that these generations are consecutive. Animals may be inbred by half sib mating, although the rate of change is somewhat slower.

I. Taxonomy and Geographical Distribution

A. Taxonomy

B. Geographical Distribution

II. Origin and Domestication

A. Historical Considerations

B. Domestication

C. Breed Formation

III. Genetics

A. Size Inheritance

B. Embryological Variants

C. Growth and Morphology

D. Pathology

E. Immunology

F. Inbreeding

G. Research Stocks

H. Mutations

I. Linkage

J. Chromosomes: Numbers and Morphology

K. Techniques for Karyotyping

L. Transgenic Rabbits

IV. Inbred Strains

References

I TAXONOMY AND GEOGRAPHICAL DISTRIBUTION

The European rabbit (Oryctolagus cuniculus) occurs on the European continent in three forms: wild, feral, and domestic. In North America, however, only the domestic and the feral forms exist. The wild or ancestral type probably evolved in the Iberian Peninsula and spread to other regions of the Mediterranean. The familiar domestic form is typified by a great variety of breeds and strains which are used for meat as well as fancy and laboratory animal production. The feral rabbit is a reversion from the domestic to the wild type, and examples may be found on the Farallon Islands off the coast of San Francisco, the San Juan Islands in the Juan de Fuca Straits in Washington, the Channel Islands off Santa Barbara, California, and Isla del Flores near Montevideo, Uruguay. The only population of wild Oryctolagus in the Americas has spread from the island of Tierra del Fuego, Chile, northward into the mainland several hundred miles north of Santiago.

A Taxonomy

Laboratory rabbits, descendents of the European wild rabbit, Oryctolagus cuniculus, along with other rabbits, hares, and pikas, were originally classified as members of the order Rodentia, or rodents. However, instead of the four incisor or chisel teeth characteristic of rodents, rabbits have six. The additional pair is reduced in size and placed directly behind the large pair in the upper jaw. These little teeth are rounded and lack a cutting edge. They are only moderately useful and cannot be seen without opening the mouth and looking in back of the large upper incisor teeth. However, they constitute the scientific basis for placing the animals in a separate order, the Lagomorpha (58). The zoological position of the lagomorphs (58, 267) can best be seen in outline form (Table I).

TABLE I

Taxonomic Outline of the Genus Oryctolagusa

aReferences 58, 198a, 224, 267.

B Geographical Distribution

The order Lagomorpha comprises two major families, the Ochotonidae (pikas) and Leporidae (rabbits and hares), with many genera and species native to all parts of the world (6, 7, 15, 130, 136, 158, 209, 216, 224, 267). The pikas, sometimes called rock rabbits or mouse hares, are small, tailless members with short, broad, rounded ears, chunky bodies, and short legs. The front pair of legs is but little shorter than the rear pair. This is in contrast to the usually larger rabbits and hares, which have long ears and relatively long hind limbs. Major genera of the Leporidae include Lepus (hares), Oryctolagus (true rabbits), and Sylvilagus (cottontail rabbits). The Idaho pygmy rabbit, Brachylagus, is the smallest rabbit, not only in the Americas but in the world. The Mexican pygmy rabbit, Romerolagus, is slightly larger and actually more like a pika than a rabbit. Examples of some of the current major species in each genus, including natural distributions, may be seen in Table II.

TABLE II

GEOGRAPHICAL DISTRIBUTION OF MEMBERS OF THE ORDER LAGOMORPHAa

aReferences 6, 7, 15, 130, 136, 158, 209, 216, 224; additional species are listed in Ref. 224, but their status is unknown.

bPRC, Peoples Republic of China.

Members of the order Lagomorpha have found their way by natural means to most parts of the world except Madagascar, New Zealand, and Australia. Rabbits were also distributed to various portions of the world by early sailing vessels whose masters wished to have a readily available source of meat at various points on their voyages. In addition, the European rabbit, Oryctolagus cuniculus, was transported to Australia and New Zealand, and the European hare, Lepus europaeus, was established at several points in North America and is now abundant in the northwestern portion of America.

