The Mouse Gene Map

Muriel T. Davisson Ph.D., Dirck W. Bradt, M.S., Jennifer J. Merriam, Sc.M., Stephen F. Rockwood, B.A., and Janan T. Eppig, Ph.D., are on the research staff and in the Mouse Genomes Informatics group at The Jackson Laboratory, Bar Harbor, Maine. Muriel T. Davisson Ph.D., Dirck W. Bradt, M.S., Jennifer J. Merriam, Sc.M., Stephen F. Rockwood, B.A., and Janan T. Eppig, Ph.D., are on the research staff and in the Mouse Genomes Informatics group at The Jackson Laboratory, Bar Harbor, Maine. Muriel T. Davisson Ph.D., Dirck W. Bradt, M.S., Jennifer J. Merriam, Sc.M., Stephen F. Rockwood, B.A., and Janan T. Eppig, Ph.D., are on the research staff and in the Mouse Genomes Informatics group at The Jackson Laboratory, Bar Harbor, Maine. Muriel T. Davisson Ph.D., Dirck W. Bradt, M.S., Jennifer J. Merriam, Sc.M., Stephen F. Rockwood, B.A., and Janan T. Eppig, Ph.D., are on the research staff and in the Mouse Genomes Informatics group at The Jackson Laboratory, Bar Harbor, Maine. Muriel T. Davisson Ph.D., Dirck W. Bradt, M.S., Jennifer J. Merriam, Sc.M., Stephen F. Rockwood, B.A., and Janan T. Eppig, Ph.D., are on the research staff and in the Mouse Genomes Informatics group at The Jackson Laboratory, Bar Harbor, Maine. Knowledge about the laboratory mouse (Mus) genome is far more advanced than that of any other experimental mammal ( Figure 1 ). The first mammalian autosomal linkage group was identified in the mouse ( Haldane and others 1915 ). Since 1915, genetic mapping in the mouse has progressed with increasing rapidity each decade, with nearly 25,000 genes and DNA loci (segments) on the current map. This article provides a brief history of the mouse mapping efforts, highlights specific advances in the last 30 years that led to rapid increments in map growth, describes the methods used to generate the mouse map, and shows the status of the map as of January 1998. Mice of a standard inbred laboratory strain (black) and an inbred Mus spretus (agouti), commonly used for genetic mapping. Mice of a standard inbred laboratory strain (black) and an inbred Mus spretus (agouti), commonly used for genetic mapping. Mice carrying mutations that alter developmental pathways or metabolic functions provide model systems for analyzing the defects in comparable human disorders and for developing methods lot prevention and therapy. Linkage conservation often provides additional evidence for identity between potential mouse models and human diseases. The dense map of the laboratory mouse, the high degree of linkage conservation between the mouse and human genomes, and the intense interest in comparative mapping between the mouse and human genomes have enhanced greatly the value of the mouse as an experimental model for human disorders. The capability to move back and forth between the human and mouse linkage maps provides a powerful method to identify (1) genes mutated in specific human and mouse diseases and (2) mouse models for human genetic diseases. As of January 1998, more than 1000 spontaneous mutations that cause genetic disease have been identified in mice (Mouse Genome Database, MGD 1 1998). More than 100 of these have been proposed to be homologues of known human diseases; some are known to be mutations in homologous loci, and others are postulated on the basis of phenotypic similarities, comparative mapping, or both ( Andersson and others 1996 ; Bedell and others 1997a , b ; Darling and Abbott 1992 ; Searle and others 1994 ; Winter 1988 ). The number of cloned spontaneously mutated genes is increasing rapidly because of (1) advances in positional cloning technology and (2) the high probability of identifying candidate genes as the density of thc mouse genetic map increases. Recent advances in technologies to molecularly manipulate the mouse genome now make it possible to create models for specific human conditions. The genetic mapping of the mouse has its most distant roots in the social context of human history. Centuries ago Chinese and Japanese “mouse fanciers” caught and cultivated wild mice bearing unusual characteristics seen as curiosities worthy of domestication and propagation. These physical traits frequently involved either coat colors distinct from those of the wild agouti type or aberrant behavioral characteristics. Interest in keeping these oddities gradually spread westward through Europe and finally to the United States ( Silver 1995 ). William Ernest Castle greatly influenced early mouse genetics. Recognizing the unique analytical opportunity these “fancy” mice presented, he first brought them into the laboratory in 1902 ( Castle 1903 ; Russell 1954 ; Silver 1995 ). He presented some of the first findings relative to the segregation and independent assortment of various coat colors in mice: albino versus colored, spotted versus solid colored, black versus brown, and yellow versus nonyellow. In 1908, he established the Bussey Institute, from which came many of the early mouse geneticists in the United States ( Russell 1954 ). Students from this original research group diversified the original field of study but propagated a common appreciation for the importance of inbred strains in their work. Within a population of mice, they found that variation of certain characteristics could be minimized by selective inbreeding. Clarence Cook Little is credited with creating the first inbred strain to study the genetics of cancer and resistance to transplanted tumors ( Little and Tyzzer 1916 ). This first inbred strain was DBA, begun in 1909 to generate a line of dilute (d), brown (b), nonagouti (a) mice ( Russell 1985 ). The popularity of inbred strains became more widespread as researchers sought to minimize random background effects on multigenic complex traits. The genetic map of the mouse was begun in 1915 when Haldane and others ( 1915 ) published a landmark paper linking the pink-eyed dilution and albino traits in the mouse. Methods of mapping in the mouse remained very much the same from 1915 through the early 1970s; they were primarily dependent on observation of the segregation of phenotypic traits in linkage crosses using inbred laboratory strains ( Figure 2 ). The number of mapped loci doubled roughly every decade ( Copeland and others 1993 ; Eicher 1981 ). Scattered groups of loci were associated in linkage groups. Chromosomal assignments could be made for a handful of loci, but determining specific relative orders of the genes was