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Physiol. Genomics 33: 205-211, 2008. First published January 22, 2008; doi:10.1152/physiolgenomics.00222.2007
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Received 23 September 2007; accepted in final form 16 January 2008.
Physiological Genomics 33:205-211 (2008)
1094-8341/08 $8.00 © 2008 American Physiological Society

Functional polymorphisms in inbred rat strains and their allele frequencies in commercially available outbred stocks

Takashi Kuramoto, Satoshi Nakanishi and Tadao Serikawa

Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Polymorphisms that have been proven to influence gene functions are called functional polymorphisms. It is significant to know the distribution of functional polymorphisms in the rat, widely used in animal models for human diseases. In this study, we assessed 16 functional polymorphisms consisting of 3 coat color and 13 disease-associated genes in 136 rat strains, as a part of the genetic profiling program of the National Bio Resource Project for the Rat (NBRP-Rat). Polymorphisms of Cdkn1a, Fcgr3, Grp10, Lss, and Fdft1, which were proven to function in prostate tumorigenesis, glomerulonephritis, hyperphagia, and cholesterol biosynthesis, were shared among various inbred strains. These findings indicated that most rat strains harbored the disease-associated alleles and suggested that many unidentified functional polymorphisms might exist in inbred rat strains. The functional polymorphisms shared in inbred strains were also observed within outbred stocks available commercially. Therefore, this implies that experimental plans based on either rat inbred strains or outbred stocks need to be carefully designed with a full understanding of the genetic characteristics of the animals. To select the most suitable strains for experiments, the NBRP-Rat will periodically improve and update the genetic profiles of rat strains.

rat resource; National Bio Resource Project; disease model; single nucleotide polymorphism


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
THE LABORATORY RAT (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development. It is used extensively as a model organism for studying normal and disease processes in humans because of our extensive knowledge of rat physiology and the large number of rat models that mimic human diseases. In drug development, rats are central to determination of drug efficacy and toxicity before human clinical trials.

Recently, a large set of genomic tools and information on the rat genome such as the rat genome draft sequences (6), the large-scale single nucleotide polymorphism (SNP) haplotype map (STAR project), and the Phenome Project (11, 13) have been developed, allowing us to identify genes responsible for monogenic as well as polygenic traits in rat models. Because these mutations have been proven to function in the pathogenesis of diseases, they are also called functional polymorphisms. Recently, the assessment of functional polymorphisms by PCR has demonstrated some not to be unique to the strain in which they were initially identified but to be shared by several rat strains (9, 16, 22). Furthermore, some functional polymorphisms were also found in outbred colonies at various allele frequencies (9, 22).

The National Bio Resource Project for the Rat (NBRP-Rat) is one of the largest resource centers for the rat (18). More than 200 inbred strains have been deposited so far in the NBRP-Rat and are maintained as live animals or cryopreserved embryos. The NBRP-Rat offers comprehensive data sets on the strains deposited that are useful for the design of experiments for genetic analysis (14). With the growing number of genes identified as causative in rat disease models, the genetic profiles of the deposited rat strains for these functional polymorphisms need to be updated.

In this study, to further improve the genetic profiles of the strains deposited in the NBRP-Rat, we examined rat strains for known functional polymorphisms such as disease-associated and coat color alleles. Because coat color mutations are involved in organelle trafficking, signal transduction, and differentiation (20), it is also important to know how prevalent coat color mutations are in the established inbred strains. We also investigated how prevalent these polymorphisms are among commercial colonies of outbred rats, and we discuss controversial points in the use of outbred stocks.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals.
A total of 136 inbred rat strains were examined. Genomic DNA samples of 114 strains were obtained from the NBRP-Rat in Japan and those of 22 strains from commercial breeders or holders of the strains.

Eleven outbred colonies were examined. Outbred rats from each colony were purchased in bulk from the following commercial breeders. Crj:CD(SD) (n = 31), Crj:CD(SD)IGS (n = 31), Crj:WI(Glx/BRL/Han)IGS (n = 31), and Crj:Wistar (n = 31) outbred rats were from Charles River Laboratories Japan (Yokohama, Japan). BrlHan:WIST (n = 32), Jcl:SD (n = 32), and Jcl:Wistar (n = 32) outbred rats were from CLEA Japan (Kawasaki, Japan). Slc:SD (n = 32) and Slc:Wistar (n = 32) outbred rats were from Japan SLC (Hamamatsu, Japan). Iar:Long-Evans (n = 30) and Kwl:Long-Evans (n = 30) were from the Institute for Animal Reproduction (Kasumigaura, Japan) and Kiwa Laboratory Animals (Wakayama, Japan). Genomic DNA was prepared from tail biopsy specimens.

