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ILAR Journal V39(2/3) 1998
Comparative Gene Mapping
Muriel T. Davisson, Dirck W. Bradt, Jennifer J. Merriam, Stephen F. Rockwood, and Janan T. Eppig
| 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. |
INTRODUCTION
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.
REASONS FOR MAPPING THIS SPECIES
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, MGD1 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; BedeIl 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.
ORIGIN AND HISTORY OF THE MOUSE MAP
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.
ADVANCES CONTRIBUTING TO THE MAP
During the 1970s and 1980s, several significant advances transformed the flow of mapping information from a trickle to a torrent. These included the discovery of additional types of polymorphic loci (first biochemical, later DNA), recombinant DNA technology, selection of the mouse as a model organism in the Human Genome Initiative, development of interspecific backcrosses (Avner and others 1988; Bonhomme and others 1979), and creation of genetic databases as communication tools. Somatic cell hybrids, used extensively for mapping human genes, were first used in the late 1970s to map mouse genes (Francke and others 1977). However, because linkage crosses between mice of defined genotypes can easily be constructed and provide higher resolution data, the role of somatic cell hybrids was always more important in the human than in the mouse map.
Early linkage studies using polymorphic markers were based on the crossing of inbred laboratory strains derived from mice that had been domesticated for many years. The number of genes that could be mapped in these crosses was limited because the strains had common origins and were genetically quite similar. It was difficult to detect crossovers in many instances where no strain-specific markers could be distinguished. Mus spretus, the most genetically distant wild mouse strain able to interbreed successfully with domestic species, was introduced in the form of interspecific crossing experiments to bring in a pool of alleles more consistently variant from laboratory strain alleles (Chapman 1978). The level of resolution between neighboring markers thus was refined through improved definition of crossover events. Because hybrid FI males between laboratory mice and M. spretus mice are sterile, precluding the more efficient inter-crosses for high-resolution mapping, and Mus musculus castaneus mice subsequently were shown to be nearly as polymorphically different from laboratory mice as M. spretus (Johnson and others 1992), intersubspecific crosses with M. m. castaneus commonly are used for high-resolution mapping of mutations to be cloned.
The discovery and development of DNA polymorphisms made it possible to store DNA from crosses and cumulatively type the DNA panels for additional markers as they were identified. The large numbers of closely spaced markers that could be mapped in such individual crosses made it possible to precisely order genes with certainty and opened the door to the concept of integrating location, structure, and function. The list of recent advances is long: cloning and expression vectors; plasmids; probes; yeast artificial chromosomes (YACs1); bacterial artificial chromosomes (BACs1); expressed sequence tags (ESTs1); gel electrophoresis; Southern, Northern, and Western blots; targeted gene mutations (knockouts); and radiation hybrids, to name just a few.
As molecular biology advanced, new types of markers were developed for mapping purposes. The utility of restriction fragment length polymorphisms was based on naturally occurring differences in enzymatic cleavage patterns in the
genomes of divergent strains (Copeland and Jenkins 1991). Polymerase chain reaction amplification of highly polymorphic loci, such as microsatellites or simple sequence length polymorphisms (SSLPs1), permitted the construction of a scaffold spanning the length of the mouse genome on which to build a descriptive map (Dietrich and others 1992, 1995). This SSLP map, developed at the Whitehead Institute for Biomedical Research (Boston, Massachusetts), now contains 7377 markers--1 for every 400,000 nucleotide bases on average-and has been integrated with the gene map created by the Copeland and Jenkins research group using an inter-specific backcross (Dietrich and others 1996). The increasing rate at which mouse genes have been mapped is depicted in Figure 3.
Physical maps of the mouse genome have been slower to develop compared with the human genome. The Whitehead Institute has undertaken the construction of a first-pass genome-wide physical map of the mouse that parallels its genetic map, including both genetically mapped SSLP markers and random sequence tagged sites (STSs1) (http://www-genome.wi.mit.edu/cgi-bin/mouse/index). A collaborative effort based at the Harwell (United Kingdom) site of the Medical Research Council is producing a high-resolution physical map of the mouse X chromosome (Boyd and others 1998). Other smaller scale physical mapping efforts are associated with projects to clone genes or "walk" through small genomic regions (see for example, Hunter and others 1996; Misumi and others 1997; Wakabayashi and others 1997).