II ORIGIN AND DOMESTICATION

A Historical Considerations

In Vom Wildtier zum Haustier (192), Nachtsheim has given the most comprehensive review of the early history of the domestication of the rabbit. Our knowledge of the natural spread of the wild rabbit in prehistoric times is somewhat limited as very little has been preserved from early periods. Rabbit bones are small, light, and fragile and are often overlooked in archaeological diggings. Also, predators often leave little for history. From records from early Tertiary strata it appears that at this time the Leporidae were lacking in Europe but were present in America and Asia. Hares and rabbits, or their predecessors, probably migrated from Asia to Europe during the early Tertiary. From the end of the Pliocene to the beginning of the Ice Age, they apparently became widely distributed in Europe. Remains have been found in France, Belgium, and Germany. During the period of glaciation the rabbit was pushed southward to southwestern Europe and the western portions of North Africa.

The Phoenicians were the discoverers of the rabbit in historical times. In their journeys to the coast of Africa and the Iberian Peninsula in 1100 B.C., they observed numerous creatures similar to their cliff terriers, the description of which resembles our rabbit very closely. Because of the numbers of these terrierlike creatures they named the coast or island as the land of this creature and called it i-shephan-im. Later, this name for the Iberian Peninsula was converted to the Latin form by the Romans, Hispania. The Hebrew word Saphan or Shaphan, for cliff terrier (Hyrax syriacus), was later incorrectly translated by Luther in his Bible translation to the word rabbit. Early accounts of the rabbit in the Greek and Roman literature, including the writings of Xenophon and Aristotle, speak primarily of the hare, up through the fourth century B.C. In the second century B.C. the Greek historian, Polybios, observed rabbits among other wild animals coming from Corsica and called them the most graceful cuniculi. Cuniculi are what the Romans called subterranean passages and mines such as they dug during sieges of city-states. There is some question as to whether the rabbits were named after the mines or the mines after the rabbit holes.

In the first century B.C., the Roman writer Varro called Spain the homeland of the rabbit and recommended keeping the rabbits in leporaria, or walled rabbit gardens. Varro described the leporaria as being surrounded by high plastered walls designed to keep out predators and having trees and bushes for shade and for protection from predatory birds. Some consider this the start of domestication, but the rabbits were still very wild. However, they did breed in these enclosed areas in contrast to the hare and were caught easily and killed for meat. Pliny also designated Spain as the original home of the rabbit and stated that in the Balearic Islands during the first century A.D. fetuses taken from pregnant does and newborn young, when uneviscerated, were considered delicacies. As rabbit meat at this time was highly regarded, animals were distributed to various islands during the first few centuries A.D. Strabo reported that a single pair was placed on one of the Balearic Islands, probably Mallorca, at the time of Christ’s birth. By Pliny’s time, the rabbit was observed on both Mallorca and Minorca but had not yet spread to the small island group of Pityusen. In many areas, however, the rabbit became a menace by multiplying rapidly and destroying the vegetation. Finally, the inhabitants of the Balearic Islands asked Emperor Augustus for aid in controlling these field-destroying gnawers. Muzzled ferrets were used to drive the rabbits out of their burrows so they could be hunted. Under Emperor Hadrian a rabbit was represented on gold and silver coins of the empire as a symbol of Spain, indicating how much the rabbit was considered characteristic of the Iberian Peninsula.

Rabbits were placed on islands by masters of sailing vessels during the Middle Ages to provide a source of food along various seafaring routes. In these favorable environments, and lacking their usual predators, the rabbits greatly increased in numbers and often did more harm than good, and the experiences of the inhabitants of the Balearic Isles in antiquity were repeated over and over again. A prime example used by Darwin was the small island of Porto Santo where rabbits were introduced in 1418 and in a short period of time took over the island; they also evolved into a new species which would no longer interbreed with other rabbits. In 1859, a single pair of Oryctolagus was released in Victoria, Australia, by an English colonist. By 1890 the rabbit population was estimated at 20,000,000 and had become a frightful plague. All imaginable means, both public and private, were used to eliminate this species. In one decade the government of New South Wales spent about 4 million dollars trying unsuccessfully to eradicate the rabbit from that portion of Australia. The rabbit succeeded best following man-made distributions of the various species in those climates resembling their original home. Thus, in Australia and New Zealand, Oryctolagus cuniculus populated very quickly and became a serious pest. Fortunately for North America, climatic conditions and native predatory animals have been more than a match for the introduced rabbit, Oryctolagus, which has nowhere established itself in the wild state (25).

