Historical Foundations

CHAPTER

Historical Foundations Muriel T Davisson and Carol C Linder The Jackson Laboratory, Bar Harbor, Maine, USA

i-

~rl

=.

Intro

d

uc

ti

on

The laboratory mouse (derived from the common house mouse) has played a key role in mammalian genetic and biomedical research. Research using the mouse spans the twentieth century, from 1902 to 2002, from the birth of mammalian genetics to having the whole genome sequence. The ability to add to and selectively alter the mouse genome increased the power of the mouse as a research tool for understanding the genetic basis of human health and disease (Gordon et al., 1980; Mansour et al., 1988; Capecchi, 1989). Mutant and inbred mice frequently have syndromes similar to human inherited diseases because of their close metabolic and internal anatomical similarities to human beings. Genes in the mouse and human genomes are >99% conserved (Consortium, 2002). Hence, the mouse provides models for research not only on mammalian biology but also on a wide variety of human diseases including cancer, diabetes, aging, atherosclerosis, endocrine diseases, immunological diseases, autoimmunity, neurological dysfunction, and numerous others. Inbred and mutant mice are universally accepted as the primary model for analyzing and understanding inherited human disorders (Paigen, 1995, 2002; Davisson, 1999; O'Brien and Woychik, 2003). The LaboratoryMouse Copyright 2004 Elsevier ISBN 0-1233-6425-6

The ultimate recognition of this value of the mouse was its selection as the first model organism to have its

genome sequenced in the Human Genome Initiative (Battey et al., 1999; Consortium, 2002).

Historical foundations

O

ITI ITI

S z

The laboratory mouse originates from ancestors in the Middle East in the area that is now Pakistan. A commensal organism, mice have emigrated to most corners of the world as human beings' traveling companions. For a detailed history of the origins of the house mouse see Silver (1995). On the tiny island of Tenedos at the mouth of the Dardanelles stands a temple to Apollo God of Mice that predates the Trojan War. Albino mice were used in auguries for Egyptian rulers (Keeler, 1978). The earliest drawings of mice may be seen in Chinese prints as early as AD 300 and mutant mice, such as albino and waltzer, appear in eighteenth- and nineteenth-century Asian prints. Mouse fanciers of the late nineteenth and early twentieth centuries were the origin of most laboratory mice of today. The mouse fancy hobby originated in Asia and later spread to Europe and from there to America.

All rights of production in any form reserved

---4 O "11 .-4 I'll

O c ITI

I-O

O ITI I"

I#1

tL U

E

o 1#1 m

0 ...A LLI

a o

Because of their origins in the mouse fancy trade, laboratory mouse strains are a genetic mix of four different subspecies: Mus musculus musculus (eastern Europe), Mus musculus domesticus (western Europe), Mus musculus castaneus (Southeast Asia), and Mus musculus molossinus (Japan). The latter is thought to be a hybrid between castaneus and musculus (Moriwaki et al., 1990). Genome analysis confirms that the laboratory mouse is a blend of these four different species or subspecies of the genus Mus (Wade et al., 2002). Phylogenetically the house mouse (Mus) belongs to the family Muridae along with several other species of mice and the common rat. Many inbred strains derive from Miss Abbie Lathrop, a mouse fancier who bred and sold mice in Granby, Massachusetts, from -1900 to her death in 1918. She obtained her mice from dealers, European fanciers, and those captured in the wild. Although Miss Lathrop is often mentally pictured as a litde old lady who collected fancy mice, she was an experimentalist and keen observer. She carried out cancer research experiments, collaborating with Dr Leo Loeb at the University of Pennsylvania (Lathrop and Loeb, 1915a, b, 1918). This collaboration grew out of her observation of tumor growths in her mice and her curiosity to learn more (Morse, 1978). She also carried out breeding experiments in collaboration with William Casde, and later Clarence Cook ('C.C.') Little, at the Bussey Institute at Harvard. Miss Lathrop's breeding records and notebooks, including such observations, are preserved in the library at The Jackson Laboratory.

>tw

0 eY-

0r e , ._1

ILl

0 W I'll

0

I-Z LIA 0-

o, LIA

History of mouse genetics and research with the laboratory mouse Genetics Ten major milestones mark the history of mouse genetics. The history of mouse genetics might have begun in the 1860s if an Augustinian bishop had not forbidden the breeding of mice within the monastery where Gregor Mendel did his classic genetic studies with sweet peas (Paigen, 2003). Thus, the first milestone in mouse genetics was the proof that mice, like sweet peas, had genes when French geneticist Lucien Cu6not

demonstrated that mammals show Mendelian inheritance using the inheritance of coat colors in mice (1902). He went on to demonstrate that a gene can have multiple alleles (1904) and that some alleles can be lethal, using the yellow allele of the agouti gene, AY(1905). In 1903 William Castle at Harvard also published a paper on coat color genetics in mice (Castle and Allen, 1903). He and his student, C.C. Little, are often credited with the first cogent report and explanation of a lethal allele, also Av (Castle and Little, 1910). The second milestone was when mouse genetic research was initiated at the Bussey Institute for Research in Applied Biology at Harvard. W'dliam Ernest Casde directed the mammalian research program (Morse, 1985; Snell and Reed, 1993). Two of Casde's first students were Sewall Wright and C.C. Little. Most of the well-known names in the history of mouse genetics can be traced to the Bussey Institute. Examples include L.C. Dunn (developmental biology), L.C. Strong, C.C. Little, and Lloyd Law (cancer genetics), Clyde Keeler (behavior genetics),~Paul Sawin (quantitative biology), and George Snell (histocompatibility genetics). A 'genealogical' tree of mouse geneticists drawn by Elizabeth ('Tibby') Russell and modified by Sandy Morse shows the extent to which students of the Bussey determined the future of mouse genetics (Morse, 1978). Genetic research using mice in the early twentieth century centered around coat color genetics, cancer, and tumor transplantability. The third major milestone was the development of inbred strains of laboratory mice. C.C. Little is credited with conceiving of and creating the first inbred strains, although others including Miss Lathrop and Leondl Strong, were inbreeding mice at the same time. Breeders from C.C. Litde's Line C (derived from Ms Lathrop's mice) founded the C57/C58 family of strains; females 57 and 58 were mated to male 52 to give rise to the C57BL, C57BR, and C58 inbred strains. Most principles of genetics in the mid 1900s were established in nonmammalian species. Studies in Drosophila and micro-organisms led to the understanding of chromosomal theory, the nature of mutation, the discovery of the genetic code, and gene structure and function. During this period, however, the study of mouse genetics and gene mapping grew steadily, creating a solid foundation for the future of mouse genetics. In the 1960s and 1970s mouse genetics became prominent again with the recognition of the need for a mammalian model for biomedical research, the development of efficient genetic mapping tools in mice, and the realization of the high degree of genomic conservation between the mouse and human genomes. In the 1980s and 1990s, of course, mouse genomics burst again into

