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1.2.1 The mouse and Mendel

The mouse played a major role in early genetic studies begun immediately after the rediscovery of Mendel's laws in 1900. All of the initial findings were based on work carried out entirely with plants and there was much skepticism in the scientific community as to how general Mendel's Laws would be (Dunn, 1965, p.86). Did the laws explain all aspects of inheritance from individuals? Were there some species groups — such as ourselves and other mammals — where the laws did not apply at all? In particular, the competing theory of blending inheritance was defended by Galton during the latter part of the 19th century. The main tenet of this theory was that a blending of the traits expressed by each of the parents occurred within each offspring. Blending inheritance and Mendelism have strikingly different predictions for the future descendants of a cross that brings a new "character" into a pure-bred race. According to the blending theory, the new character would remain in all of the descendants from the original "contaminating" cross: even upon sequential backcrosses to the pure-bred parental strain, the contaminating character would only slowly be diluted out. Of course, the Mendelian prediction is that a contaminating allele (to use current language) can be eliminated completely within a single generation.

The main support for blending inheritance came through a cursory observation of common forms of variation that exist in animal as well as human populations. It can certainly appear to be the case that human skin color and height do blend together and dilute from one generation to the next. However, skin color, height, and nearly all other common forms of natural variation are determined not by alternative alleles at a single loci, but instead by interactions of multiple genes, each having multiple alleles leading to what appear to be continua of phenotypes. 2 Mendel's leap in understanding occurred because he chose to ignore such complicated forms of inheritance and instead focused his efforts on traits that came in only two alternative "either/or" forms. Of equal importance was his decision to begin his crosses with pairs of inbred lines that differed by only a single trait, rather than many. It was only in this manner that Mendel was able to see through the noise of commonplace multifactorial traits to derive his principles of segregation, independent assortment, and dominant-recessive relationships between alleles at single loci.

How could one investigate the applicability of Mendel's laws to mammals with the use of natural variants alone? The answer was with great difficulty — not only does natural variation tend to be multifactorial, there is just not very much of it that is visible in wild animals, and without visible variation, there could be no formal genetics in 1900. The obvious alternative was to use a species in which numerous variants had been derived and were readily available within pure-breeding lines. And thus begun the marriage between the fancy mice and experimental genetics.

Evidence for the applicability of Mendel's laws to mammals — and by implication, to humans — came quickly, with a series of papers published by the French geneticist Cuénot on the inheritance of the various coat color phenotypes (Cuénot, 1902; Cuénot, 1903; Cuénot, 1905). Not only did these studies confirm the simple dominant and recessive inheritance patterns expected from "Mendelism", they also brought to light additional phenomena such as the existence of more than two alleles at a locus, recessive lethal alleles, and epistatic interactions among unlinked genes.

1.2.2 Castle, Little, and the founders of mouse genetics

The most significant force in early genetic work on the mouse was William Ernest Castle, who directed the Bussey Institute at Harvard University until his retirement in 1936 (Morse, 1985). 3 Castle brought the fancy mouse into his laboratory in 1902, and with his numerous students began a systematic analysis of inheritance and genetic variation in this species as well as in other mammals (Castle, 1903; Morse, 1978; Morse, 1981; Snell and Reed, 1993). The influence of Castle on the field of mammalian genetics as a whole was enormous. Over a period of 28 years, the Bussey Institute trained 49 students, including L.C. Dunn, Clarence Little, Sewall Wright, and George Snell; thirteen were elected to the National Academy of Sciences in the U.S. (Morse, 1985), and many students of mouse genetics today can trace their scientific heritage back to Castle in one way or another. 4

A major contribution of the Castle group, and Clarence Little in particular, was the realization of the need for, and development of, inbred genetically homogeneous lines of mice (discussed fully in Section 3.2). The first mating to produce an inbred line was begun by Little in 1909, and resulted in the DBA strain, so-called because it carries mutant alleles at three coat color loci — dilute (d), brown (b), and non-agouti (a). In 1918, Little accepted a position at the Cold Spring Harbor Laboratory, and with colleagues that followed — including Leonell Strong, L. and E. C. MacDowell — developed the most famous early inbred lines including B6, B10, C3H, CBA, and BALB/c. Although an original rationale for their development was to demonstrate the genetic basis for various forms of cancer, 5 these inbred lines have played a crucial role in all areas of mouse genetics by allowing independent researchers to perform experiments on the same genetic material, which in turn allows results obtained in Japan to be compared directly with those obtained halfway around the world in Italy. A second, and more important, contribution of Little to mouse genetics was the role that he played in founding the Jackson Laboratory in Bar Harbor, Maine, and acting as its first director (Russell, 1978). The laboratory was inaugurated in 1929 — as "the natural heir to the Bussey" (Snell and Reed, 1993) — with eight researchers and numerous boxes of the original inbred strains.