Although the completion date to sequence the entire mouse genome is not until 2008 (Dove and Cox 1998), several regions are being sequenced at the time of this writing, largely in conjunction with human sequencing. For example, a region of mouse Chromosome X that is being physically mapped at the Medical Research Council Mouse Genome Centre (http://www.mgc.har.mrc.ac.uk/xmap/xmap_about.html) is being sequenced in collaboration with the Sanger Centre (Hinxton, Cambridge, United Kingdom) human X chromosome sequencing effort (http://www. sanger.ac.uk/HGP/ChrX/). Other resources that will facilitate detailed physical mapping and sequencing in mouse are being produced. These include the T31 mouse radiation hybrid panel developed in Peter Goodfellow's laboratory (McCarthy and others 1997), the Integrated Molecular Analysis of Genomes and their Expression (I.M.A.G.E.) consortium project that arrays and makes available large numbers of clones from defined cDNA libraries (Lennon and others 1996), and the Washington University/Howard Hughes Medical Institute mouse EST project that performs rapid sequencing of a few hundred bases from the ends of these clones (Hillier and others 1996). YAC, BAC, and PAC libraries have been prepared and are available from Peter DeJonge (http://bacpac.med.buffalo.edu/), Hans Lehrach (Larin and others 1993; http://www.rzpd. de/), and Eric Lander (Haldi and others 1996, distributed by Research Genetics, Inc, http://www.resgen.com).
MAPPING METHODS
The methods most commonly used to order and assign loci in mouse chromosomes are genetic linkage crosses (especially using wild-derived inbred strains) and recombinant inbred (Rib strains. Also used are recombinant congenic (RC1) strains, congenic strains, somatic cell hybrids, and in situ hybridization of probes to chromosomes. Mapping in the future will include increased use of radiation hybrids and physical mapping using overlapping DNA segments. Each method is described briefly below.
Genetic Crosses
Genetic crosses still contribute substantially to the genetic order of loci in the map, especially backcross DNA panels from interspecific and intersubspecific crosses, which can be cumulatively genotyped. Haplotype analyses of the progeny from backcrosses and intercrosses enable the estimation of genetic recombination for alleles at 2 or more mutant genes or polymorphic loci segregating in a cross. Genetic recombination is the result of physical crossing over between homologous chromosomes; genetic distance and ordering of loci can be derived from the number of crossover events between loci divided by the total number of progeny genotyped. Interspecific and intersubspecific backcross mapping panels have been generated and found useful in mapping loci polymorphic between the 2 parental strains. Additionally, DNA extracted from the N2 mice making up these panels has provided useful community resources that can be used repeatedly to map many DNA loci in the mouse genome (Copeland and Jenkins 1991; European Backcross Collaborative Group 1994; Rowe and others 1994).
Based on recombination estimates (probabilities), genetic distances may differ between different crosses for the same interval, although gene order is expected to be consistent, barring undetected chromosomal rearrangements. In addition, it should be noted that interspecific crosses with M. spretus generate only female maps because of the sterility of F1 males. For most parts of the genome, genetic recombination distances are greater in female mice than in male mice although there are notable exceptions, such as distal Chr 15 (Davisson and others 1989). The phenomenon of interference helps in ordering loci in that 2-strand double recombinants rarely occur in intervals of 10 to 15 cM; in crosses with M. spretus mice, interference may extend up to 40 cM in some regions (MGD 1998). Genetic crosses establish gene order and thus pave the way for subsequent physical mapping of genetic intervals.
Recombinant Inbred Strains
RI strains are sets of inbred strains created from sibmated F2 progeny produced by crossing mice from different inbred progenitor strains, such as C57BL/6J and DBA/2J. Crossover events can be detected by strain distribution patterns (SDPs1) of alleles among the RI lines, typically using a series of regional markers. Most such RI sets were originally characterized with biochemical markers; now Southern analysis of restriction fragment length polymorphisms or polymerase chain reaction analysis of gene or microsatellite polymorphisms is more commonly used. As with crosses, the probability of loci recombining is directly proportional to the genetic distance between them. Linkage of polymorphic loci between the 2 progenitor strains is ascertained by comparing SDPs; similar SDPs are considered to identify linked markers, and genetic distances can be estimated by formulae (Bailey 1971; Taylor 1989).
RI sets are like a linkage cross frozen in time, and genotyping is cumulative. RI strains are valuable for mapping phenotypic or quantitative traits that differ between the progenitor strains, especially when there is environmentally caused variability in the trait, because several genetically identical mice from each line in a set can be typed to score the line for a trait. Because apparent double crossovers can occur due to single crossovers in 2 different generations of inbreeding, R1 sets are most useful for short chromosomal segments. Since RIs are only useful as a set, especially in the context of complex traits, the mapping data derived from RIs are more reliable as set size increases.