the limelight at center stage with the development of powerful methods to manipulate the mouse genome.

The genetic map of the mouse Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome. The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino (Haldane et al., 1915). This fourth milestone of mouse genetics was the beginning of the genetic linkage mapping effort that continued through the rest of the twentieth century and into the twenty-first. Until the early 1970s, the mouse genetic map was composed of such linkage groups in which two or more genes were linked together. Linkage groups were not assigned to specific mouse chromosomes until the early 1970s (see next section on Physical Mapping). Composite linkage maps were compiled at The Jackson Laboratory (Margaret Dickie, Margaret Green, James Womack, Thomas Roderick, and Muriel Davisson) and at the Medical Research Council (MRC) Genetics Unit at Harwell in England (Colin Beechey, J. Butler, Susan Hawkes, and R. Meredith) by statistically combining data from all scientists' linkage crosses. As more and more genes were identified and mapped, the number of linkage groups and genes mapped within them grew increasingly rapidly until it was impossible to graphically depict the whole mouse linkage map in print publications. The last such published map was by Davisson etal. (1990). Most mouse genetic and biological research in the middle of the twentieth century was carried out at a triumvirate of mouse research centers: the Harwell MRC Genetics Unit, the Biology Unit at the Atomic Energy Commission's facility in Oak Ridge, Tennessee, and The Jackson Laboratory in Bar Harbor, Maine. During the 1940s, the two major focuses for genetic mapping were identification of histocompatibility genes and discovery and characterization of visible, morphological markers resulting from spontaneous mutations. Study of the latter also provided the first mouse models of human inherited diseases. Genetic mapping with spontaneous mutations that created visible phenotypes, such as

changes in coat color/texture (e.g. albino, Tyrq piebald, Ednrb~; satin, sa; fuzzy,s~) or behavior (e.g. waltzer, v; reeler, Relnrl; shiverer, Mbp shi) was laborious and sometimes took years. This was because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross. Determining linkage demanded sophisticated statistical analysis and large numbers of progeny were required to obtain statistical significance (Green, 1963). It was not uncommon to generate thousands of intercross (F2) progeny - but the results did not lead to the high resolution maps that such crosseswith today's genetic markers provide. During the 1950s and 1960s, linkage testing stocks (e.g. V/Le, SB/Le) combining multiple visible markers were created to speed the mapping process. The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose pt}osphate isomerase 1, Gpil; Hutton, 1969; Hutton and Coleman, 1969; Hutton and Roderick, 1970). Thus, the fifth milestone was the transition from visible markers to polymorphisms. In the 1980s and 1990s, DNA markers revolutionized genetic mapping. Their use was greatly facilitated by the development of the polymerase chain reaction (PCR) in 1983. DNA polymorphic markers, restriction fragment length polymorphisms (RFLPs) (Elliott, 1996), and later simple sequence length polymorphisms (SSLPs), such as the MIT markers (Dietrich et al., 1994), are widespread throughout the genome. One of the biggest advantages of DNA markers for mapping is that newly discovered markers can be typed in indefinitely stored DNAs from linkage crosses or mapping panels. In 2003 came the identification and use of single nucleotide polymorphisms (SNPs) of which millions are present in the mouse genome (Lindblad-Toh et al., 2000). During this period as well, several scientists developed inbred strains from wild populations to increase genetic variability in mapping crosses (Kozak et al., 1984; Guenet, 1986). Verne Chapman (Roswell Park), Michael Potter (National Institutes of Health), JeanLouis Guenet (Pasteur Institute, France), and Eva Eicher and Tom Roderick (The Jackson Laboratory) developed wild-derived inbred strains. Mus musculus castaneus (e.g. CAST/Ei), Mus spretus (e.g. SPRET/Ei), and Mus musculus molossinus (e.g. MOLD/Rk) are the most widely used. Johnson et al. (1994) improved mapping mutations with RFLP loci by combining intersubspecific intercrosses (F2) using inbred CAST/Ei

~"

w" ~1

~n / ~

m < m m z --4 O -I'1

re:l: 0 C mt~ :~ r~ m ~ d "< O m r-

tL

,I

Id

E

8 -r

O -A ILl

a o

>ev"

O ew

O re, _.1 I/3 IdA

O LIA "rFkl.