B Domestication

The actual process of domestication may have started when the Romans learned that the rabbit, in contrast to the hare, propagated itself very easily within the leporaria, or rabbit gardens. Thus, the original simple holding pen used for the hares now became a breeding pen for the propagation of rabbits. The rabbit gardens had many uses, depending on the size. In the sixteenth century, Queen Elizabeth of England had a leporarium and King Henry IV of France had a large rabbit enclosure which he used as a hunting area. The hunting of rabbits for sport was also taken up by women of this time, in part because it was an easy and safe hunting sport. Rabbit gardens persisted in Europe for many centuries after the fall of the Roman Empire, with frequent escapes aiding in the spread of the species in the wild.

True domestication, with breeding in captivity, probably started in monasteries during the sixteenth century. Under domestication, the coat has varied greatly in color and to a minor extent in length and texture. By 1700, seven different mutant types were known, namely, nonagouti, brown, albino, dilute, yellow, silver, and Dutch spotting (263). It seems surprising that with this knowledge the formulation of Mendel’s laws had to wait until his experiments with peas. Nachtsheim (192) also refers to changes in brain weights, spinal cord, various sense organs, the eyes, and the ability to hear, associated with domestication. The ear length has varied considerably from approximately 7 cm long in wild rabbits to varied lengths in the domesticated races ranging up to the grotesque lop-eared rabbit having an ear length of approximately 25 cm. There has been a diminution in the number of taste buds in the tongue. All in all, there are many changes that have occurred during domestication since the critical senses essential for survival are not needed under the confinement that we have with the cage system employed today. These differences are also reflected in muscles, heart size, capacity of the stomach, and bone weight; body weight has varied considerably from an approximate 2 kg for wild rabbits to the hermelin dwarf of around 1 kg on the one hand and to the German giant of 8 kg or more on the other.

Sirks (268) quoted from a letter written by Leeuwenhoek in 1683 showing that he was well aware of the dominance of the wild-type coat over albinism, nonagouti, etc. However, little use was made of this until after the rediscovery of Mendel’s laws. In the period 1700–1850, two new mutations for coat color and the factor causing angora hair became known (181). After 1850, and especially during the early twentieth century after Mendel’s principles of recombination became known, the differentiation of new races or strains of rabbits varying in coat color, body size, and hair morphology increased rapidly. Currently there are over 50 well-established breeds of domestic rabbits, but there is still a potential for many additional combinations of genes to be utilized, depending on the needs and desires of the rabbit fancier or the investigator using rabbits in research.

C Breed Formation

The European rabbit, Oryctolagus cuniculus, has, however, been the only species that has yielded to domestication. All of the laboratory rabbits and all of the rabbits bred by fanciers for coat color or hair characteristics are descended from it. The early breeders took advantage of the large variation in body size, coat colors, and coat characteristics to establish, by selection, a variety of new breeds valuable for both meat and fur, and some especially for pets. A variety of coat colors and body sizes are evident in breeds of rabbits in common use today.

Serious attempts to analyze the genetics of the domestic rabbit did not start until after the rediscovery of Mendelism and is discussed later in Section III. It is possible to describe many of the differences in coat color and hair characteristics represented by the various breeds in the light of present knowledge of genetics. Table III lists and illustrates this by giving the recognized American breeds of rabbits as found in the 1966–1970 Standards of Perfection of the American Rabbit Breeders Association and the known genotype of these breeds. Details on the gene symbols involved are in Table V.

TABLE III

GENOTYPES OF AMERICAN BREEDS OF RABBITSa

aReferences 28, 199, 233, 263, 272.

bOnly the mutated genes are indicated in list. Genotypes indicated are the most common ones.

TABLE V

Recognized Gene Mutations in the Rabbit (Oryctolagus cuniculus)

Note: A mutation for distal foreleg curvature was published by Pearce (211) posthumously. The condition is a bowing deformity of the radius and ulna resulting in a seallike or flipper position of the forepaws. I propose the symbol fc for this autosomal recessive gene for foreleg curvature reported by Dr. Pearce.

aThe provisional symbol Hc is proposed for the hyperlipidemic rabbit reported by Watanabe.

An extensive listing of the British, Continental, and American breeds by Robinson in 1958 (233) shows that many of the genotypes in the American breeds are duplicates of those found in the other countries. Moreover, many additional combinations are seen elsewhere. To establish breeds of rabbits, one starts basically with a wild-type rabbit (i.e., normal white-bellied agouti) and by substitutions of mutant alleles at specific loci obtains a variety of color types and patterns which can be selected for by the animal breeder. Substitution at the A locus of at for normal agouti A gives a black and tan rabbit with a white belly, black nonagouti on the dorsal surface, whitish eye circles, and tan on the foot pads, under the tail, and at the edge of the white belly. Replacement by nonagouti a results in a solid black animal. At the B locus substitution by b replaces the black eumelanin with brown. Agouti brown rabbits are cinnamon colored, whereas nonagouti brown rabbits are solid brown colored as in the case of the Havana rabbit.