Recombinant Congenic Strains
RC strains are sets of inbred strains derived in a manner similar to RI sets except I or more backcrosses to 1 parental (designated the background) strain are made alter the Fl generation before inbreeding is begun. The other parental strain is designated the donor. The proportion of background and donor genomes is determined by the number of back-crosses preceding inbreeding. Because these sets are typically constructed following 2 backcrosses, each RC strain usually contains approximately 87.5% of its genes from the background strain and approximately 12.5% of its genes from the donor strain (Moen and others 1991; Stassen and others 1996).
As with recombinant inbred strains, a detailed characterization of SDPs of genes within a strain set is used to determine linkage relationships between loci and chromosomal segments associated with a trait such as tumor susceptibility. Typing of recombinant congenic strains is useful in the analysis of complex genetic traits in the mouse (Moen and others 1991).
Congenic Strains
Congenic strains are derived by successive backcrosses in which I strain (the donor) donates a segment of chromosome to the recipient (background or host) strain. Congenic strains are genetically almost identical to the background strain except for a short chromosomal segment contributed by the donor strain (Snell and Bunker 1965). Linkage in congenic stains can be assessed by determining which genes co-segregated as passengers in the genomic segment transferred from the donor strain to the recipient strain.
Somatic Cell Hybrids
Somatic cell hybrids are derived from the fusion of cells from unrelated species, such as Chinese hamster and mouse, to generate cell lines containing a subset of mouse chromosomes in an otherwise foreign host genome. Somatic cell hybrids enable the quick mapping to chromosomes of genes for which no polymorphic differences have as yet been identified. Mouse chromosome assignments of loci are determined by the concordant segregation of a locus of interest with identified mouse chromosomes and other mouse loci. The mouse chromosome complement of the hybrids is determined by karyotyping or by the analysis of gene markers that have known chromosome locations (Francke and others 1977; Kozak and others 1977; Schwarz and others 1992). Somatic cell hybrid panels can be used to rapidly assign genes, whether polymorphisms exist or not, as long as the genes derived from the mouse and the other species cell line partner can be distinguished.
Fluorescence in Situ Hybridization
In situ hybridization of radiolabeled or fluorescent probes to metaphase spreads of mouse chromosomes is useful in mapping genes to physical chromosomal regions. Chromosomes are "banded" by various chemical or fluorescent means to reveal characteristic staining patterns; superimposed probe signals localize genes to specific chromosomal regions or bands. Fluorescent in situ hybridization (FISH1) with multiple probes labeled with different fluorochromes allows the physical ordering of genes on a chromosome. Application of this method to extended chromosomes--so called fiber-FISH--permits estimation of intergenic distances for several loci or alignment of clone contigs on a chromosome (Duell and others 1997). FISH resolution on the order of several kilobases is now feasible (Palotie and others 1996).
Complementation Mapping
Specific locus tests, initially designed to test radiation-induced mutation frequencies, provided the first opportunities for extensive genetic complementation mapping in mouse (Russell 1971). Complementation analysis using a series of overlapping deletion mutations allows loci within the deletion region to be unambiguously ordered and has proved valuable in the identification of new recessive mutations in chromosomal regions and subregions. For example, loci within the pink-eyed dilution (p) (Russell and others 1995) and tyrosinase (Tyr) regions of mouse Chromosome 7
(Rinchik and others 1993; Russell and others 1982) and the myosin 5a (Myo5a) region of mouse Chromosome 9 (Kingsley and others 1990) have been extensively analyzed by deletion complementation methods. New techniques for saturating regions with deletion mutations and analyzing these deletion regions to discover new loci and order of known loci are expanding the application of complementation analysis for mouse (You and others 1997).
Radiation Hybrids
Radiation hybrids (RHs1) are another mapping tool that have been successfully developed for human data (Cox and others 1990; Rodriguez-Tome and Lijnzaad 1997; Stewart and others 1997; Walter and others 1994; Stanford Human Genome Center--http://www-shgc.stanford, edu/Mapping/rh/). During 1998, a RH panel for mouse (T31 ) consisting of 100 cell lines of mouse chromosome fragments on a hamster background has been made available. Initial characterization of the panel indicates a 25 to 27% retention rate per locus. Like backcross panels, data from the typing of the RH panel is cumulative. The methods are complementary in that back-cross panels, which produce recombination-based maps, provide highly reliable positioning for polymorphic loci; RH mapping can potentially provide high-resolution gene ordering for nonpolymorphic regions and fine mapping of regions not separable in the recombination map.