O F.-

with RFLPs for gene families, allowing multiple genes to be detected on a single Southern blot. Taylor et al. (1994) further improved the efficiency of mapping mutations with polymorphic markers by pooling F2 progeny DNAs for the initial genome screen with PCR. Panels of backcross DNAs have been developed for efficient mapping of polymorphic markers that can be typed in DNA. The C57BL/6Ros • Mus spretus panel of Neal Copeland and Nancy Jenkins (Ceci et al., 1994) and the C57BL/6J • SPRET/Ei backcross panel at The Jackson Laboratory are mapping resources available to investigators (Rowe et al., 1994). Identification (or cloning) of mutated genes in the last decades of the twentieth century was made possible by the development of libraries of artificial chromosomes containing inserts of mammalian DNA: plasmid clones (Pl-derived artificial chromosomes, PACs), bacterial artificial chromosomes (BACs), and yeast artificial chromosomes (YACs), listed in order of size. High resolution genetic crosses with sometimes thousands of progeny are used to narrow the chromosomal interval harboring the gene of interest. Once a mutant gene is mapped to a segment less than a fraction of a centiMorgan, contigs of overlapping clones can be constructed across the region by hybridizing PACs, BACs, and/or YACs to each other. Although laborious, this approach to identifying mutated genes became increasingly successful as DNA sequencing technologies and quality of libraries improved. With the electronic publication of the entire mouse genome sequence (CDS, 2001; Consortium, 2002), candidate gene cloning became more common and has yielded gene identification more rapidly than positional cloning did. It is now a simple matter to examine electronically the chromosomal interval identified by the high resolution genetic cross for candidate genes whose mutation might lead to the phenotype observed. With both methods, candidate genes are tested by assessing RNA expression levels or examining the gene itself by Southerns for large DNA alterations and, ultimately, by sequencing exons. In either case, that the mutated gene identified causes the phenotype must be proved by showing mutations in the same gene in multiple alleles (if available) or by creating transgenic mice with the mutated gene.

Z LI.I es

q

The physical map of the mouse

LIA LIA

a

Of course, a major milestone for all genetics, the sixth for the mouse, was the determination of DNA's physical structure in 1953 by Watson and Crick (1953) using X-ray crystallography images produced by Rosalind

Franklin. The seventh major milestone in mouse genetics was the development of chromosomal banding techniques in the late 1960s. This was particularly important because all laboratory mouse chromosomes are telocentric (the centromere is located at one end) and identification of most individual chromosomes prior to banding technology was virtually impossible. Development of fluorescent Q-banding (Q- for quinacrine; Francke and Nesbitt, 1971) and G-banding (Giemsa; Buckland et al., 1971) enabled the assignment of linkage groups to physical chromosomes by combining knowledge of linkage groups associated with reciprocal translocations with cytological identification of the chromosomes involved based on alterations in banding patterns (Miller et al., 1971). This approach is credited to John Hutton but drew on the accumulated data of many laboratories. However, prior to chromosomal banding, Eva Eicher assigned the frst linkage group to a chromosome, based on the size and unusual unbanded cytological appearance of Chromosome 19 and linkage analysis of Linkage Group XII (Eicher, 1971). The first composite linkage map showing both chromosome numbers and linkage groups was published by Margaret Green (1973). Davisson and Roderick (1978) published the first linkage map in which linkage groups were adjusted to chromosome size based on physical measurements of the chromosomes (Committee, 1972). The final advance in the cytological physical map was the development of fluorescent in situ hybridization (FISH; Kranz et al., 1985). FISH allows mapping of single genes to cytological bands on the physical chromosome and identification of chromosomal rearrangements using paints (Rabbitts etal., 1995; Liyanage etal., 1996). Because genetic crosses are possible in mice, somatic cell hybrid panels, enabling the assignment of genes to chromosomes, were never used in mouse gene mapping to the extent they were in human mapping. Somatic cells of two species are fused and one species' chromosomes are segregated out during cell line propagation, creating a panel of cell lines, each with one or a few chromosomes of the species of interest. Radiation hybrid (RH) panels, in which the chromosomes of the species of interest have been fragmented by irradiation prior to fusion, have been used effectively in the mouse as well as human to physically locate and order genes in chromosomal segments. The T31 mouse RH mapping panel also is available through The Jackson Laboratory mapping resource (Rowe et al., 2003). Mary Lyon at Harwell maintained, and published in Mouse News Letter for many years, the composite 'Chromosome Atlas' map, which combined linkage

data and physical mapping by FISH or cytological location of chromosomal rearrangement breakpoints. Updates of the Atlas were published for several of the final issues o f Mouse News Letter.

Comparative mapping The mouse is a powerful model organism for research on human disease because it is a mammal and because of the high degree of conservation between the mouse and human genomes. Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002. The first conserved mouse and human auto~ somal linkage was reported in 1978 (Lalley etal., 1978). At the 4th Human Gene Mapping (HGM) Workshop, six autosomal linkages and the X Chromosome, were known (Pearson and Roderick, 1978). In 1984, Nadeau and Taylor (1984) identified 13 conserved autosomal segments and estimated 178 + 39 chromosomal rearrangements between mouse and human chromosomes. By the last formal meeting of the HGM Comparative Mapping Committee, 105 conserved linkages were known (Andersson et al., 1996). Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium, 2002).

Bioinformatics The development of large, comprehensive databases must be recognized as a milestone, the eighth, because without their development the rapidly increasing accumulation of genetic and biological data in the last three decades of the twentieth century would be overwhdming and impossible to manage. In the late 1970s, the linkage data Margaret Green had accumulated on 4 • 6 in. cards was entered into a computer 15rogramknown as GBASE (the Genetic Database of the Mouse) developed by Thomas Roderick, Muriel Davisson, and Carolyn Blake at The Jackson Laboratory. The data were proof read by Mary Lyon while she was on an extended visit to the Laboratory. GBASE became the first on-line database of mouse genetic information. Subsequendy, Margaret Green's catalog describing mouse genes (Green, 1979) was added as Mouse Locus Catalog, which was maintained for many years by Donald Doolittle. At about this time, Thomas Roderick coined the term 'genomics' for the new journal of that name, providing a name for the expanded science that encompasses genetic mapping, sequencing, and genome analysis. In 1995, GBASE was combined with a linkage analysis database developed by Janan Eppig and homology database developed by Joseph