Mutations at the C locus reduce pigmentation. The cch3 dark chinchilla, will reduce only yellow pigment to white. The cch2mutation will, in addition, reduce black to a sepia brown, and the cch1, or light chinchilla, will further reduce pigment to pale brown. Next in the series, the Himalayan gene, cH, restricts all pigment to the extremities, as in the case of the Californian or Himalayan rabbits. An interesting phenomenon associated with the Himalayan allele is its temperature sensitivity. If a portion of the hair is shaved and the rabbit placed in an environment of 25°C or more, the new hair growth will resemble the old. If, however, the temperature is, say, 10°C, a two-step process, first enzyme production, then oxidation, will result in the new hair being pigmented on the tips. Pigment in the eye is also reduced in all mutant alleles at this locus. The c, or albino allele, eliminates all pigment.

The dilute locus, when homozygous dd, results in a pigment change from either black to a blue-gray, brown to lilac, or yellow to cream, depending on the other genes present. At the E locus dominant black, ED, tends to reduce or eliminate the agouti band of phaeomelanin and darken the belly. An EDEDindividual is indistinguishable from a nonagouti black (aa), EDe is very similar to EDED in coloration, and EDE rabbits are agouti-black. In contrast ee animals are a fawn color. Another allele, eJ, results in Japanese brindling as is seen in the Harlequin rabbit. ES has also been reported as a weaker edition of ED (233).

The Vienna white allele, v, modifies the wild-type phenotype by removing all pigment from the hair and from the anterior surface of the iris (239), resulting in a blue-eyed white rabbit. It was thought at one time that the presence of the gene in homozygous condition was necessary for epileptic seizures; however, just as many Vv rabbits develop epilepsy-like seizures as do vv rabbits.

In addition to these six sets of alleles for color, many other factors modify the color, including the width of the agouti band (28), Dutch (222) and English spotting (20), and silvering (174). Further variations in phenotype may be seen by modifying the hair morphology. Loci include rex (38, 164), angora (17), wuzzy (242), satin (37), wirehair (242), waved (217), furless (30), and naked (144). Innumerable combinations are possible, depending on the fancy of the animal breeder (233, 263).

III GENETICS

Prior to 1900, only minimal work had been done on the genetics of the rabbit. The dominance of wild type over nonagouti and other genes was evident as early as 1683 (268); however, this was believed to be associated with paternal inheritance since the crosses were made only with tame white females and wild colored males. A few color genes and hair morphology genes were known (192), but it was not until after the rediscovery, about 1900, of the paper by Mendel that he had presented before the Natural History Society of Brunn in 1865 that the science of genetics was actually applied to the rabbit. Initially, certain genes were recombined into the progenitors of some of the current breeds, selection being based on colors and on hair type, depending on the fancy of the animal breeder. Study of the inheritance of coat color has been of interest to many people because of the obvious variations that may be seen. To list all the references here would be impossible; the literature on the inheritance of coat color in the rabbit can best be seen in the review articles of Castle (28, 32), Sawin (242), Robinson (233), and Searle (263).

A Size Inheritance

At about the beginning of the twentieth century, studies involving body size and body weight (size being different from weight) were attempted. MacDowell (165, 166) made a series of linear measurements on a large and a small strain. He then crossed the strains and obtained F1, F2, and backcrosses to the larger parent. He observed that bone growth was less subject to environmental variations than soft tissue weights and presented prima facie evidence for a polygenic basis of size inheritance. Castle (19), in an appendix to the 1914 paper by MacDowell (165), showed that size inheritance was determined by general size genes. Wright (289), following a more sophisticated statistical analysis of the data, contended that, although Castle was correct that general factors affecting size were present, other lesser influences were also at work. He did not differentiate whether these were genetic or environmental.