Because each RH cell line represents a highly fragmented subset of the mouse genome, error detection is difficult and a framework map tied to the well-defined genetic map is needed. A first report describing the T31 mouse RH panel has been published (McCarthy and others 1997) and collaborating public Web sites for data submission have been established in the United States at The Jackson Laboratory, Bar Harbor, Maine (http://www.jax.org/resources/documents/ cmdata), and in the United Kingdom at thc European Bioinformatics Institute, Hinxton, Cambridge, United Kingdom (http://www. ebi.ac.uk/RHdb/index.html).
Physical mapping locates various molecularly detectable genetic markers, genes, STSs, clones, and ESTs on larger genomic clones (YACs, BACs, P1 s, cosmids). Markers that "hit" multiple large clones can be used to assemble these into larger contigs of overlapping clones. Thus, for instance, YACs of approximately kilobase size can be screened and assembled into contiguous regions covering megabases of genome. High-resolution map building of the physical content of genomic regions is a prerequisite to developing sequence-ready maps.
CURRENT MAP STATUS
The mouse genome is estimated to contain approximately 300,000 megabases of DNA (or 3 x 109 bp). Based on chiasma frequencies, it has been estimated to have a genetic length of about 1600 cM (Carter 1955; Searle and others 1970). More recently, however, recombination data from the Massachusetts Institute of Technology SSLP map and the Frederick (Copeland/Jenkins) interspecific backcrosses have estimated this number to be in the range of 1450 or 1350 cM, respectively (Copeland and others 1993), and the current composite MGD map has a total of 1583 cM (MGD 1998).
The map includes many different types of loci. Genes represent discrete expressed elements of the genome defined molecularly or by the segregation of a single phenotypic trait. Related sequences are so designated for their nucleotide sequence similarity to known genes, but their expression status is usually undetermined. Pseudogenes have coding sequences but lack introns and are not expressed. Quantitative trait loci represent regions of the genome associated with particular phenotypes displaying complex inheritance. DNA segments are anonymous loci recognized by variation in DNA sequence. They designate uncharacterized points in the genome such as anonymous DNA segments, microsatellites, YAC ends, or sequence tag sites.
MGD, which is accessible through http://www.informatics.jax.org, contains collective mapping data from numerous strains and multiple mapping methods generated by hundreds of research groups. As of September 1998, these composite data provide an estimated genome length of 1583 cM for the mouse genome. Approximately 9000 genes are currently listed in MGD. More than 6300 of these genes, in addition to more than 13,000 DNA segments, are genetically mapped. Dividing the total number of mapped loci (genes and anonymous DNA segments) by the total cM length of the genome reveals an average of 12.4 loci per cM along the 19 autosomes and X chromosome of the mouse. At the time of this writing, MGD lists 3181 mouse/human homologue pairings, of which 2391 are mapped in both species. In Table 1, the types of genes are listed by chromosome as of September 1998.
Graphical maps depicting the current understanding of gene arrangements on mouse chromosomes come in several primary forms: cytogenetic, linkage, physical, and comparative. Cytogenetic maps depict the approximate location of loci relative to chromosomal bands identified by karyotypic methods (such as Giemsa banding and staining with 4'6-diamidino-2-phenylindole 2 HCI, DAPI). From the early 1970s through the mid-1980s, cytogenetic mapping was typically done using genetic crosses in which chromosome anomalies were segregating. Genes were mapped with respect to the known Giemsa-banded chromosomal break-points of these chromosomal anomalies. Now in situ and fluorescent in situ (FISH) hybridization of molecular probes to banded chromosomes is commonly the source of such mapping information.
Linkage maps represent the relative positions of loci on a given chromosome. Genetic distances are calculated centi-Morgan units from recombinational frequencies between genes derived from mouse crosses. Haplotype analysis is best for gene orders. These maps can be constructed on the basis of individual crosses, or composite linkage maps derived from all available experimental data can be displayed. Maps derived from a single source, such as the Whitehead SSLP map, are internally consistent since all mapping is based on the same experimental samples. Composite maps, because they combine data from many experiments using various mapping techniques, contain the most information, incorporating all mapped loci and placing loci with conflicting locations in reasoned, but imprecise, estimated positions.
Physical maps typically display an ordered array of genes, anonymous probes, and STSs relative to a set of overlapping clones (BACs, YACs, cosmids, and so forth). Genes or genetically mapped anonymous DNA sequences anchor the physically assembled contigs to the genetic linkage map. These maps are among the newest to be constructed on a large-scale basis, with particular view to localizing the increasing abundance of ESTs becoming available.