Nadeau to become the predecessor of the Mouse Genome Database (MGD). Today's Mouse Genome Informatics program at The Jackson Laboratory encompasses the MGD of genomic and phenotype information, a gene expression database (GXD), a mouse genome sequence (MGS) analysis database, a tumor biology database, and related analysis tools (MGI, 2003). The advent of DNA sequencing, culminating in the sequencing of entire genomes, has generated sophisticated bioinformatics systems beyond the scope of this chapter to describe. The many sequence databases and analysis software packages that are available are valuable tools for the mouse geneticist. A critical aspect of all genetic mapping and the bioinformatics programs that support it is the use of controlled genetic nomenclature. Conventions of genetic nomendature are described in Chapter 3 on Strains, Stocks, and Mutant Mice.

s

Genetic manipulation of the mouse genome The ninth milestone in mouse genetics - genetic engineering - has catapulted the mouse into the lead mammalian model organism for biomedical research. With transgenesis and gene targeting, it is possible to selectively modulate the amount or composition of a gene product (see Chapter 5 on Generation of Mouse Mutants by Sequence Information Driven and Random Mutagenesis for a detailed explanation). The first technology introduced was the insertion of foreign genes into mouse chromosomes to produce gain-offunction mutants. The first transgenic mouse was created and described by Jon Gordon in Frank Ruddle's laboratory in 1980 (Gordon et al., 1980). Creation of loss-of-function mutations followed the pioneering demonstration by Leroy Stevens that embryonic teratocarcinoma cell lines could give rise to differentiated tissues that led to the discovery that pluripotent embryonic stem (ES) cells could be grown in culture (Evans and Kaufman, 1981). In 1988, two research groups reported the first successful alteration of a mouse gene by homologous recombination or targeting (Doetschman et al., 1988; Mansour et al., 1988; Capecchi, 1989). The early efforts with this technology basically created null mutations or 'knockouts'. The discovery that many such mutations led to embryonic lethality instigated the development of targeting technology that makes it possible to determine tissue and temporal specificity using conditional mutation systems. The first developed was the creLox system. Mice carrying a transgene containing the gene for the

5

0 U7 I"11 m

5 -0 I'n Z "4

0

-n --4 "1" m

0 C m

2~ V" C70

0 70 -<

0 i'n i--

tL u

o ,n

.!-

.-I LU

O >ew

O ew

O _A Ill

O U.I

ill O Fz

prokaryotic cre recombinase enzyme linked to a tissue-specific promotor are mated with mice carrying insertions of the LOxP target sequence flanking the gene to be removed (Utomo et al., 1999; Nagy, 2000). Tissue-specific expression of the cre enzyme enhances recombination between the LOxP sites and deletes the targeted gene's function in that tissue. A similar system can be created with the Flp recombinase (Dymecki, 1996; Rodriguez et al., 2000). Temporal control is achieved using Tetracycline-inducible mutations (Saam and Gordon, 1999; Schonig and Bujard, 2003). Finally, it is possible to replace an endogenous gene with another functional gene (Hanks et al., 1995). We can now go from gene to phenotype (reverse genetics) as well as from phenotype to gene (forward genetics). Nevertheless, it should be noted that being able to manipulate specific genes is still a long way from being able to generate specific phenotypes; frequently targeted mutations cause an unexpected phenotype or, sometimes, no detectable phenotype at all. High-throughput mutagenesis is making it possible to increase the mutation rate and screen for subtle phenotypes that will be the key to identifying novel genes. The widespread use of the powerful mutagen ethylnitrosourea (ENU) has developed from the research of William Russell's group at Oak Ridge National Laboratory (Russell et al., 1979). Several large-scale mutagenesis centers or multi-center programs were established in Europe and North America during the latter 1990s (e.g. Hrab6 de Angelis et al., 2000; Justice, 2000; Nolan et al., 2000). Insertional mutagenesis can be used to randomly mutate genes by insertion of a DNA sequence which can be subsequently used to identify the mutated gene. The first of these was developed by Rick Woychik, then at Oak Ridge; using insertion of transgenes carrying a selectable construct (Moyer et al., 1994). This approach has largely been replaced by gene-trapping technology using sequences that integrate only into gene-specific genomic regions such as promotors (Friedrich and Soriano, 1991) or other gene-specific sequences in ES cells (Skarnes et al., 1995; Stanford et al., 2001).

Sequencing the mouse genome

LU e~

o IdA LU

a

In 1999, three major sequencing centers, the Wellcome Trust Sanger Institute, the Whitehead Center for Genome Research, and Washington University Genome Sequencing Center, combined efforts to form the Mouse Genome Sequencing Consortium (MGSC) to sequence the mouse genome. C57BL/6J was chosen as the first inbred strain to be sequenced. The ultimate physical map

is the sequence of the genome. This tenth major milestone was achieved in the year 2001, only 1 year after this achievement for the human genome and 2 years ahead of schedule, when Celera (2001) announced completing frst pass sequence in May of 2001 of a mixed mouse genome derived from the following inbred strains: 129S1/SvImJ, 129X1/SvJ, A/J, C57BL/6, and DBA/2J (CDS, 2001). In December 2002, the MGSC public consortium announced the complete draft sequence of C57BL/6J (Consortium, 2002). One hundred years after Mendel's principles were shown to operate in the mouse, we can relate the genetic map to the cytological map to the ultimate physical map of the genome. Yet having the sequence reinforces the need for the genetic map because we need to genetically map traits in order to locate their positions in the sequence and identify candidate genes.