often difficult, if not impossible, because of the limitations of the technologies of the time. Not until the 1970s were these linkage groups finally assigned to all chromosomes of the mouse genome ( Davisson and Roderick 1978 ; Eicher 1981 ). Eva M. Eicher associated the first linkage group (LGXII) with the smallest chromosome (Chr 19) using chromosomal translocations ( Eicher 1971 ). The advent of chromosomal banding ( Caspersson and others 1968 ) permitted the identification of all mouse chromosomes for the first time. Rapidly thereafter, the combination of banded chromosomes and reciprocal translocations—the idea of John Hutton working in Orlando J. Miller's laboratory—was used to assign linkage groups to most chromosomes ( Miller and others 1971 ). The last mouse linkage map to display only linkage group numbers (designated as Roman numerals) was published in 1971 ( Beechey 1971 ; Green 1971 ). Assignment of linkage groups to all chromosomes was completed in 1976 when the mahoganoid (md) gene was assigned to Chr 16 ( Roderick and others 1976 ). In 1972, an official chromosomal numbering system was first established by the Committee on Standardized Genetic Nomenclature of the Mouse to eliminate conflicting terminology in the literature ( Committee 1972 ). In 1973, an expandable chromosomal banding nomenclature was proposed ( Nesbitt and Francke 1973 ). The main effort in synthesizing mapping data and maintaining the mouse map was exerted by Margaret C. Green, who maintained the map for more than 20 yr from the mid- 1950s to 1977. Living linkage map of the mouse. This map was created by geneticists from the research staff of The Jackson Laboratory for the of in in mouse carrying the was at each chromosomal on the linkage map. Living linkage map of the mouse. This map was created by geneticists from the research staff of The Jackson Laboratory for the of in in mouse carrying the was at each chromosomal on the linkage map. the 1970s and advances the of mapping from a to a These the of additional of loci DNA of the mouse as a model in the Genome of ( and others 1988 ; and others and of genetic as used for mapping human were first used in the 1970s to map mouse genes ( Francke and others ). because linkage crosses between mice of be and provide the of was more in the human than in the mouse map. linkage using were on the of inbred laboratory strains from mice that been for many The number of genes that could be mapped in these crosses was because the strains common and were was to in many could be Mus the most distant wild mouse strain to with was in the of to in a of more from laboratory strain ( 1978 ). The of between was through of between laboratory mice and M. spretus mice are the more for mapping, and Mus mice were to be nearly as from laboratory mice as M. spretus ( and others 1992 crosses with M. commonly are used for mapping of mutations to be The and of DNA made it possible to DNA from crosses and type the DNA for additional as they were The numbers of that could be mapped in crosses made it possible to genes with and the to the of and The of advances is cloning and chromosomes 1 chromosomes 1 1 and gene mutations and to a As of were for mapping The of was on in in the genomes of strains ( Copeland and ). of loci, as or 1 permitted the of a the of the mouse genome on which to a map ( and others 1992 , 1995 ). This map, at the for now for every on has been with the gene map created by the Copeland and research group using an ( and others 1996 ). The increasing at which mouse genes have been mapped is in Figure at which mouse genes have been mapped from 1915 to 1998. at which mouse genes have been mapped from 1915 to 1998. maps of the mouse genome have been to with the human The has the of a physical map of the mouse that its genetic map, both mapped and random 1 ) ( ). effort at the of the is a physical map of the mouse chromosome ( and others ). physical mapping are associated with to genes or through for and others 1996 ; and others ; and others ). the to the mouse genome is not until ( and are at the of this in with human a of mouse that is mapped at the Mouse Genome ( ) is in with the United human chromosome effort ( ). that physical mapping and in mouse are These the mouse in laboratory ( and others the of Genomes and their that and numbers of from ( and others 1996 and the mouse that rapid of a from the of these ( and others 1996 ). and have been and are from ( ( and others 1993 ; and ( and others 1996 , by ). The methods most commonly used to and assign loci in mouse chromosomes are genetic linkage crosses using inbred and inbred used are 1 ) and in of to in the of and physical mapping using DNA method is Genetic crosses to the genetic of loci in the map, DNA from and which be of the from and the of genetic for at 2 or more genes or loci in a Genetic is the of physical between homologous genetic and of loci be from the number of between loci by the number of and mapping have been and found in mapping loci between the 2 DNA from the mice these has that be used to map many DNA loci in the mouse genome ( Copeland and ; 1994 ; and others 1994 ). on genetic between crosses for the same gene is to be chromosomal In it be that crosses with M. spretus generate only maps because of the of most of the genetic are in mice than in mice are as Chr ( Davisson and others ). The of in loci in that in of to in crosses with M. spretus mice, to in some ( MGD ). Genetic crosses gene and the for physical mapping of genetic strains are of inbred strains created from by mice from inbred as and be by strain 1 ) of the using a of were with now of or of gene or is more commonly As with the probability of loci is to the genetic between Linkage of loci between the 2 strains is by are to identify and genetic be by ( 1971 ; ). are a linkage in and is strains are for mapping phenotypic or traits that between the when is in the because mice from each line in a be to the line for a to in 2 of are most for chromosomal Since are only as a in the context of complex the mapping data from are more as increases. strains are of inbred strains in a to or more to 1 (designated the strain are made alter the is The other strain is the The of background and genomes is by the number of inbreeding. these are 2 each strain of its genes from the background strain and of its genes from the strain ( and others ; and others 1996 ). 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