Later, Castle (22), using bone measurements, body weight, and ear length, tackled this problem again with animals of Polish, Himalayan, and Flemish races of as pure stock as possible. He made standard matings for genetic analysis and was able to support his earlier findings and point out that genetic influence was primarily general in nature and not correlated with albinism, dilute, yellow, or the angora loci. Also, sex appeared to have little effect on the measurements. For the data he was able to show that there were at least 10 to 12 pairs of chromosomes in the rabbit. This, we will see later, was an underestimate. Wright (292), using a more refined technique, reanalyzed both MacDowell’s 1914 data and the 1922 data of Castle. Wright was in general agreement with the earlier reports and concluded that genetic factors were prominent in the general size influences, but were also present to a lesser extent in the regional and specific size factors. The data, when reanalyzed by Tanner and Burt (276) using factor analysis, resulted in conclusions similar to those of Wright (292).

Concurrently, Pease (214) and Punnett and Bailey (221), employing crosses between large and small stocks of rabbits, reported two studies using body weight and ear length as the major criteria of size. Pease used the turning point in the growth curves as an estimate of the age of puberty and as the criterion for mature body weight. He reported that the age at maturity was influenced by genetic factors but was not affected by sex, litter size, or season, either season of birth or season of maturity. Castle (27) criticized Pease’s report based in part on the variability in weight of the stocks used and in part on the fact that with 14-day intervals between weighings it would be difficult to determine accurately the point of maturity. Castle provided data to prove the point.

B Embryological Variants

Robb (228, 229) and Castle (29) investigated the nature of the growth curves of body and organ weights in a large strain and in a small strain of rabbits. Robb pointed out that, although differences in size and in organ weights between breeds of rabbits did occur, the relationship of organ size to total body mass was a constant. However, Castle in 1932 refuted this conclusion and maintained that growth rates are not identical in the large and small races at any time, either subsequent to birth or prior to it. This was particularly evident in the papers of Castle and Gregory (34, 35) and Gregory and Castle (126) in which they showed that the size genes of the rabbit act by altering the rate of development. Eggs of a genetically large-bodied race of rabbits underwent cleavage more rapidly than the eggs of a small-bodied race, so that a larger embryonic disk was formed and larger bodied young were born. These continued to grow at a more rapid rate until maturity. The parental influence on size was exerted through sperm and egg alike, but there was some maternal influence which was greater than the paternal influence in affecting the ultimate body size. Castle believed that this might act through the cytoplasm; however, another very realistic possibility is the factor of how much the doe is actually lactating and hence giving the young a greater (or lesser) initial start in life. Castle also summarized in 1932 (29),

The important general conclusion to which all of our studies on size inheritance in rabbits point is that differences in adult body size are determined primarily by different growth potentials inherent in the gametes (eggs and sperm) of each race. The effects of these differences in growth potential are manifested first in differences in rate of segmentation of the fertilized egg, then in differences in the size of the blastocyst and of the embryonic area which develops upon it, later in differences in size of the young at birth and in (percentage) growth rate subsequent to birth, and finally in a more prompt and complete arrest of growth at puberty.

A succinct review of size inheritance has been given by Castle (33).

C Growth and Morphology

Sawin, who started a scientific career studying the hereditary variations of the chinchilla rabbit involving an allele for full color, the three chinchilla alleles, the Himalayan allele, and the albino allele of the C locus (238, 239), made a major contribution to the study and understanding of the process of growth. He used the skeleton of the rabbit as a grid on which to record changes in growth associated with specific gene or genome differences. Originating with a paper on homeotic variations in the axial skeleton (240), a series of about 40 papers has been pub-. lished by Sawin and associates on morphogenetic studies of the rabbit. They deal with qualitative and quantitative variations of skeleton and soft tissues in several strains of rabbits differing in size and conformation and with respect to the effect of three specific dwarf genes, including two chondrodystrophies. For a complete bibliography, see Sawin and Gow (251).

Tendencies for changes in rib and presacral vertebrae number (241), in numbers of crural insertions of the diaphragm (255), and in patterns of incidence of primary and secondary centers of ossification known to be associated more often with some of the strains than with others have demonstrated the genetic control of the localized gradients of vertebral growth (66, 245). However, none of the variations studied have been attributed to single specific genes. Studies of strain differences in gradient growth pattern and in F1 and backcross generations of reciprocal crosses have revealed the nature of growth interaction in different genomes (247) and the mechanism by which such epigenetic variations arise. They show that the gradients can be analyzed by standard genetic procedures and also demonstrate the importance of the ontogenetic approach in direction and in time. The importance of these findings has been confirmed by studies of the Da chondrodystrophy gene (251, 257). In studies focusing on specific types of mating (252) and on additional epigenetic variants as reference points, the interaction of additional genetic growth influences becomes manifest (254, 256) and the relationships of gene, genome, gradient, and specific functions more clearly portrayed. A further analysis of the sex and strain correlations between strains III and X, reported in early communications in the morphogenetic series by Sawin and Latimer, has revealed gradient pattern and differences in correlation associated with the functions of locomotion and posture, suggesting a possible newer approach to the study of growth (249). Zarrow, Ross, and Denenberg, in collaboration with Sawin, summarize the effects of hereditary factors on maternal behavior in the rabbit and its endocrine basis (235, 296, 297).