Biomedical research The earliest biomedical research using the mouse involved ghe genetics of tumor transplantability and cancer susceptibility. Initial studies suggested that the genetic component in these traits was weak or nonexistent because of the use of outbred mice and the complexity of the trait (Loeb, 1902; Tyzzer, 1909). The development of defined genetic backgrounds by inbreeding encouraged the continuation and growth of research on cancer. C.C. Little and others continued to develop inbred strains to analyze the genetics of susceptibility and resistance to cancer and tumor transplantation (Strong, 1978). Haldane suggested in 1933 that cancer had a genetic component (Haldane, 1933). Jacob Furth at the University of Pennsylvania developed the high leukemia strain AKR (Furth, 1978). Leonell C. Strong studied the genetics of susceptibility and resistance to tumor transplantation. Howard Andervont studied the genetics and viral etiology of cancer and went on to head the National Cancer Institute until 1961 (Deringer, 1978). Walter Heston began his early work on lung cancer (Heston, 1978). In 1933 the StaffofThe Jackson Laboratory published a paper describing maternal inheritance of mammary tumors in mice (Staff, 1933). This phenomenon was later shown to be nonmendelian transmission by a factor in the dam's milk (Bittner, 1936), which was subsequently identified as a virus (Bryan et al., 1942; Visscher et al., 1942). Ultimately, it was shown that the virus could be integrated into the mouse genome and transmitted as a gene by both females and males. George Snell, inspired by Little and his early work on tumor transplantation, began his lifelong study of the genetics of transplantation (Snell, 1978) that

became the basis for all histocompatibility and tissue transplantation research. He joined the staff at The Jackson Laboratory in 1935. During the 1940s, Snell created congenic strains (strains differing at a locus of interest and a linked chromosomal segment carried over during backcrossing) to isolate, identify, and map genes involved in tissue rejection or acceptance (Snell, 1948). He rediscovered the mouse major histocompatibility complex (MHC), described by Peter Gorer in 1938 as a red blood cell antigen affecting transplantation. Snell and Gorer's joint research on histocompatibility genes (Gorer et al., 1948) became the foundation for the medical field of tissue and organ transplantation in humans today. Because Gorer died prematurely, it was Snell who was awarded the Nobel prize in 1980 for this research. During the 1940s and 1950s, spontaneous and induced mutations created in radiation risk assessment studies following the Second World War were used to map genes in the mouse. As the effects of these mutations were studied, the potential of mutant mice to provide research tools for studying human inherited disease became evident and the types of biomedical research broadened. Areas of research expanded from cancer genetics and histocompatibility to hematopoietic stem cell research, hematological disorders, skeletal abnormalities, neurological and neuromuscular diseases, kidney disease, and many more. In the 1980s and 1990s molecular technology advances made it possible (1) to more rapidly identify mutated genes and (2) to genetically manipulate the mouse genome to alter genes shown to be mutated in human diseases (see section on Genetic Manipulation of the Mouse Genome). The transgenic strain overexpressing the promoter region and exon 1 of the human Huntington's disease gene, B6CBA-TgN(HDexonl) 62Gpb/J, causes disease symptoms that mimic the human condition beginning at 9-11 weeks of age (Mangiarini et al., 1996). A transgenic mouse carrying the human superoxide dismutase 1 gene with the mutation associated with amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) provides a good model for that disease (Gurney et al., 1994). One of the early targeted mutations created was in the gene encoding the transmembrane protein mutated in human cystic fibrosis (Cftr; Koller et al., 1991), but the mutant mice died early in life because of intestinal abnormalities. Combining the Cftr knockout with a functional human C F T R transgene expressed in the intestine allowed cystic fibrosis null mice to survive long enough to provide a model to study and test therapies for the debilitating lung phenotype that affects human

patients (Manson et al., 1997). Recently created conditional targeted mutations allow control of the tissue specificity of the mutation or onset of gene expression (temporal control; Utomo et al., 1999; Nagy, 2000; Schonig and Bujard, 2003). Completion of the draft sequence of the mouse genome (Consortium, 2002) provides the most comprehensive map of the mouse genome to date. Direct sequence analysis enables more rapid identification of mutated genes and sequence mining to identify as yet unrecognized genes. The mouse is expected to be a major player in the post genome era of identifying the functions of these genes. Large-scale mutagenesis programs using mice are taking advantage of powerful mutagens and sophisticated bioimaging and behavioral screening methods to provide tools for understanding how mouse, and ultimately mammalian, genes function and what disorders occur when their function goes awry. A selected list of electronic resources available to gain entry into the broad areas of mouse genetics and biomedical research is provided in Chapter 3 on Strains, Stocks, and Mutant Mice.

"T' O r" ~1 O

The future ITI

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene prediction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. ES cell deletion banks will allow the recovery of recessive mutations in ES cells (You et al., 1997). More than 5000 knockouts and more than 9000 gene-trapped mouse genes already were estimated in 2003 (Nagy etal., 2003). In 1998, Cumulina the mouse joined Dolly in being a mammal that can be cloned from somatic cells (Wakayama et al., 1998), making possible the creation of mice from somatic mutations. This technology is only likely to be exploited to its full potential if the efficiency and success rate of whole mouse cloning equals or exceeds that of mutating ES cells and turning them into mice. The whole mouse will continue to be the final test bed for determining how genes function,

m "O m

z O -I'1 -I rn:l: --4

O C t~ m :> ~" ~. (Jm "< O ~ m r-

the science of functional genomics. Ironically, one of the most rapidly growing areas of mouse genomic research, the genetic analysis of complex traits and diseases, combines the latest molecular technology, such as SNPs for gene mapping, with "breeding technologies developed in the mid-twentieth century. Initiatives have begun to develop larger panels of recombinant inbred strains and their variant recombinant congenic strains, and panels of consomic (chromosome substitution) strains (Nadeau et al., 2000; Threadgill et al., 2002). In the latter, one can search for complex trait genes on individual chromosomes and then narrow the analysis with segmental congenic strains. Thus, while other model organisms, such as Drosophila, yeast, worms (C. elegans), and zebrafish may be easier to manipulate and allow analyses that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases. u

E o Acknowledgments O We are grateful to Herbert 'Sandy' Morse, "!"