The comparative map illustrates homologous associations among species. These maps are useful in that they help to reveal regions of evolutionarily conserved chromosomal segments between species. MGD provides comparative maps that are constructed dynamically and show genes of the selected species superimposed on a mouse chromosome background.
Many published and electronic/computerized resources are available that present, in various forms, mouse genetic maps and mapping information. Annual published reports of the Mouse Chromosome Committees are available in the journal Mammalian Genome. Complete reports of the Chromosome Committees are also available electronically through the MGD from 1995 onward. Committees are encouraged to provide updates throughout the year (http://www.informatics.jax.org/bin/ccr/index).
COMPARATIVE MAPPI NG
The mouse genetic map was dense relative to maps of other mammalian species when it was formally included as I of the 5 model organisms whose genomes were to be characterized under the auspices of the Human Genome Initiative. Intense interest in comparative mapping, bolstered by many new technologies, has led to a dramatic increase in the number of identified conserved regions between species. As map detail increases, it serves as a tool for its own refinement and, more importantly, as an aid in the effort to define gene function by relating the phenotypic effects of mutations to specific structural genes.
Comparative genomic research using the mouse may be thought of as falling into 2 very broad categories. The first includes those studies that attempt to gain evolutionary insights into genome organization. Such studies are used to determine the rate of chromosomal rearrangements through time and between lineages, construct phylogenetic trees, and examine structural and functional relationships in gene clustering and separation. The second includes those studies designed to utilize a well-defined genetic map in 1 species to accelerate mapping of the genome of a poorly mapped species or to identify and clone candidate genes for human genetic diseases. The latter application has become prominent because of improvements in phenotypic testing, genome manipulation techniques, and the increased ease of sequencing.
An often understated concern associated with comparative genomic research is whether true orthologues are being observed in the species being considered. The criteria for discerning an orthologous relationship can vary between researchers. Often, sequence similarity is the sole criterion used in determining orthology, but it is frequently inadequate for this purpose. High sequence similarity can occur among paralogous gene family members. On the other hand, the extent of sequence similarity between orthologous genes may be surprisingly low, especially with large gene families containing many similar members. In 1 study of l 196 confirmed mouse/human orthologues, the degree of sequence similarity in mRNAs and proteins ranged between 36 and 100%, with an average of 85% (Makalowski and others 1996). In an attempt at standardization, the Human Genome Organization Committee on Comparative Genome Mapping has compiled a list of recommended criteria. They note that the strongest basis for discerning orthology is sequence similarity in conjunction with a conserved map position between homologous markers (Andersson and others 1996).
The high marker density found in mouse and human maps has allowed the construction of an exceptionally good comparative map that has resulted in the mouse being the comparative genome of choice, despite the fact that other potential model organisms possess genomes that have undergone fewer evolutionary chromosomal rearrangements relative to human (O'Brien and others 1997; Ehrlich and others 1997). Access to high-quality comparative maps, especially in conjunction with transgenic and mutagenesis technology, continues to aid the ongoing effort to delineate the functional significance of individual loci, contiguous multigene chromosomal segments, and the ever-growing collection of cDNAs represented as ESTs. In Figure 4, human-mouse conserved segments in the mouse map are depicted graphically. An electronic version of this comparative map that is continually updated can be found on the MGD web site (URL: http://www.informatics.jax.org/map/html. An electronic version of a mouse-human comparative map that includes physical mapping data is maintained at the National Center for Biotechnology Information site (see paragraph below).
When all of the genes in the human genome have been mapped and sequenced, the more daunting task of analyzing the functions of-70,000 genes will still lie ahead. The ability to map and sequence genes has outpaced our ability to attribute functions to them. The comparatively slow process of converting voluminous amounts of sequence into meaningful phenotypic information will undoubtedly require many and diverse resources. Included among these resources will be the many mouse ESTs amassed in public databases that have been generated by Washington University and others (Gerhold and Caskey 1996). As the name implies, ESTs serve as probes that allow the specific identification of nucleotide sequences that are likely to be expressed. Initially controversial, the use of ESTs as tools in gene mapping, especially in conjunction with radiation hybrids and YAC library mapping, has become routine. Use of ESTs in mapping projects has resulted in the generation of "transcript maps" (Boguski and Schuler 1995; Schuler and others 1996). A high-resolution comparative map that incorporates EST-based physical map information can be accessed at the World Wide Web site maintained by the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/Homology/). When such maps approach saturation, the rapid identification of mouse gene equivalents to human disease genes will be possible and will facilitate the development of mouse disease models.