D Pathology

Workers at the Rockefeller Institute (now Rockefeller University) have also contributed greatly to the knowledge of the rabbit, in part from the genetic standpoint but predominantly by studying the pathology of those mutations and the diseases, including neoplasia, of the rabbit bearing on problems of human constitutional disease. Major contributions to the genetics of the rabbit from the Rockefeller Institute include the works of Greene, Pearce, Brown, and co-workers. The contributions include hereditary variations of the skull (117, 123), the modifying influence of breed of rabbit on such conditions as toxemia of pregnancy (120), rabbit pox (119), and uterine adenocarcinoma (122), and the description of specific mutations of the rabbit: pituitary dwarfism (121, 124), brachydactylia (118, 125), achondroplasia (212), and osteopetrosis (213).

Contributions by Nachtsheim to the genetics of the rabbit have also been extremely important, particularly in relation to the pathology of many of the mutant genes. Genetic contributions include the inheritance of shaking palsy or tremor (183), hypoplasia pelvis (184), supernumerary incisors (185), audiogenic seizures (186), rex 2 and rex 3 (38), absent incisors (188), lethal muscle contracture (189), marbled eye (190), and hydrops fetalis (191). Nachtsheim also reported a dwarf gene in 1937 (187) which, based on a series of test matings and gross morphology, appears to be the same as Greene’s Dw gene and the dwarf reported by Kröning (151). The Pelger anomaly, while not originally reported by Nachtsheim, has been extensively studied by him (193) and co-workers (132). Extensive contributions by Nachtsheim to the pathology of inherited diseases of the rabbit may be seen in two reviews, one in 1937 (186) and a more recent monograph in 1958 (195). Three other excellent review papers covering the influence of genes in the pathology of the rabbit are those of Sawin (242), Robinson (233), and Fox (89).

E Immunology

Another area of study in the rabbit which has been of importance in early genetic analysis has been the field of immunology, where it was observed by Hulot and Raymond in 1901 that rabbits could produce hemolysins and agglutinins against red blood cells of other rabbits (51). Genetic analysis was initiated by Cameron and Snyder (16), Castle and Keeler (36), and Keeler and Castle (142, 143). On the basis of this work rabbits were classified into four blood types. A number of different blood group systems have been studied since then, and these are best reviewed in the papers of Cohen (48, 49, 51) and Cohen and Tissot (53a). In 1958 Cohen clarified some of the confusion arising from the varied nomenclature used by different authors and listed the symbols that had been reported for the same blood groups (50). In 1965 Cohen and Tissot (53) reported two new isoantibodies in the rabbit. Added to these early studies on blood groups are other studies starting with Oudin (202, 203) and involving a series of reports, the genetics of which have come in good part from the laboratories of Mage, Dray, Oudin, Dubiski, Stormont, and co-workers, ranging from γ-globulins (55, 56, 79, 80, 115, 131, 150, 168, 173, 204–206>) to hemebinding proteins (127), low-density lipoproteins (1–3>), red cell esterases (128, 259), α2-macroglobulin (13, 148), and α1-aryl esterases (4). Some of the loci (e.g., the low-density lipoproteins) are still not clearly defined as to whether they constitute two closely linked loci or a single composite locus (3).

F Inbreeding

The need for uniform research stocks was recognized early. It was Castle (22), in fact, who showed in 1922 the importance of obtaining races of rabbits as uniformly true breeding as possible to study the inheritance of differences in size. Inbreeding may be defined as the process of mating together individuals which are more closely related than the average of the particular population. Since the early 1930s, rabbits have been inbred to varying degrees. The process of inbreeding rabbits is really no different from that of inbreeding mice or any other species.