1.2.3 The mouse as a model prior to the recombinant DNA revolution

With the demonstration in the mouse of genetic factors that impact upon cancer, millions upon millions of animals were used to elucidate the roles of these factors in more detail. However, for the most part, these biomedical researchers did not breed their own animals. Rather, they bought ready-made, off-the-shelf, specialized strains from suppliers like Taconic Farms, Charles River Laboratories, and the Jackson Laboratory (addresses of these and other suppliers are provided in Appendix A). The strong focus of mouse research in the direction of cancer can be seen clearly in the table of contents from the first edition of the landmark book Biology of the Laboratory Mouse published in 1941: five of 13 chapters are devoted to cancer biology, with only two chapters devoted to other aspects of genetic analysis (Snell, 1941).

Until the last decade, the community of geneticists that actually performed their own in-house breeding studies on the mouse was rather small. For the most part, individual mouse geneticists worked in isolation at various institutions around the world. Typically, each of these researchers focused on a single locus or well-defined experimental problem that was amenable to analysis within a small breeding colony. Members of the mouse community kept track of each other's comings and goings through a publication called The Mouse Newsletter. In its heyday during the 1960s, more than sixty institutions would routinely contribute "a note" to this effect. These contributed notes served the additional purpose of providing researchers with a means for announcing and reading about the various strains and mutations that were being bred around the world. A characteristic of the genetics community, during this period, was the openness with which researchers freely traded specialized mouse stocks — not available from suppliers — back and forth to each other.

Apart from this cottage industry style of conducting mouse genetics, there were three institutions where major commitments to the field had been made in terms of personnel and breeding facilities. These three institutions were the Oak Ridge National Laboratory in Oak Ridge, Tennessee, the Atomic Energy Research Establishment in Harwell, England, and the Jackson Laboratory (JAX) in Bar Harbor, Maine. The genetics programs at both Harwell and Oak Ridge were initiated at the end of the second world war with the task of defining the effects of radiation on mice as a model for understanding the consequences of nuclear fallout on human beings. Luckily, researchers at both of these institutions — prominently including Bill and Lee Russell at Oak Ridge and T. C. Carter, Mary Lyon and Bruce Cattanach at Harwell — appreciated the incredible usefulness of the animals produced as byproducts of these large-scale mutagenesis studies in providing tools to investigate fundamental problems in mammalian genetics (see Section 6.1).

The third major center of mouse genetics — the Jackson Laboratory — has always had, and continues to maintain, a unique place in this field. It is the only non-profit institution ever set up with a dedication to basic research on the genetics of mammals as a primary objective. Although the JAX originally bred many different species (including dogs, rabbits, guinea pigs and others), it has evolved into an institution that is almost entirely directed toward the mouse. Genetic mapping and descriptions of newly uncovered mutations and variants have been a focus of research at the laboratory since its inception in 1929. But in addition to its own in-house research, the JAX serves the worldwide community of mouse geneticists in three other capacities. The first is in the maintenance and distribution of hundreds of special strains and mutant stocks. The second is as a central database resource. The third is in the realm of education in mouse genetics and related fields with various programs for non-scientists and high school and college students, as well as summer courses and conferences for established investigators.

Even with the three centers of mouse research and the cottage industry described above, genetic investigations of the mouse were greatly overshadowed during the first 80 years of the 20th century by studies in other species, most prominently, the fruit fly Drosophila melanogaster. The reasons for this are readily apparent. Individual flies are exceedingly small, they reproduce rapidly with large numbers of offspring, and they are highly amenable to mutagenesis studies. In comparison to the mouse, the fruit fly can be bred more quickly and more cheaply, both by many orders of magnitude. Until the 1970s, Drosophila provided the most tractable system for analysis of the genetic control of development and differentiation. In the 1970s, a competitor to Drosophila appeared in the form of the nematode, Caenorhabditis elegans, which is even more tractable to the genetic analysis of development as well as neurobiology. So why study the mouse at all?

The answer is that a significant portion of biological research is aimed at understanding ourselves as human beings. Although many features of human biology at the cell and molecular levels are shared across the spectrum of life on earth, our more advanced organismal-based characteristics are shared in a more limited fashion with other species. At one extreme are a small number of human characteristics — mostly concerned with brain function and behavior — that are shared by no other species or only by primates, but at a step below are a whole host of characteristics that are shared in common only with mammals. In this vein, the importance of mice in genetic studies was first recognized in the intertwined biomedical fields of immunology and cancer research, for which a mammalian model was essential. Although it has long been obvious that many other aspects of human biology and development should be amenable to mouse models, until recently, the tools just did not exist to allow for a genetic dissection of these systems.

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