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The Rat Gene Map Goran Levan, Fredrik Stahl, Karin Klinga-Levan, Josiane Szpirer, and Claude Szpirer INTRODUCTION The Norway rat (Rattus norvegicus) was the first mammal to be domesticated primarily for research purposes, perhaps as many as 150 yr ago. The rat is 1 of the 2 most widely used experimental animals in biomedical research; and a wealth of knowledge, primarily in physiology, is available (Jacob and others 1995; James and Lindpaintner 1997). Many genetically defined strains have been developed and maintained. Some strains display specific susceptibility to complex traits such as hypertension, diabetes, arthritis, or cancer; and others evidence certain immune dysfunctions or neurobiological disorders (Hedrich 1990). When attempting to elucidate the role of genetic and environmental factors that underlie such diseases, studies with these models will be extremely useful complements to research on human subjects (Gill and others 1989). Until the 1980s, 2 main drawbacks with the rat as a genetic model organism have been the poor development of the rat gene map and the paucity of useful polymorphic genetic markers. Although these factors have hampered high-level genetic research with the rat model, developments beginning in the mid-1980s have largely overcome these problems. Perhaps the most important advance has been the discovery and development of microsatellite markers (simple sequence repeat length polymorphism [SSLP1]), which has led to a revolution in rat linkage mapping. In addition, the new regional chromosome mapping methods (such as fluorescence in situ hybridization [FISH1]) have had a great impact on the development of an integrated rat gene map. GENE MAPPING IN THE RAT With the advent of the chromosome banding techniques developed in the early 1970s, the rat banded karyotype was characterized and standardized (Committee for a Standard- Goran Levan, Ph.D., is Professor, Fredrik Stahl, Ph.D., Curator of the RATMAP database, and Karin Klinga-Levan, Ph.D., are with the Department of Cell and Molecular Biology-Genetics at Goteborg University, Sweden. Josiane Szpirer, Ph.D., and Claude Szpirer, Ph.D., Professor, are with the Department of Molecular Biology, Free University of Brussels, Rhode-St-Genese, Belgium. 'Abbreviations used in this paper: FISH, fluorescence in situ hybridization; MIT, Massachusetts Institute of Technology; QTL, quantitative trait locus; SSLP, simple sequence repeat length polymorphism. 132 ized Karyotype of Rattus norvegicus 1973; Levan 1974). This primary step in the development of the rat chromosomal map was essential for the characterization of mapping panels of cell hybrids that segregate rat chromosomes, first developed in the mid-1980s (Szpirer and others 1984; Yasue and others 1991). At the time, the rat gene map was quite limited and contained approximately 70 loci that were associated in 13 linkage groups, none of which was connected to any specific chromosome. As soon as the mapping panels came into use, most of the linkage groups could be assigned to specific rat chromosomes. In addition, many new chromosomal assignments of rat genes were made (Levan and others 1990, 1991, 1993). Thus, chromosomal mapping using the hybrid panels rapidly led to the chromosomal assignment of several hundred genes (the count in July 1992 was 369; Levan and others 1993). As described above, the major advances during the 1990s were the development of efficient methods for regional mapping, which included linkage mapping by the SSLP technique, and regional gene assignments with FISH. Many partial linkage maps were published in the early 1990s (Remmers and others 1992; Serikawa and others 1992; Zha and others 1993). The first comprehensive linkage map based on a single F 2 interstrain cross was published in 1995 (Jacob and others 1995); additional large linkage maps based on recombinant inbred strains (Pravenec and others 1996) or on other interstrain crosses (Bihoreau and others 1997) were released later. Using available cell hybrid panels, it became possible to anchor the linkage groups developed from the SSLP analysis to specific chromosomes. At the time of this writing, rat genome projects have been launched both in the United States and in Europe, with the goal of producing an integrated genetic map containing more than 6000 SSLP markers in the rat (Table 1). When completed, these efforts will have provided the