Rabbits may be inbred by a number of different breeding systems; the simplest is the brother–sister inbreeding (Fig. 1A) where the change in the theoretical level of inbreeding can be predicted from a table by Wright (291). In this system it is possible to intersperse father–daughter or mother–son matings (Fig. 1B) with no change in the theoretical rate of inbreeding provided that no one animal is used more than two generations and that these generations are consecutive. Animals may be inbred by half sib mating (Fig. 1C), although the rate of change is somewhat slower. The process of linebreeding (Fig. 1D) is commonly practiced in a commercial rabbit breeding program, particularly where a male is of some specific type, either coat color or conformation that is of interest to the breeder. Also, in many laboratories, especially where the maintenance of specific mutant genes in a particular stock is essential, it is sometimes necessary to deviate from a regular pattern of inbreeding. Although this does not constitute any real problem, it does slow down the process of inbreeding and makes it more difficult to estimate the theoretical level of inbreeding achieved.

Fig. 1 Schematic diagram of regular systems of breeding where squares denote males and circles denote females. (A) Full sib brother by sister mating; (B) full sib with parent offspring interspersed; (C) half sib mating scheme where females are full sibs; and (D) type of linebreeding where selected males are used more than one generation. The exact scheme may be varied greatly depending on the situation.

Level of inbreeding is usually estimated by the coefficient of inbreeding, a value that ranges from 0 to 1. This coefficient defines that proportion of loci for which an original or base population was heterozygous but which, through the various means of inbreeding, theoretically has become homozygous. In a random breeding or panmictic base population, one might make the estimate that 50% of the loci were homozygous by chance and the other 50% were heterozygous. Hence, the process of inbreeding from the population would then tell what proportion of the remaining 50% of the loci became homozygous through the process of inbreeding.

There are three major ways of determining the theoretical level of inbreeding. First, if the breeding program is a regular pattern, such as either full sib mating, half sib mating, or double first cousin mating, the theoretical coefficient of inbreeding has been calculated by Wright (290, 291), and the numerical values can be seen in Table IV. In a half sib mating program, where the females are half sibs, the theoretical level of inbreeding may be taken from Table IV. If, however, the females are full sibs this will increase the rate of homozygosity slightly. Conversely, if a single first cousin mating system is used, the coefficient of inbreeding will be slightly less than half the value given for double first cousins. If, however, the pattern is irregular, then one can use either Wright’s method of path coefficients (293) or the method of Cruden based on the relationship of the parents (70). Both processes involve considerable computation, when a large number of generations is involved. However, Li and Roderick (163) have computerized the Cruden method. The program has the advantage that overlapping generations, which often occur in an irregular system of breeding, can be taken into account.

TABLE IV

COEFFICIENTS OF INBREEDING FOLLOWING A VARIETY OF REGULAR MATING SYSTEMS

aRepeated backcrosses to an inbred line will result in the same rate of increase in homozygosity, that is, the same coefficient of inbreeding.

bParent–offspring matings may be interspersed with no change in theoretical expectations as long as no individual used is more than two generations.

cMating of one male in each line with an indefinite number of half sisters which are also half sisters to one another. If females are full sibs the coefficient of inbreeding will go up slightly more rapidly (290).

G Research Stocks

With the development of a wide variety of rabbit breeds (Table III), marked differences occurred in body size and in specific genes for coat color, etc., based on the needs and desires of animal breeders and research workers. Since the early 1930s rabbits have been inbred to varying degrees as have mice. Initially, there was no formal listing of the stocks of rabbits that were available. Instead, individual investigators had their own stocks with their own names associated with them. In 1963, Jay (139) started a list of the stocks that were then under the direction of C. K. Chai, C. Cohen, M. Lurie, and P. B. Sawin. However, in this early listing little was done to characterize the different strains with respect to anything but the barest morphological variations. Subsequently a series of papers reporting data on some of the physiological variants in strains maintained at the Jackson Laboratory has been published (42, 43, 62, 76, 78, 79, 91–93>, 103–105>, 109–111>, 114, 134, 156, 157, 227, 247, 248, 260, 269, 281, 303). These reports cover such things as antibody production, serum allotypes, response to teratogens, blood pressures, biochemical variations, and skin grafting. A review article (89) presents the role that the rabbit has played in biomedical research.

H Mutations

During the process of inbreeding, segregation of many recessive genes has been observed. Because many of the mutant genes are covered in depth in other sections of this book, depending on their morphological grouping, I have listed here alphabetically all of the known genes of the rabbit, giving the gene symbols, names, and appropriate references (Table V). The first reference insofar as possible gives the original description of the gene and the data showing its Mendelian inheritance, and the second provides one of the more current articles on the particular mutation, enabling one to search the literature for additional references on the subject. As there has been some discrepancy in gene symbols for particular mutations, I have attempted to verify all the original references to ensure that, barring duplication, the symbolism is not only in keeping with the recommendations of Dunn, Gruneberg, and Snell (81) on mouse genetic nomenclature, but also is that gene designation given by the original authors.