III, Elizabeth 'Tibby' Russell, Ken Paigen, Lee Silver, Eva Eicher, and Margaret Green from whose previous writings on the history of the laboratory mouse and mouse genetics we have borrowed heavily.

0

References

0 ee~

.../ Lt~

O IJJ

FLI. O FZ

LIA e~

LIA I.U

Andersson, L., Archibald, A., Ashburner, M., Audun, S., Barendse, W., Bitgood, J., Bonema, C., Broad, T., Brown, S., Burt, D., Charlier, C., Copeland, N., Davis, S., Davisson, M., Edwards, J., Eggen, A., Elgar, G., Eppig, J.T., Franklin, I., Grewe, P., Gill, T., 3rd, Graves, J.A.M., Hawken, R., Hetzel, J., Hillyard, A., Jacob, H., Jaswinska, L., Jenkins, N., Kunz, H., Levan, G., Lie, O., Lyons, L., Maccarone, P., Mellersh, C., Montgomery, G., Moore, S., Moran, C., Morizot, D., Neff, M., Nicholas, E, O'Brien, S., Parsons, Y., Peters, J., Postlethwait, J., Raymond, M., Rothschild, M., Schook, L., Sugimoto, Y., Szpirer, C., Tate, M., Taylor, J., VandeBerg, J., Wakefield, M., Wienberg, J. and Womack, J. (1996). Mamm. Genome 7, 717-734. Battey, J., Jordan, E., Cox, D. and Dove, W. (1999). Nat. Genet. 21, 73-75. Bitmer, J.J. (1936). Science 84, 162.

Bryan, W.R., Kahler, H., Shimkin, M.B. and Andervont, H.B. (1942).J. Natl. Cancerlnst. 2, 451. Buckland, R.A., Evans, H.J., Sumner, A.T. (1971). Exp. Cell Res. 69, 231-236. Capecchi, M.R. (1989). Science 244, 1288-1292. Castle, W.E. and Allen, G.M. (1903). Proc. Am. Acad. Arts Sci. 38, 602-622. Castle, W.E. and Little, C.C. (1910). Science32, 868-870. Ceci, J.D., Matsuda, Y., Grubber, J.M., Jenkins, N.A., Copeland, N.G. and Chapman, V.M. (1994). Genomics 19, 515-524. Celera Discovery System (CDS) (2001). http://cds.celera.com Committee on Standardized Genetic Nomenclature for Mice. (1972).J. Hered. 63, 69-72. Consortium (Mouse Genome Sequencing Consortium). (2002). Nature 420, 520-562. Cu~not, L. (1902). Arch. Zool. Exp. Gen. 3, 27-30. Cu~not, L. (1904). Arch. Zool. Exp. Gen. 4, 33-38. Cu~not, L. (1905). Arch. ZooL Exp. Gen. 4, 123-132. Davisson, M.T. (1999). Lab. Anim. (Millenium Issue) 28, 2-5. Davisson, M.T. and Roderick, T.H. (1978). Cytogenet. Cell Genet. 22, 552-557. Davisson, M.T., Roderick, T.H., Doolinle, D.P., Hillyard, A.L. and Guidi, J.N. (1990). In Genetic Maps, 5th edn (ed. S.J. O'Brien), pp. 4.3-4.14. Cold Spring Harbor Laborarory Press, Cold Spring Harbor. Deringer, M.K. (1978). In Origins of Inbred Mice, Proceedings of a Workshop, Bethesda, MD, February 1978 (ed. H.C. Morse, III), pp. 99-102. Academic Press, New York. Dietrich, W.E, Miller, J.C., Steen, R.G., Merchant, M., Damron, D., Nahf, R., Gross, A., Joyce, D.C., Wessel, M., Dredge, R.D., Marquis, A., Stein, L.D., Goodman, N., Page, D.C. and Lander, E.S. (1994). Nat. Genet. 7, 220-245. Doetschman, T., Maeda, N. and Smithies, O. (1988). Proc. Natl. Acad. Sci. USA 85, 8583-8587. Dymecki, S.M. (1996). Proc. Natl. Acad. Sci. USA 93, 6191-6196. Eicher, E.M. (1971). Genetics69, 267-271. Elliott, R.W. (1996). In Genetic Variants and Strains of the Laboratory Mouse, 3rd edn (eds M.E Lyon, S. Rastan and S.D.M. Brown), pp. 1312-1423. Oxford University Press, New York. Evans, M.J. and Kaufman, M.H. (1981). Nature292, 154-156. Francke, U. and Nesbitt, M.N. (1971). Cytogenetics 10, 356-366. Friedrich, G. and Soriano, P. (1991). GenesDev. 5, 1513-1523. Furth, J. (1978). In Origins of Inbred Mice, Proceedings of a Workshop, Bethesda, MD, February 1978 (ed. H.C. Morse, III), pp. 69-97. Academic Press, New York. Gordon, J.W., Scangos, G.A., Plotkin, D.J., Barbosa, J.A. and Ruddle, EH. (1980). Proc. Natl. Acad. Sci. USA 77, 7380-7384.