COMPARATIVE MAPPING IDENTIFIES HUMAN GENES UNDERLYING COMPLEX TRAITS
The complex nature of many important human health conditions makes it virtually impossible to identify single genes involved. Examples are multigenic conditions, traits whose identification requires genetic manipulation (such as defined crosses) to isolate individual genes involved, and genes that cause subtle changes difficult to detect without special screening procedures.
Contiguous syndrome models (multigenic). Contiguous gene syndromes are conditions that result from deletion or duplication of whole chromosomal segments with many genes, including trisomy for some whole chromosomes. The resulting abnormalities are presumed to be a mixture of single gene effects and, for duplications, gene interactions. Dissecting the single gene effects involved is virtually impossible in human beings. For example, trisomy 21 causes Down syndrome (DSJ), which is one of the most common causes of mental retardation, occurring as one in 800 to 1000 live births (Hassold and Jacobs 1984). Detailed comparative mapping has enabled the creation of a mouse model called Ts(17ts)65Dn (abbreviated Ts65Dn) (Davisson and others 1993). At least 25 conserved genes have been identified that span most of the long (q) arm of human Chromosome 21 and the conserved segment in mouse Chromosome 16. The segment conserved is estimated to contain between 10 and 12 Mb and several hundred genes.
Because of the degree of conservation within comparable mouse and human chromosomal segments, the fact that the genes are closely linked in distal Chromosome 16 and in the same order as in human Chromosome 21 provides indirect evidence and experimental confidence that most of the segment is conserved intact. The trisomic segment contains several genes, including the following, which are being actively studied at the time of this writing as having a role in the DS phenotype: amyloid beta A4 precursor protein (App)~ which is also implicated in Alzheimer Disease; superoxide dismutase 1 (Sod1), implicated in aging; and phosphoribosylglycinamide formyltransferase (Gart, formerly Prgs), important in purine metabolism. Ts65Dn mice already have been shown to have several of the features seen in people with DS, such as developmental delay early in life and severe behavioral and learning deficits (Reeves and others 1995).
Cancer genes. Many human diseases, such as diabetes or some forms of human cancers, clearly have a genetic component but cannot be associated with a single mutant gene. The genes underlying such complex diseases often can be identified by making specially constructed mouse stocks that isolate individual genes implicated in similar mouse diseases. For example, a set of recombinant congenic strains was created from 2 inbred mouse strains differing in their susceptibility to colon cancer induced by the carcinogen 1,2-dimethylhydrazine: BALB/cHeA mice (relatively resistant) and STS/A mice (highly susceptible). Five colon tumor susceptibility genes have been identified, so far, and mapped to chromosomal regions (Moen and others 1992). Identification of these genes in the mouse now makes it possible to narrow the search for association between human familial colon cancer and specific regions of the human genome that are homologous to the regions identified in the mouse.
Circadian rhythm loci. A recent series of publications illustrates the synergistic benefits of comparative mapping and sequence comparison to identify genes underlying mammalian circadian behavior (Vitaterna and others 1994; King and others 1997; Antoch and others 1997). The predictability of mouse wheel-running behavior was used to screen the offspring of mice treated with the mutagen N-ethyl-N-nitrosourea. Under conditions of total darkness, 1 mouse had a circadian period that was I hr longer than considered normal. The trait was found to be inherited as a semidominant autosomal mutation; and homozygous mice, when completely deprived of light, exhibited even longer periods before losing circadian periodicity altogether. The trait was mapped to mouse Chromosome 5, in a region that has conserved synteny with human Chromosome 4. Using candidate gene and positional cloning techniques, the gene associated with the trait, Clock (for circadian locomotor output cycles kaput) has been cloned and sequenced.
The human homologue subsequently has been cloned and its position on human Chromosome 4 confirmed (J. S. Takahashi, Northwestern University, Evanston, Illinois, personal communication, 1997). Interestingly, Clock is widely expressed throughout the body. It is anticipated that new insights related to sleep disorders and mammalian periodicity in general will be gained as the expression of the Clock gene continues to be characterized.
MOUSE DATA RESOURCES
Mapping data for the mouse generated by multiple complementary techniques are growing rapidly, comparative mapping information among species is recognized as increasingly important, and the development of mouse models for human diseases has accelerated with the ability to clone mutant genes and create models through genomic manipulation. These factors contribute to a deluge of information that must be integrated and made globally available if it is to be useful and contribute to our overall understanding of the mammalian genome. Computer technology permitted the indexing of published materials as early as the 1950s; the more powerful and comprehensive electronic databases of the late 1990s make it possible for investigators to access more information much more quickly and easily than previously. As more data are accumulated and new technologies are developed for high-throughput analysis of increasingly complex biological phenomena, new electronic resources will be developed. Synthesis of genetic, physiological, expression, and systemic information will facilitate construction of the "complete" mouse map and its functional blueprint. A brief listing of some of the currently available database resources for mouse-related genome data is included as Table 2.
