Download The Rat Gene Map

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).
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