Gorer, P.A., Lyman, S. and Snell, G.D. (1948). Proc. R. Soc. Lond. (Biol.) 135, 499. Green, M.C. (1963). In Methodology in Mammalian Genetics (ed. W.J. Burdette), pp. 56-82. Holden-Day, San Francisco. Green, M.C. (1973)..MouseNewsLett. 49, 17. Green, M.C. (1979). In Genetic Variants and Strains of the Laboratory Mouse (ed. M.C. Green), pp. 8-278. Oxford University Press, New York. Guenet, J.L. (1986). Curr. Top. Microbiol. Immunol. 127, 109-113. Gurney, M.E., Pu, H., Chiu, A.Y., Dal Canto, M.C., Polchow, C.Y., Alexander, D.D., Caliendo, J., Hentati, A., Kwon, Y.W., Deng, H.X., etal. (1994). Science264, 1772-1775. Haldane, J.B.S. (1933). Nature 132, 265-267. Haldane, J.B.S., Sprunt, A.D. and Haldane N.M. (1915). J. Genet. 5, 133-135. Hanks, M., Wurst, W., Anson-Cartwright, L., Auerbach, A.B. and Joyner, A.L. (1995). Science 269, 679-682. Heston, W.E. (1978). In Origins oflnbredMice, Proceedings of a Workshop, Bethesda, MD, February 1978 (ed. H.C. Morse, III), pp. 109-117. Academic Press, New York. Hrab~ de Angelis, M.H., Flaswinkel, H., Fuchs, H., Rathkolb, B., Soewarto, D., MarschaU, S., Heffner, S., Pargent, W., Wuensch, K., Jung, M., Reis, A., Richter, T., Alessandrini, E, Jakob, T., Fuchs, E., Kolb, H., Kremmer, E., Schaeble, K., Rollinsk, B., Roscher, A., Peters, C., Meitinger, T., Strom, T., Steckler, T., Holsboer, E, Klopstock, T., Gekeler, E, Schindewolf, C., Jung, T., Avraham, K., Behrendt, H., Ring, J., Zimmer, A., Schughart, K., Pfeffer, K., Wolf, E. and BaUing, R. (2000). Nat. Genet. 25, 444-447. Hutton, J.J. (1969). Biochem. Genet. 3, 507-515. Hutton, J.J. and Coleman, D.L. (1969). Biochem. Genet. 3, 517-523. Hutton, J.J. and Roderick, T.H. (1970). Biochem. Genet. 4, 339-350. Johnson, K.R., Cook, S.A. and Davisson, M.T. (1994). Mamm. Genome 5, 670-687. Justice, M.J. (2000). Nat. Rev. Genet. 1, 109-115. Keeler, C. (1978). In Origins of Inbred Mice, Proceedings of a Workshop, Bethesda, MD, February 1978 (ed. H.C. Morse, III), pp. 179-193. Academic Press, New York, 719 pp. Koller, B.H., Kim, H.S., Latour, A.M., Brigman, K., Boucher, R.C. Jr., Scambler, P., Wainwright, B. and Smithies, O. (1991). Proc. Natl. Acad. Sci. USA 88, 10730-10734. Kozak, C.A., Hartley, J.W. and Morse, H.C. III. (1984). J. Virol. 51, 77-80. Kranz, D.M., Saito, H., Disteche, C.M., Swisshelm, K., Pravtcheva, D., Ruddle, EH., Eisen, H.N. and Tonegawa, S. (1985). Science 227, 941-945. Lalley, P.A., Francke, U. and Minna, J.D. (1978). Proc. Natl. Acad. Sci. USA 75, 2382-2386. Lathrop, A.E.C. and Loeb, L. (1915a). J. Exp. Med. 22, 646--673.

Lathrop, A.E.C. and Loeb, L. (1915b). J. Exp. Mea( 22, 713-731. Lathrop, A.E.C. and Loeb, L. (1918). J. Exp. Med. 28, 475-500. Lindblad-Toh, K., Winchester, E., Daly, M.J., Wang, D.G., Hirschhorn, J.N., Laviolette, J.P., Ardlie, K., Reich, D.E., Robinson, E., Sklar, P., Shah, N., Thomas, D., Fan, J.B., Gingeras, T., Warrington, J., Patil, N., Hudson, T.J. and Lande, E.S. (2000). Nat. Genet. 24, 381-386. Liyanage, M., Coleman, A., du Manoir, S., Veldman, T., McCormack, S., Dickson, R.B., Barlow, C., WynshawBoris, A., Janz, S., Wienberg, J., Ferguson-Smith, M.A., Schrock, E. and Ried, T. (1996). Nat. Genet. 14, 312-315. Loeb, L. (1902).J. Med. Res. 3, 44-82. Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S.W. and Bates, G.P. (1996). Cell 87, 493-506. Manson, A.L., Trezise, A.E., MacVinish, L.J., Kasschau, K.D., Birchall, N., Episkopou, V., Vassaux, G., Evans, M.J., Colledge, W.H., Cuthbert, A.W. and Huxley, C. (1997). EMBDJ. 16, 4238-4249. Mansour, S.L., Thomas, K.R. and Capecchi, M.R. (1988). Nature 336, 348-352. Miller, O.J., Miller, D.A., Kouri, R.E., Allderdice, P.W., Dev, V.G., Grewal, M.S. and Hutton, J.J. (1971). Proc. Natl. Aca~ Sci. USA 68, 1530-1533. Moriwaki, K. Sagai, T., Shiroishi, T., Bonhomme, E, Wang, C.-H., He, X.-Q., Jin, M-L. and Wu, Z-A. (1990). Biol. J. Linnean Soc. 41, 125-139. Morse, H.C., III. (1978). In Origins of Inbred Mice, Proceedings of a Workshop, Bethesda, MD, February 1978 (ed. H.C. Morse, III), pp. 3-21. Academic Press, New York. Morse, H.C., III. (1985). Immunogenetics21, 109-116. Mouse Genome Informatics (MGI), The Jackson Laboratory, Bar Harbor, Maine. (2003). http:/lwww. informatics.jax.org/ Moyer, J.H., Lee-Tischler, M.J., Kwon, H.Y., Schrick, J.J., Avner, E.D., Sweeney, W.E., Godfrey, V.L., Cacheiro, N.L., Wilkinson, J.E., and Woychik, R.P. (1994). Science 264, 1329-1333. Nadeau, J.H., Singer, J.B., Matin, A. and Lander, E.S. (2000). Nat. Genet. 24, 221-225. Nadeau, J.H. and Taylor, B.A. (1984). Proc. Natl. Acad. Sci. U.S.A. 81,814-818. Nagy, A. (2000). Genesis26, 99-109. Nagy, A., Perrimon, N., Sandmeyer, S. and Plasterk, R. (2003). Nat. Genet. 33 (Suppl.), 276-284. Nolan, P.M., Peters, J., Strivens, M., Rogers, D., Hagan, J., Spurr, N., Gray, I.C., Vizor, L., Brooker, D., Whitehill, E., Washbourne, R., Hough, T., Greenawa7, S., Hewitt, M., Liu, X., McCormack, S., Pickford, K., Sdlcy, R., Wells, C., Tymowska-Lalanne, Z., Roby, P., Gleniste:, P.,Thornton, C., Thaung, C., Stevenson, J.A., Arkell, R., Mburu, P.,

