Table Of ContentJean Louis Guénet · Fernando Benavides
Jean-Jacques Panthier · Xavier Montagutelli
Genetics of
the Mouse
Genetics of the Mouse
Jean Louis Guénet · Fernando Benavides
Jean-Jacques Panthier · Xavier Montagutelli
Genetics of the Mouse
1 3
Jean Louis Guénet Jean-Jacques Panthier
Institut Pasteur (Emeritus) Mouse Functional Genetics Unit
Paris Institut Pasteur
France Paris
France
Fernando Benavides
and
Division of Basic Science Research
Department of Molecular Carcinogenesis Ecole Nationale Vétérinaire d’Alfort
The University of Texas MD Anderson Maisons-Alfort
Cancer Center France
Smithville, TX
USA Xavier Montagutelli
Mouse Functional Genetics Unit
Institut Pasteur
Paris
France
ISBN 978-3-662-44286-9 ISBN 978-3-662-44287-6 (eBook)
DOI 10.1007/978-3-662-44287-6
Library of Congress Control Number: 2014945779
Springer Heidelberg New York Dordrecht London
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This book is dedicated to
the memory of
Professor François Jacob
(June 1920–April 2013)
Foreword
The science of experimental biology rests on the analysis of causative factors, fol-
lowed by synthesis. Commonly, the analytic step involves determining the con-
sequences of a known perturbation. Classical experimental biology rested on
perturbations of the environment, or on surgical operations such as transplantation.
When the science of genetics reached molecular resolution in the twentieth cen-
tury, mutational perturbation became prominent. In organisms for which sophisti-
cated genetic methods have been developed, it is feasible, either through positional
cloning of the mutated gene or through directed mutagenesis, to make connections
between changes in phenotype and specific molecular changes. The laboratory
mouse is the first experimental mammalian species allowing these sophisticated
methods. Thus, The Genetics of the Mouse by Guénet, Benavides, Montagutelli,
and Panthier is more than a genetics textbook. It is also a talisman, containing
instructions by which the experimental mammalian biologist can analyze a pro-
cess of interest at molecular resolution. It is a twenty-first-century version of the
twelfth-century tome on the crafts of the medieval guilds authored by Theophilus:
On Divers Arts.
The chapters delve deeply into the biology of the mouse. They range from
detailed presentations of the natural history of the species, its handling in the labo-
ratory, and its classical genetics, to contemporary issues including the epigenet-
ics of parental imprinting and X-chromosome inactivation. Further, they provide a
detailed discussion of the strategies for creating and cloning constitutive and con-
ditional mutant alleles. Finally, they present a platform from which the analysis of
complex quantitative traits is currently addressed. When the in-depth details of a
subject exceed reasonable limits in length, the authors provide footnotes to more
extensive treatments. As experienced geneticists, the authors appreciate the impor-
tance of phenotyping, not letting it get lost in the details of analyzing and manipu-
lating the genotype. At the core of their presentation is the importance of inbred
strains and isogenicity for the identification of single causative factors.
The ultimate goal of many mammalian experimental biologists is to develop
an understanding of issues in human biology. The authors recognize the circum-
stances in which a particular mouse model fails to present the phenotype expected
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viii Foreword
from the cognate condition in the human, and they outline ways in which mice can
be made chimeric for human tissues. Because any one model gives at best only a
first approximation to the human case, a diverse set of models may provide further
approximations. The methods presented can lead to the development of a homol-
ogous series of mouse models in any of their distinct inbred backgrounds, or in
their genetically homogeneous F1 hybrids, or in other mammalian genera that can
be inbred.
Seen broadly, The Genetics of the Mouse connects the past, present, and future
in the experimental biology of mammals.
William F. Dove
Streisinger Professor of Experimental Biology, Emeritus
University of Wisconsin
Madison
Preface
This book is intended for several different categories of potential readers. First,
are students who have completed their university studies in biology or medical
sciences and wish to undertake a PhD project making use of mice but who have
no experience with this model organism. Reading this book will enable them to
acquire, rapidly and in a relatively condensed form, a background that will be
helpful for the critical reading of primary scientific publications and for the opti-
mal design of their projects. Genetics instructors will also find useful examples
to illustrate undergraduate biology courses. Molecular and developmental biolo-
gists whose research program is focused on a gene or gene family will also be
interested and will realize that the mouse is an exceptional model with which they
may be able to develop studies impossible or difficult to achieve with any other
mammalian species. For example, they may be able to produce a variety of point
mutations in the same genetic background or exactly the same point mutation in a
variety of different backgrounds, allowing exploration of the function of this gene
and its interplay within gene networks. This book will also be helpful to physi-
cians and pediatricians by allowing them to choose or design the best possible
model for their research related to a specific human pathology. This would be true
not only for the diseases resulting from point mutations in orthologous genes but
also, and more interestingly, for those mutations whose phenotypic expression is
influenced by the environment or the genetic background of the animal. Finally,
laboratory animal veterinarians and technicians, who are in charge of the breed-
ing and preservation of mouse models, will find useful explanations about their
increasing complexity.