In addition to the Mendelian characters mentioned in Table V, a series of other hereditary deviants has been reported which, for one reason or another, is not yet classed as due to single genes. In some cases the stocks were lost before sufficient matings could be made to prove the precise mode of inheritance. Sometimes the traits were polygenic. These hereditary deviants include anophthalmia, Nachtsheim (186); avitaminosis, L. Pearce (unpublished); brachygnathia, Nachtsheim (184); conjoined twins, Chai and Crary (45); cretinoid, L. Pearce (unpublished); droopy ear, Chai and Clark (44); lop ear, Castle and Reed (39); nasal horns and cranioschisis, Nachtsheim (195); oxycephaly, Greene (117); scoliosis, Sawin and Crary (244); thoracogastroschisis, Crary (59) and Sawin (242); motor neuron disease, Shields and Vandevelde (266); entropion, Fox et al. (88); splay leg, Joosten et al. (140); and serum-induced proliferation of peripheral blood lymphocytes, Yonish-Rouach et al. (295).

I Linkage

As the process of inbreeding progressed and new breeds were formed, based on hereditary differences in coat color and morphology, the question of linkage of some of the specific genes involved became important. Since the first discovered case of linkage in the rabbit was reported by Castle (24) to exist between the b locus and the c locus, many papers have been published covering 10 linkage groups, 11 identified chromosomes, and 69 known loci. Some variation in crossover frequencies has been observed associated with sex (26, 31). Two articles, one by Castle and Sawin (40) and the other by Robinson (232), review the early linkage studies. By the end of the 1970s the available information had doubled. This was through the efforts primarily of groups involving Cianfriglia (Cosenza, Italy), Echard (Toulouse, France), Mage (National Institutes of Health), Tissot and Cohen (Chicago), Usher (Newark, Delaware), and van Zutphen (Utrecht, The Netherlands). During the 1980s the combined efforts of Echard, van Zutphen, de Grouchy (Paris, France), Sandberg and Anderson (Uppsala, Sweden), and Martin-DeLeon (Newark, Delaware) also resulted in a doubling of the information. The culmination of these studies is presented in the fifth edition of Genetic Maps by Fox (90). In 1990 Komatsu and co-workers in Ibaraki, Japan, reported that the third component of complement (C3) is linked to a genetic deficiency of α–γ subunit of the eighth component of complement (C8D). C3 and C8D are separated by 24 cM, establishing a new linkage group (LG)X (145). Work by Xu and Hardison at the Pennsylvania State University (294) and Echard et al. at Toulouse (113, 133) enabled us to add a number of loci to the map and assign linkage group I (LG I) to chromosome 1. The current map (Fig. 2) includes 10 autosomal linkage groups, 11 identified chromosomes, and 5 X-linked loci, for a total of 69 loci.

Fig. 2 Established linkages of the rabbit showing number of crossover units between loci. Dashed lines also denote linkage. In linkage group I, for example, the dashed lines show that the linkage between the Hbb locus and the c locus is 8.7 units; however, it is not known on which side of c that Hbb is located. The current map includes 10 autosomal linkage groups, 11 identified chromosomes, and 5 X-linked loci, for a total of 69 loci.

In linkage groups I, IV, V, and VII, the linear order of some of the genes is uncertain (Fig. 2). We know, for example, that in linkage group IV the a locus and the w locus are linked by approximately 29.9 crossover units and that the a locus and the Dw locus are linked by approximately 14.7 units, but we do not known the linkage relationship of w to Dw. It has been suggested that the Dw gene is located between the a locus and the w locus, but there has been no concrete evidence to prove this point, as pointed out by Robinson (232). The same holds true with reference to the location of Hbb to c (LG I), Hg to a (LG IV), Hb to an and f to br (LG V), and sa to RLA-MLC (LG VII).

J Chromosomes: Numbers and Morphology

Following the original work in 1926 by Painter (207) showing that the diploid chromosome number in the rabbit was 44, a series of confirmatory reports was made (for a list, see Makino, 171). In 1956, Melander (176), using lung cells from 19-day-old rabbit embryos, showed clearly