FUTURE DEVELOPMENT OF THE MAP
The genetic map of the mouse will continue to grow through linkage analysis. New spontaneous mutations will continue to be discovered. Large-scale mutagenesis projects will uncover new phenotypically defined genes. Quantitative and complex trait analyses will expand as methods to characterize phenotypes improve. Inbred strains and specially constructed genotypic backgrounds will be important resources for discovering and identifying genes that modify phenotypic expression and disease susceptibility.
One or more radiation hybrid maps for mouse will likely be developed. The T31 hybrid panel is being evaluated as a resource by Dr. Rosemary Elliott at Roswell Park Cancer Institute, Buffalo, New York, and The Jackson Laboratory Backcross DNA Panel Mapping Resource (Lucy Rowe), Bar Harbor, Maine, and McCarthy and others (1997). This panel, or others that may be constructed, can provide important supplementary information to the genetic map and be an intermediate level mapping tool between the genetic and physical maps.
The mouse physical map will develop rapidly, combining small physical maps generated around genes that are being positionally cloned and large-scale genome-wide physical mapping efforts. We anticipate that a substantial physical mapping effort will develop when interest in molecular level comparative mapping increases. The need for developing sequence-ready maps will further push the physical mapping effort because of the importance of sequencing more than a single mammalian species. The mouse is the clear candidate for this effort, given its extensive genetic map, the array of available genetic tools, the ability to manipulate its genome, and the interest in comparative disease models. From this effort will come sequence-based variation maps for both polymorphisms and mutations and, ultimately, the sequence of the mouse genome.
New types of maps also will appear as "functional genomics" really begins to develop. Not only is there interest in where genes are located on chromosomes and how they are organized, but also where and when they are expressed, how they are regulated, and how they interact. To this end, transcript maps, expression pattern maps, and maps describing metabolic and developmental cascades will be created to graphically represent genome function.
The developing technologies for high-throughput screening and data collection, including high-density microarrays and DNA chips, will ultimately make it possible to compare individual genetic variation and individual "maps." The potential of these technologies to revolutionize how we think about mapping and its possibilities for affecting health and our genetic future is staggering.
To make these important and exciting advancements of real benefit, significant bioinformatics tools will be needed. Data must be deposited directly into publicly accessible database resources. Databases must expand to incorporate new information types and develop associated analytical tools for integration of various data. New ways to handle large amounts of data and display them in human-comprehensible formats need to be developed. The realization of the "complete" mouse map is only a matter of time, and beyond the map is ultimately our understanding of the biological process.
1Abbreviations used in this paper: BAC, bacterial artificial chromosome; DS, Down syndrome: EST, expressed sequence tag; FISH, fluorescence in situ hybridization; MGD, Mouse Genome Database; RC, recombinant congenic; RH, radiation hybrid; RI, recombinant inbred; SDP, strain distribution pattern; SSLP, simple sequence length polymorphism; STS, sequence tagged site; YAC, yeast artificial chromosome.
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TABLE 1 Data derived from MGDa, September 1998
| Chromosome | Mapped Length (cM) | Genes/cM | No. of Genesb | No. of Dsegb | No. of Cytob | No. of Human Homologues |
| 1 | 111.1 | 3.4 | 375 | 1038 | 56 | 145 |
| 2 | 110.0 | 3.9 | 434 | 965 | 51 | 207 |
| 3 | 95.0 | 3.2 | 301 | 646 | 31 | 112 |
| 4 | 84.0 | 4.9 | 409 | 839 | 43 | 128 |
| 5 | 98.0 | 3.4 | 332 | 851 | 44 | 138 |
| 6 | 76.5 | 5.1 | 387 | 765 | 35 | 138 |
| 7 | 74.0 | 7.2 | 535 | 747 | 49 | 192 |
| 8 | 84.0 | 3.4 | 286 | 657 | 37 | 116 |
| 9 | 74.0 | 4.0 | 296 | 612 | 27 | 122 |
| 10 | 77.0 | 3.1 | 236 | 528 | 46 | 99 |
| 11 | 85.0 | 5.5 | 465 | 976 | 34 | 209 |
| 12 | 61.0 | 4.1 | 253 | 518 | 35 | 65 |
| 13 | 75.0 | 3.1 | 231 | 624 | 33 | 72 |
| 14 | 69.0 | 4.6 | 318 | 486 | 48 | 77 |
| 15 | 72.5 | 3.1 | 224 | 520 | 32 | 94 |
| 16 | 70.0 | 2.6 | 182 | 472 | 43 | 79 |
| 17 | 58.0 | 8.3 | 484 | 721 | 44 | 138 |
| 18 | 58.0 | 2.2 | 130 | 378 | 20 | 53 |
| 19 | 55.0 | 3.1 | 169 | 303 | 16 | 72 |
| X | 96.5 | 2.8 | 270 | 622 | 28 | 129 |
| Y | NKa | NK | 39 | 73 | 4 | 5 |
| XY | NK | NK | 8 | 15 | 1 | 1 |
| Mapped total | 1583.6 | 6364 | 13356 | 757 | 2391c | |
| Unmapped | NK | NK | 2738 | 235 | 1 | 544d |
bGenes = genes, pseudogenes, related sequences; Dseg = anonymous DNA segments; Cyto = cytogenetic markers (chromosomal aberratios, insertions, deletions, heterochromatin).