Animal care and experimental procedures were approved by the Animal Research Committee of Kyoto University and were conducted according to the Regulation on Animal Experimentation at Kyoto University.

Genotyping.
Sixteen functional polymorphisms were picked up by searching the literature (Table 1). They comprised 3 coat color genes and 13 disease-associated genes. PCR primer sequences and methods for the detection of functional polymorphisms are listed in Table 2. Genotyping of Fdft1 or Ian5 was performed by the direct sequencing of the PCR products. PCR products were treated with ExoSAP-IT (Amersham Biosciences) to digest single-stranded DNA and excess primers. Cycle sequencing was performed with BigDye Terminator Ready Reaction Mix version 3.1 according to the manufacturer's instructions (Applied Biosystems). PCR samples were purified with CleanSEQ (Agencourt Bioscience) and then loaded into an ABI PRISM 3100 genetic analyzer (Applied Biosystems).


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  		Table 1. Functional polymorphisms examined in this study

 

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  		Table 2. PCR primers for genotyping

 

   RESULTS
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Disease-related functional polymorphisms shared among rat strains.
Six disease-related functional polymorphisms were common among rat strains. The distribution of alleles of each functional polymorphism is listed in Table 3.


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  		Table 3. Disease-related functional polymorphisms shared among rat stains

 
When a common origin of the polymorphism is postulated, it would be expected that all strains that carry the polymorphism would cluster in the same branch of the rat phylogenic tree. To test this hypothesis, we analyzed the distribution of each disease-related allele with the distribution of the strains on the phylogenic tree made by the NBRP-Rat with 132 inbred rat strains (http://www.anim.med.kyoto-u.ac.jp/nbr/phylogenetictree.htm). The SCR-type (K) allele of Fdft1 only clustered in a branch that contained Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR) substrains (Supplemental Fig. S1).1 The remaining alleles distributed throughout the phylogenic tree (data not shown).

Functional polymorphisms unique to strain in which mutation has been identified.
Seven mutant alleles that were unique to the original strain included the 7-bp deletion at the splicing donor site in the Alb gene in the NAR strain, the nonsense mutation at codon 455 (R455X) of the Cblb gene in the KDP rat, the 6.8-kb deletion spanning the promoter region, exon 1, and exon 2 of the Cckar1 gene in the OLETF rat, the deletion spanning the region Cd36 and Cd36-ps2 in the SHR/Crl strain, the missense mutation at codon 340 (R340W) of the Cox50 gene in the UPL rat, the frameshift mutation of the Ian5 gene in the BB rat, and the 12-bp deletion in exon 15 of the Lss gene in the SCR strain (2, 4, 12, 15, 21, 23, 26) (Table 4). These mutations might have significant effects so that the mutation itself worked as a selective marker in establishment of the strain and exaggerates the clinical phenotype of these strains.


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  		Table 4. Genotypes of functional polymorphisms in 137 rat strains

 
Coat color mutations.
P and Rab38 are causative genes for the Pink-eyed dilution (p) and Ruby (r) in the rat (9, 17). Genotyping of P and Rab38 could not detect any strains other than those described to carry these mutations (9, 17). The functional polymorphism at the A locus (agouti or nonagouti) was evaluated in the albino rat strains. Among 91 albino rat strains, 11 had the A/A genotype, 79 had the a/a genotype, and 1 was heterozygous (Table 4).

Survey of functional polymorphisms commonly shared in inbred strains in commercially available outbred stocks.
Because most inbred rat strains are descended from outbred colonies, we speculated that functional polymorphisms common among inbred strains could be observed in various outbred rat colonies. We then surveyed 6 disease-related polymorphisms and 3 coat color mutations found in multiple strains in a total of 344 outbred rats from 11 stocks available commercially.

