My aim in writing this book has been two-fold. First, to provide students, in the broadest sense of the term, with a comprehensive introduction to the mouse as a model system for genetic analysis. Second, to provide practicing scientists with a detailed guide for performing breeding studies and interpreting experimental results. The impetus to write this book arose through a decade of formal and informal teaching at Princeton University. I became increasingly frustrated during this time with the lack of a current book on mouse genetics that could be provided to new students and postdoctoral fellows. I also found myself spending increasing amounts of my own time answering mouse questions not only from Princeton students but colleagues as well. Although some may consider it to be an extreme response, I wrote this book to answer all of the questions that I have been asked in the past and those that I can imagine being asked in the future.
In consideration of the broad range of students and scientists that may find a book of this type useful, I have made few assumptions about background knowledge. I have attempted to develop each topic completely from the kinds of first principles that are taught in a contemporary introduction to biology course for undergraduates. In particular, critical concepts in genetics and molecularbiology have been fully explained.
It is my hope that this book will serve the interests of three different types of readers. First is the advanced undergraduate or graduate student who may be taking a course or entering a mouse laboratory for the first time. This reader will find a complete description of the laboratory mouse, the molecular tools used for its analysis, and the procedures used for carrying out genetic studies. Second is the established molecular biologist who intends to incorporate the mouse into his or her future studies. This reader will be able to skip over molecular topics, and focus on background material and chapters devoted to genetics. Finally, there is the practicing mouse geneticist. My inclusion of graphs, charts, and statistical formulations for the interpretation of genetic data is meant to provide this reader with a single toolbox for day-to-day use in data analysis. I should like to highlight the fact that, although this book is directed toward the genetics of the mouse, many of the genetic and molecular areas covered in the second half of the book will apply equally well to the genetic analysis of other mammalian species.
It is important for the reader to know what not to expect here. The mouse is used in many areas of biological research today, but I have focused this book entirely on its genetics with a particular emphasis on the application of molecular techniques to traditional breeding studies. In particular, I have notcovered one very hot area of research—developmental biology—partly because this fieldis so well covered in a number of other recently published books. These are listed in the appendix along with other classic and contemporary books on other aspects of mouse biology.
In 1977, I began my career in mouse genetics as a postdoctoral fellow with Karen Artzt in Dorothea Bennet's laboratory at the Sloan-Kettering Institute. Dorothea had a rule (handed down from her mentors, L.C. Dunn and Salome Waelsch) that each scientist in her lab, herself included, had to spend at least two mornings each week in the "mouse room" examining animals, recording litters, and setting up new matings. Mouse room time was meant to serve two purposes. The first was meant to maintain and track a large breeding colony with hundreds of genetic variants in various experimental crosses. The second purpose was to provide each student and postdoc passing through the lab with an intimate look at the creature that is the mouse. Although my initial choice of the mouse as an experimental system was based on the many purely rational reasons presentedin the first chapter of this book, my experience in the Bennett mouse room radicallychanged my outlook on science. As Dorthea intended, I acquired what the brilliant corn geneticists Barbara McClintock referred to as "a feeling for the organism" (Keller, 1983). Seventeen years later, the mouse—with its fascinating habits, amazing variation, elaborate social structures, and rich history—continues to amuse me even as it provides a tool for nearly all of my scientific investigations. I always find myself in special company when talking to other self-described "mousers", many of whom continue to work in their own mouse rooms long after their colleagues have retired to their offices.
I have presented this one aspect of my personal history as an explanation for the scattered sections throughout this book where I provide details about the mouse that may seem extraneous to some readers. My intent, and my hope, is that in some small way, these details will provide readers with some points of departure on their own paths to a feeling for the organism that is the mouse. Of course, it should go without saying that such a feeling can only be acquired through a "hands-on" approach to the animal itself. The student who successfully follows such a path will develop an intangible, yet powerful, tool for enlightened interpretation of experimental data.
I am indebted to those who guided me in the development of my own feeling for the mouse including Karen Artzt, Dorthea Bennet, Mary Lyon, Salome Waelsch, Jan Klein, and Vicki Sato. I am also indebted to other teachers who helped me mature as a scientist including Sandy Schwartz, Sally Elgin, and Joe Sambrook, and a long-lost college friend named Barry Gertz who explained the wonders of modern biology to an ignorant physics major, and in so doing, caused that physics major to alter the course of his career in a direction that led ultimately to the publication of this book. There are many other colleagues and students who taught me as much as I have taught them. I would like to especially thank those who provided critical commentary on particular chapters in this book or insight into particular topics that I covered. These include Jiri Forjet, Kristie Ardlie, François Bonhomme, Bill Paven, Muriel Davisson, Tom Vogt, Shirley Tilghman, Ken Manly, Eva Eicher, Joe Nadeau, Jean-Louis Guénet, Ken Paigen, members of the Priceton Play Group, and a cyberspace pen pal (whose voice I have never heard) named Karen Rader. I am extremely delighted that both Earl and Margaret Green found the time to read the entiremanuscript—from start to finish—with insightful comments and corrections of various errors and misconceptions. In the end, though, any mistakes that remainare of my own making. Finally, this book would never have been written withoutthe wholehearted support of my family. I want to thank my parents for their support and encouragement throughout my life, and my wife and children fortheir patience and understanding over the three years that I spent hovering infront of a computer screen; now Becka and Ari, it is your turn to play.