cMapped in both mouse and human.
dUnmapped in either mouse or human or both.
TABLE 2 Mapping and comparative mapping sites for mouse on the World Wide Web.
| Site | Map data and displays a | URL |
| EBIb Radiation Hybrid Database | T31 RHb panel data set | http://www.ebi.ac.uk/RHdb/ |
| Jackson Laboratory Backcross DNA Mapping Resource & Radiation Hybrid Database | Genetic mapping panel data sets T31 RH panel data set Genetic and RH maps | http://www.jax.org/resources/documents/cmdata/ |
| Whitehead Institute/MITb | Genetic mapping panel data set Physical mapping data Genetic and physical maps | http://www.genome.wi.mit.edu/cgi-bin/mouse/index |
| MRCb Mouse Genome Center | Genetic mapping data set Physical mapping data, Chr b XGenetic and Chr X physical maps | http://www.hgmp.mrc.ac.uk/MBx/MBxHomepage.html |
| Animal Genome Database in Japan | Mapping data Genetic, cytogenetic maps | http://ws4.niai.affrc.go.jp/ |
| Mouse Genome Database | Mapping data (all techniques) Genetic, cytogenetic, physical maps Comparative mapping data and maps | http://www.informatics.jax.org |
| LaTrobe University | Comparative mapping data and maps | http://www.latrobe.edu.au/www/genetics/compmap.html |
| Dysmorphic Human-Mouse Homology Database | Comparative mapping data | http://www.hgmp.mrc.ac.uk/DHMHD/dysmorph.html |
| MRC Mammalian Genetics Unit | Comparative mapping data and maps Genetic and cytogenetic maps | http://www.mgu.har.mrc.ac.uk/ |
| National Center for Biotechnology Information | Comparative mapping data | http://www.ncbi.nlm.nih.gov/Homology/ |
| GeneCards | Comparative mapping data | http://bioinformatics.weizmann.ac.il/cards/index.html |
bEBI, European Bioinformatics Institute; MIT, Massachusetts Institute of Technology; MRC, Medical Research Council; RH, radiation hybrid.
FIGURE 1 Mice of a standard inbred laboratory strain (black) and an inbred Mus spretus (agouti), commonly used for genetic mapping.
FIGURE 2 Living linkage map of the mouse. This map was created by geneticists from the research staff of The Jackson Laboratory for the Tenth International Congress of Genetics in Montreal in 1958. A live mouse carrying the mutant allele was displayed at each gene's chromosomal location on the linkage map.
FIGURE 3 Cumulative rate at which mouse genes have been mapped from 1915 to 1998.
Chromosome 1
Chromosome 2
Chromosome 2 (Continued)
Chromosome 3
Chromosome 4
Chromosome 5
Chromosome 6
Chromosome 7
Chromosome 8
Chromosome 9
Chromosome 10
Chromosome 11
Chromosome 12
Chromosome 13
Chromosome 14
Chromosome 15
Chromosome 16
Chromosome 17
Chromosome 18
Chromosome 19
Chromosome X
Chromosome Y
FIGURE 4 Linkage map of the mouse showing mouse genes that have human homologues in the Mouse Genome Database as of September 1998. Extreme left, a stick figure depicting the chromosome. Along the chromosome length, a box indicates the expanse of the chromosome shown in the enlarged region to the right. A centimorgan scale displays the metric distance for the chromosome panel. Right of this scale for each locus on the chromosome: mouse gene symbol, gene symbol for human homologue, and cytogenetic assignment of the human homologue.
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