Five functional polymorphisms and two coat color mutations showed different allele frequencies from colony to colony, but any prevalence of the Fdft1 mutation or the ruby mutation could not be found (Table 5). In the colonies of Slc:Wistar and Kwl:Long-Evans, all functional polymorphisms examined seemed to be genetically fixed to homozygosity for single alleles, even if the sample size was only 32 or 30.


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  		Table 5. Allele frequencies of functional polymorphisms in commercially available outbred stocks

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Our study revealed that most rat strains harbored the mutant alleles that were already identified and whose effects were relatively large (Table 3). These mutant alleles distributed throughout the strains and were found in outbred rat stocks, except for the Fdft1 missense mutation. These findings suggested that the mutant alleles examined in this study were already present in the ancestral outbred rats of the modern inbred strains and then fixed during establishment of the strains. The Fdft1 missense allele, which was clustered on a particular branch of the phylogenic tree but not found in the outbred rats, might occur in the Wistar-related strains kept in Japan and be inherited by the SHR strains. It is likely that functional polymorphisms can be divided into two categories: those that existed before the establishment of many rat strains and those that occurred after many strains were produced. The later polymorphism might help us to speculate on the genotype of the strains that are in the same branch of the phylogenic tree.

The prevalence of the disease-related polymorphisms among different inbred strains raises concern about using rat strains as models for diseases such as prostate cancer, experimental glomerulonephritis, and obesity. Cyclin-dependent kinase inhibitor 1a (Cdkn1a), also called p21, is a tumor suppressor gene and considered a good candidate for one of the prostate cancer susceptibility genes. The 119-bp insertion was associated with high Cdkn1a expression in the rat prostate, which might imply resistance to prostate cancer in the BUF/NacJcl rat (24, 25). The insertion was shared in 49 strains including the prostate cancer-resistant BUF/NacJcl, but not in 92 strains including the prostate cancer-susceptible ACI/NJcl. Interestingly, BUF/Mna, a substrain of the BUF rat, did not share the insertion. These findings suggested that both insertion-positive and -negative strains should be employed in carcinogenicity tests of a chemical for the prostate.

Fcgr3-related sequence (Fcgr3-rs) has been identified as a determinant of macrophage overactivity and glomerulonephritis in WKY. Rats carrying the Fcgr3-rs gene in addition to Fcgr3 showed resistance to macrophage-dependent mesangial cell damage and glomerular necrosis in experimentally induced nephrotoxic nephritis (1). Fcgr3-rs was shared in 79 strains including the glomerulonephritis-resistant LEW strains, but not in 56 strains including the glomerulonephritis-susceptible WKY strains. In humans, the copy numbers of FCGR3B, a paralog of Fcgr3, varied from zero to six and were associated with susceptibility to systemic autoimmunity (5). In this study, we could assess the presence or absence of Fcgr3-rs, but not the actual copy number in the rat genome. It would be worth surveying the copy numbers of Fcgr3-rs in rat strains and evaluating the association of copy number with macrophage overactivity and glomerulonephritis.

Gpr10 encodes the receptor for prolactin-releasing peptide (PrRP) and has been identified as a determinant of hyperphagia leading to obesity and dyslipidemia in the OLETF rat (22). The translation initiation codon mutation (ATG-to-ATA) was shared in several strains: 45 strains had ATA/ATA, and 95 had ATG/ATG. Among the 136 strains genotyped in this study, 85 were phenotyped for body weight in males at 10 wk of age in the Rat Phenome Project (13). The average body weights of the Grp10-mutant strains (n = 31) were significantly higher than those of the wild-type strains (n = 54): 282.2 ± 50.1 vs. 247.6 ± 45.0 g (means ± SD, P < 0.001). Furthermore, it has been described that body weights of outbred rats carrying the Gpr10 mutation were significantly greater than those of wild-type rats (22). These findings suggested a significant role for the Grp10 gene in the control of body weight in the rat.