r" ~1

~ A

I'N

<

I'1"1

-o I'1"1

Z -4 O -PI -4 re"l" O

~, I" ~o O .~ O O m r-

LL U

E

8 I#1

O 8 O tw

O ts-*

tt~ LI.I

O UJ "r FLI..

O Fz e,

q W

Hardisty, R., Kiernan, A., Erven, A., Steel, K.P., Skarnes, W.C., Moss, J.E., Hurtley, S.M. and Beddington, R.S. (1995). Proc. Natl. Acad. Sci. USA 9 2 , 6592-6596. Voegeling, S., Guenet, J.L., Nickols, C., Sadri, R., Nasse, M., Isaacs, A., Davies, K., Browne, M., Fisher, E.M., Martin, Snell, G.D. (1948).J. Genet. 49, 87. J., Rastan, S., Brown, S.D. and Hunter, J. (2000). Nat. Snell, G.D. (1978). In Origim oflnbredMice, Proceedings of a Workshop, Bethesda, MD, February 1978 (ed. Genet. 25, 440-443.' H.C. Morse, III), pp. 119-156. Academic Press, New York. O'Brien, T. and Woychik, R. (2003). Nat. Genet. 33, 1-2. Snell, G.D. and Reed, S. (1993). Genetics 133, 751-753. Paigen, K. (1995). Nat. Mea( 1,215-220. Staff of the Roscoe B. Jackson Memorial Laboratory. (1933). Paigen, K. (2002). ILARJ. 43, 123-135. Science 78, 465-466. Paigen, K. (2003). Genetics 163, 1-7. Pearson, P.L. and Roderick, T.H. (1978). Cytogenet. Cell Stanford, W.L., Cohn, J.B. and Cordes, S.P. (2001). Nat. Rev. Genet. 2, 756-758. Genet. 22, 150-162. Rabbitts, P., Impey, H., Heppell-Parton, A., Langford, C., Strong, L.C. (1978). In Origins of Inbred Mice, Proceedings of a Workshop, Bethesda, MD, February 1978 Tease, C., Lowe, N., Bailey, D., Ferguson-Smith, M. and (ed. H.C. Morse, III), pp. 45-67. Academic Press, Carter, N. (1995). Nat. Genet. 9, 369-375. New York. Rodriguez, C.I., Buchholz, E, Galloway, J., Sequerra, R., Kasper, J., Ayala, R., Stewart, A.E and Dymecki, S.M. Taylor, B.A., Navin, A. and Phillips, S.J. (1994). Genomics 21, 62(->--632. (2000). Nat. Genet. 25, 139-140. Rowe, L.B., Nadeau, J.H., Turner, R., Frankel, W.N., Threadgill, D.W., Hunter, K.W. and Williams, R.W. (2002). Mamm. Genome 13, 175-178. Letts, V.A., Eppig, J.T., Ko, M.S., Thurston, S.J. and Birkenmeier, E.H. (1994). Mature. Genome 5, Tyzzer, E.E. (1909).J. Med. Res. 21,519. Utomo, A.R., Nikitin, A.Y. and Lee, W.H. (1999). Nat. 253-274. BiotechnoL 17, 1091-1096. Rowe, L.B., Barter, M.E., Kelmenson, J.A. and Eppig, J.T. Visscher,/01.B., Green, R.G. and Bitmer, J.J. (1942). Proc. (2003). GenomeRes. 13, 122-133. Soc. Exp. BioL Me~ 49, 94. Russell, W.L., Kelly, E.M., Hunsicker, P.R., Bangham, J.W., Maddux, S.C. and Phipps, E.L. (1979). Proc. Natl. Acad. Wade, C.M., Kulbokas, E.J., 3rd, Kirby, A.W., Zody, M.C., Mullikin, J.C., Lander, E.S., Lindblad-Toh, K. and Sci. USA 76, 5818-5819. Daly, M.J. (2002). Nature 420, 574-578. Saam, J.R. and Gordon, J.I. (1999). J. BioL Chem. 274, Wakayama, T., Perry, A.C., Zuccotti, M., Johnson, K.R. and 38071-38082. Yanagimachi, R. (1998). Nature 394, 369-374. Schonig, K. and Bujard, H. (2003). In Transgenic Mouse Methods and Protocols(eds M. Hofker and J. van Deursen), Watson, J. and Crick, E (1953). Nature 171,737-738. You, Y., Bergstrom, R., Klemm, M., Lederman, B., Nelson, H., pp. 69-104. Humana Press, Totowa, New Jersey. Ticknor, C., Jaenisch, R. and Schimenti, J. (1997). Silver, L.M. (I 995). Mouse Genetics, Conceptsand Applications, Nat. Genet. 15, 285-288. pp. 3-31. Oxford University Press, New York.