foundation for the full exploitation of the many possibilities offered by the available rat models. RAT DATABASES AND SINGLE CHROMOSOME COMMITTEES Important factors in the more recent developments of the rat map include the emergence of sites on the Internet containing rat mapping information. Several useful sites are listed in Table 1. The major rat genome database is RATMAP, which contains assimilated mapping information, comparative maps, rat strain lists, and information about rat genetic no- ILAR Journal TABLE 1 Useful rat genomic resources on the Internet WWW a address Host site http://ratmap.gen.gu.se/ Goteborg University, Sweden World consortium map, nomenclature, list of rat strains, rat-human and rat-mouse homologies Wellcome Trust Centre Oxford consortium genetic map, physical for Human Genetics, resources Oxford, UK Whitehead Institute, MITfa and Wisconsin genetic map, physical Center for Genome resources Research, Boston, MA The Jackson Laboratory, Homology database, list of rat strains, rat Bar Harbor, ME bulletin board Research Genetics Inc., Commercial suppliers of genetic markers, rat Huntsville, AL YACa clones http://www.well.ox.ac.uk http://www.genome.wi.mit.edu http://www.informatics.jax.org http ://www. resgen. com Resource ''MIT, Massachusetts Institute of Technology, Boston, MA; WWW, World Wide Web; YAC, yeast artificial chromosome. menclature. The rapid development of the mapping information in RATMAP since 1994 is illustrated in Figure 1. Single chromosome committees have been active in compiling reports on each of the rat chromosomes based on the information available in RATMAP. These reports are published in 4500 n 4000 3500 3000 25002000- 1500 1000 the journal Rat Genome and will also become available at the RATMAP Web site. The curators of the RATMAP database collaborate with the Homology Database at the Mouse Genome Database by supervising the rat-mouse and rat-human homologies and providing regular updates of them. The Homology Database covers more than 60 mammalian species and is an excellent starting point when looking for homology among different species. At the time of this writing, there are 2 major Web sites for rat linkage markers (Table 1): the Wellcome Trust Centre for Human Genetics Web site, which has an integrated linkage map from 3 crosses with more than 750 markers, and the Whitehead/Massachusetts Institute of Technology (MIT1) Web site, which exhibits maps from 2 crosses with more than 2000 markers. The number of linkage markers is rapidly increasing. The Wellcome laboratories linkage maps contain both genes and DNA markers, whereas the Whitehead/MIT maps are almost exclusively built up from anonymous DNA markers, most of which have been isolated and characterized within the new rat genome project. Both Web sites present information on primer sequences and rat strain polymorphism for each locus, and the Whitehead/MIT Web site also sustains a very useful search function for markers by chromosomal position and strain polymorphism. CURRENT MAP STATUS FIGURE 1 Developments of rat loci mapped according to RATMAP at different time points since June 1994. Filled squares represent gene loci, and open squares, anonymous DNA markers (mainly simple sequence repeat length polymorphism linkage markers). It can be seen that the rate of gene mapping corresponds to a rather steady increase in the number of loci, whereas anonymous markers are being generated and released at rapidly increasing rates. Volume 39, Numbers 2 and 3 1998 Markers that have been mapped in the rat may be subdivided into 2 major groups: (1) those corresponding to genes (type I markers; O'Brien and others 1993), and (2) anonymous DNA markers (mostly microsatellite [SSLP] markers [type II markers]). At the time of this writing, mapping information exists for about 900 of the former kind and about 4000 of the latter (Table 2). Especially valuable are the approximately 100 loci that have been mapped regionally both by FISH and by linkage. Because these loci can be used to "anchor" the linkage groups on the physical chromosomes, 133 TABLE 2 Subdivision of markers contained in the rat gene map with respect to type of marker and mode of mapping3 Type of marker No. of markers Genes (type 1 loci) =100 =450 =100 =250 Anonymous microsatellite markers (type II loci) =3500 13 Mapping method Regional mapping both by physical (FISH6) and genetic (linkage) means Regional genetic mapping only (SSLPfe, linkage) Regional physical mapping only (FISH) Assigned to chromosome (somatic cell hybrids) Regional genetic mapping (SSLP, linkage) -•Data from RATMAP, December 1997. fa FISH, fluorescence in situ hybridization; SSLP, simple sequence repeat length polymorphism. 