Genotyping of the functional polymorphism could also nominate a potential candidate gene for the existing mutant strain. Lss (lanosterol synthase) and Fdft1 (farnesyldiphosphate farnesyltransferase) function in the cholesterol biosynthesis pathway and are determinants for hereditary cataracts in the Syumiya Cataract Rat (SCR) (15). Both functional polymorphisms of Lss, D139K and Q481R, reduce LSS activity and comprise the major susceptibility allele for cataracts, Cats1S. The functional polymorphism of Fdft1, I196K, reduces FDFT1 activity and is likely to be a strong candidate for the second major susceptibility allele for cataracts, Cats2S. In this study, we demonstrated that the Lss mutations and the Fdft1 mutation are shared by 23 inbred strains that include not only the SCR but also the Ihara Cataract Rat (ICR) strain. The ICR strain displays bilateral cataracts by 4 mo of age, and the two causative loci were identified as Cati1 on chromosome 8 and Cati2 on chromosome 15 (27). Interestingly, Cati2 modified the timing of the onset and was mapped between D15Rat52 (32.8 Mb in the Celera Rat Map) and D15Rat20 (52.4 Mb), where Fdft1 was also mapped (37.1 Mb). Thus it is reasonable to consider Fdft1 as a potential candidate for Cati2.

We showed that disease-related alleles have penetrated different outbred stocks available commercially (Table 5). Because these alleles have been proven to function in the pathogenesis of prostate cancer, nephritis, obesity, or cholesterol biosynthesis, one should pay attention to the usage of outbred rats especially in such experiments. Although the p mutation was found only in four strains, several outbred colonies harbored the p mutation at allele frequencies of 0.05–1.00 (Table 5). Besides having a critical role in controlling tyrosinase processing and melanosome biogenesis, P protein might modulate arsenic sensitivity and intracellular glutathione metabolism when expressed in the yeast (19). Considering the extensive utility of the rat in toxicological testing and the prevalence of the p mutation in commercial stocks, it would be worth examining sensitivity to arsenicals and other metalloids in rats with or without the p mutation.

The genetic makeup of outbred colonies can be affected by historical events such as directional selection and bottlenecks, leading to reduced variation, and genetic drift, mutation, and genetic contamination, which result in genomic differences in individual colonies (3). Thus it is important to recognize that genetic characteristics of outbred colonies tend to change over time. Our genotyping results suggested the occurrences of such genetic alterations in the main outbred colonies that are currently in use. For example, Crj:CD(SD), Jcl:SD, and Slc:SD rat colonies share a common origin, the SD rat colony of Charles River Laboratories of the United States (data sheets from Charles River Laboratories Japan, CLEA Japan, Japan SLC), but they showed different allele frequencies for several functional polymorphisms (Table 5). Although the years when the founders of each colony were imported were different (Crj:SD in 1975, Slc:SD in 1968, and Jcl:SD in 1964), genetic characteristics seemed to have altered during the more than 30 years since their separation from the original stock. Considering the possible genetic alterations of the outbred stock, excellent reproducibility of animal experiments with outbred stocks, for example, for determining sensitivities to substances or for examining physiological parameters, would not be expected. Thus experimental plans based on outbred stocks need to be fully justified to avoid wasting animals and funding.

In this study, we inventoried 16 functional polymorphisms in 136 rat strains and also examined their distribution in several outbred stocks. This study has resulted in a useful catalog of the distribution of disease-related alleles in commonly used rat strains. The finding that 6 of the 13 disease-associated polymorphisms are shared between different strains is important for experimental design, because this principle is likely to hold true for many other uncharacterized functional polymorphisms. To help research interests to select the most suitable strains for their experiments, the NBRP-Rat will periodically improve and update the genetic profiles of rat strains.


   GRANTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (18300141 to T. Kuramoto and 16200029 to T. Serikawa) and a Grant-in-aid for Cancer Research from the Ministry of Health, Labour and Welfare.


   ACKNOWLEDGMENTS
 
We are grateful to M. Yokoe and R. Okajima for excellent technical assistance. OLETF and LETO rats were provided by Otsuka Pharmaceutical Co. Ltd. (Tokushima, Japan). F344/Snk was provided by Medicinal Safety Research Laboratories, Sankyo Co., Ltd. (Shizuoka, Japan).

This work was supported by the National Bio Resource Project for the Rat and carried out as a part of the genetic profiling program of the Project.


   FOOTNOTES
 
Address for reprint requests and other correspondence: T. Kuramoto, Institute of Laboratory Animals, Graduate School of Medicine, Kyoto Univ., Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan (e-mail: tkuramot{at}anim.med.kyoto-u.ac.jp).

Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

1 The online version of this article contains supplemental material. Back


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 MATERIALS AND METHODS
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 DISCUSSION
 GRANTS
 REFERENCES
 

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