This book covers all aspects of mouse genetics. The first four chapters describe
the origin of laboratory mice, the reproductive biology, the cytogenetics, and the
mapping of genes. The establishment of highly detailed genetic maps was a major
and fundamental contribution to mouse geneticists during the twentieth century
that ultimately led to the complete sequencing of the genome. This topic has been
presented in a relatively condensed form in this book, because we have consid-
ered that the excellent book published in 1995 by Lee M. Silver, which is freely
available on the site “Mouse Genome Informatics”, is still a major reference in
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x Preface
this matter. On the contrary, the transcriptome and the parental imprinting of the
genome are topics that have been the subject of intensive research over the last 10
years. For this reason they are presented in more detail along with the techniques
for the production of mutations, which is one of the most attractive features of the
mouse. Finally, quantitative genetics, a branch of genetics that is in expansion, is
presented in a didactic manner.
This book greatly benefited from the contributions of some of our colleagues
whom we would like to cordially thank. François Bonhomme, an old friend with
whom we have collaborated many times in the past, reviewed and commented on
Chap. 1. Marie-Geneviève Mattei read and amended Chaps. 3 and 6 and allowed
us to share her extensive knowledge of cytogenetics. Yann Herault also made inter-
esting suggestions about Chap. 3 and provided us with a schematic figure repre-
senting the best models of Down syndrome. Benoît Robert accepted the difficult
task of writing an original synthesis concerning the regulation of gene expres-
sion (Chap. 5). Edith Heard, Luisa Dandolo, and Deborah Bourc'his abundantly
corrected and commented on Chap. 6 dealing with X-inactivation and parental
genetic imprinting. Michel Cohen-Tannoudji corrected and completed our initial
versions of Chap. 8, and Tomoji Mashimo read the section of the same chapter
dealing with the production of targeted alterations using engineered nucleases and
provided a summary picture. Finally, Robert P. Erickson kindly read the whole
of our manuscript, making many insightful comments. The authors also wish to
thank Drs. Hesed M. Padilla-Nash and Thomas Ried from the Genetics Branch,
National Cancer Institute, National Institutes of Health, Bethesda for providing
a picture of a mouse spectral karyotyping, Dr. Dianne Creasy, Huntingdon Life
Sciences, East Millstone, for providing a picture of the seminiferous epithelium
with identification of the different cell types, and Ms Annie Orth for providing a
picture of a sample of her unique collection of wild mice. Finally, the authors are
greatly indebted to their colleague Dominique Simon, who helped in the prepara-
tion of many illustrations and to Mrs. Sarah Adai, MD Anderson Cancer Center,
who undertook to “translate” their awkward English into a more readable form.
Writing this book has kept us busy for nearly two years, but it was really an
enthralling experience. Whatever the chapter, we realized that the Genetics of the
Mouse has changed considerably over the last 20 years and, with an increasing
number of transnational collaborative projects, we can expect even more dramatic
changes in the years to come.
Contents
1 Origins of the Laboratory Mouse ............................. 1
1.1 Introduction .......................................... 1
1.1.1 Phylogenetic Relationships of Laboratory Mice
with Other Mammals ........................... 1
1.1.2 How the House Mouse Became a Domestic Species ... 5
1.1.3 How the House Mouse Became a Model
for Geneticists ................................ 8
1.1.4 The Community of Mouse Geneticists ............. 12
1.1.5 The Main Institutions Involved in Mouse Genetics .... 12
1.1.6 Books and Other Sources of Information
Concerning the Mouse .......................... 13
1.1.7 The Future of Mouse Genetics .................... 14
References ................................................. 15
2 Basic Concepts of Reproductive Biology and Genetics ............ 19
2.1 Introduction .......................................... 19
2.2 Reproduction in the Laboratory Mouse ..................... 19
2.2.1 The Estrous Cycle and Pregnancy ................. 19
2.2.2 Inducing Ovulation in the Mouse (Superovulation) .... 24
2.2.3 Artificial Insemination .......................... 25
2.2.4 In Vitro Fertilization in the Mouse ................. 26
2.2.5 Ovary Transplantation .......................... 27
2.2.6 Intra Cytoplasmic Sperm Injection ................ 28
2.2.7 Cryopreservation of Mouse Embryos
and Spermatozoa .............................. 28
2.2.8 Twinning in the Mouse .......................... 29
2.2.9 Cloning Laboratory Mice ........................ 30
2.2.10 Mosaics and Chimeras .......................... 31
2.3 Basic Notions of Genetics ............................... 34
2.3.1 Genes and Alleles .............................. 34
2.3.2 Allelic Interactions ............................. 37
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