1 A 14 15 16 21 22 23 24 25 26 31 32 33 34 41 they are prerequisite to producing a single, truly integrated map that contains all the mapping information. The first papers presenting integrated maps covering the whole rat genome are in preparation at the time of this writing (Szpirer and others 1998). Through these efforts, it is now possible to construct physical maps in which the mapped loci are properly positioned in their approximate location on the chromosome shown (Figure 2). As mentioned in the Introduction, many valuable model strains for complex diseases exist in the rat. Many of these models are used extensively in research; and a number of quantitative trait loci (QTLs1), which control some of the disease phenotypes, have been identified and are shown in Table 3. Candidate genes have been suggested for some of these QTLs, and this type of research clearly emphasizes the usefulness of the rat in biomedical research. COMPARATIVE MAPPING, WITH SPECIAL REFERENCE TO MOUSE AND HUMAN The RATMAP database covers homology data for rat loci to human and to the mouse. For comparative mapping, only type I markers are useful. For rat and human, a total of 555 mapped pairs of homologous loci have been registered, 527 of which are autosomally located. The number of mapped homologous pairs is somewhat smaller (517 total; 491 autosomal loci) when rat and mouse loci are compared. The number of homologous loci for which mapping information is available in all 3 species is 489 (465 autosomal loci). Since it is well documented that X-linked genes are conserved within the sex chromosomes and subject to different con134 42 43 44 45 RNO2 FIGURE 2 Combined data from regional chromosomal mapping (fluorescence in situ hybridization [FISH]) and regional genetic mapping (linkage analysis) can be amalgamated to provide a clear picture of both order and position of rat gene loci in rat chromosome 2. Gene symbols in bold have been mapped by FISH; remaining loci have been added at their deduced position after inspection of the linkage map. Adapted from a single chromosome report (Szpirer and others 1997). straints from the autosomes (Ohno 1967; Millwood and others 1997), the analysis of conserved segments below is restricted to autosomes. The status and level of regional sublocalization of genetic markers are quite different in the 3 species. Thus, very good chromosomal maps are available for the human, whereas more limited amounts of regional chromosomal mapping has been performed in the mouse. In contrast, the linkage map for the mouse contains regional assignments of numerous type I markers. Rat, like human, linkage maps contain mainly type II markers, but the number of genes that have been regionally mapped by FISH is rapidly increasing. This means that comparisons of the rat with the human map are most informative if they are made using the physical ILAR Journal TABLE 3 Polygenic traits analyzed in the rat with QTLsa localized Cardiovascular traits Blood pressure control (hypertension) (1-9fa) Cardiac mass (8) Stroke (10) Hematocrit (11) Renal failure (7) Body weight, obesity, lipid level (12-14) Diabetes and insulin action (IDDMa and NIDDMa) (12, 13, 15) Arthritis (16) Cancer susceptibility (1 7, 18) Behavior (hyperactivity) (19) Morphology: polydactyly (20, 21) RNO6 RNO9 RNO4 a IDDM, insulin-dependent diabetes mellitus; NIDDM, non-insulindependent diabetes mellitus; QTL, quantitative trait locus. b Text references are numbered as follows in the body of this table: (1) Jacob and others 1991; (2) Hilbert and others 1991; (3) Deng and others 1994a; (4) Deng and others 1994b; (5) Schork and others 1995; (6) Pravenec and others 1995; (7) Brown and others 1996; (8) Kren and others 1997; (9) Kren and others 1996b; (10) Rubattu and others 1996; (11) Pravenec and others 1997; (12) Galli and others 1996; (13) Gauguier and others 1996; (14) Bottger and others 1996; (1 5) Aitman and others 1997; (16) Remmers and others 1996; (1 7) Hsu and others 1994; (18) Wendel and Gorski 1997; (19) Moisan and others 1996; (20) Kren and others 1990; (21) Kren and others 1996a. map; however, in comparisons with the mouse, the linkage map provides more information. Examples of the results of such comparisons are shown in Figure 3. 2 Based on the status of the maps at the time of this writing, it is possible to distinguish 70 autosomal chromosome segments, each containing 2 or more genes (range 2 to 51) that appear to have been conserved between rat and human. This is clearly a minimal estimate, since there are also 41 single genes that might represent the first gene located in a conserved segment. Furthermore, apparently continuous segments may in fact be composed of several smaller pieces, since it is usually not known whether there is strict colinearity in the order of the genes. If, in fact, each singleton represents the first gene in a true conserved segment (rather than a gene mapped to the wrong position), 10 of them will split an existing conserved segment into 2 smaller segments. Thus, 41 singletons will generate 41 new segments with 10 additional segments, for a total of 121. Although this figure compares well with the number of segments detected between 2 In this article, the older nomenclature for species is retained (ISCN, 1995: An International System for Human Cytogenetic Nomenclature. Mitelman, editor. Basel: S. Karger, 1995). In this system, the species is abbreviated by 3 capital (Roman) letters; for example, Homo sapiens is HSA and Rattus norvegicus is RNO. Elsewhere in this volume, the more recent recommendations of the Comparative Genome Organization Workshop (1996; Mamm Genome 7:717-734) have been followed. Volume 39, Numbers 2 and 3 1998 RNO3 RNO13 RNO9 RNO8 HSA2 MMU1 FIGURE 3 Examples of comparative mapping analysis with human and mouse. Left, human chromosome 2 (Hsap2) diagram with 4 conserved homologous segments from rat chromosomes (Rnor) 3, 4, 6, and 9 aligned. The homologue of a singleton from Rnor8 resides.inband//sa/?2g37.3. Right, mouse chromosome 1 (Mmusi) linkage diagram with 2 conserved homologous segments from Rnor9 and Rnor 13 aligned. human and mouse, which has been found to be 120 (DeBry and Seldin 1996) in a material comprising nearly 1400 pairs of homologous genes, one must take into account the fact that some of the singletons are likely to have appeared due to incorrect mappings and/or incorrect homology. As one might expect, the corresponding comparison between rat and mouse yields much longer (and therefore 135 fewer) conserved segments. Thus, the number of apparently conserved autosomal chromosome segments is only 33. Of the 20 singletons, 8 appear to be located inside existing segments. The maximal number of conserved segments indicated by the present data set is 61—about half the number of segments found when either species is compared with human. It should be kept in mind that these calculations are very approximate due to the scarcity of data, but they might still provide hints of genomic relationships among the 3 species. Thus, what appears to be a considerable amount of genome rearrangement between rat and mouse is perhaps more than would be expected on the basis of evolutionary distance. In certain other mammalian species, the rate of genome scrambling appears to be quite slow (O'Brien and others 1997). Thus, between human and cat, only 30 homology segments were identified by cross-species chromosome painting (so-called ZOO-FISH), and these 2 species are thought to have had a common ancestor 65 to 80 million yr ago. Rat and mouse, which shared a common ancestor about 25 million yr ago, have a minimum of 33 (but perhaps as many as 61) different conserved segments as discussed above. Therefore, the rat-mouse data appear to suggest that the rate of chromosomal evolution in rodents is comparatively rapid among mammals, corroborating conclusions from cytogenetic studies (such as Arnason 1972). ACKNOWLEDGMENTS This work was supported by a joint grant from the European Commission (contract ERBBIO4CT960562) and by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the IngaBritt and Arne Lundberg Research Foundation Sweden), as well as the CGER-Assurances, the Association Contre le Cancer, the "Communaute Francaise de Belgique" (ARC), and the National Fund for Scientific Medical Research (FRSM). REFERENCES Aitman T, Gotoda T, Evans A, Imrie H, Heath KE, Trembling PM, Truman H, Wallace CA, Rahman A, Dore C, Flint J, Kren V, Zidek V, Kurtz TW, Pravenec M, Scott J. 1997. Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive rats. Nat Genet 16:197-201. Arnason U. 1972. 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