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BXSB/long-lived Is a Recombinant Inbred Strain Containing Powerful Disease Suppressor Loci¹

Michelle E. K. Haywood^2,*, Luisa Gabriel^2,*, S. Jane Rose^*, Nicola J. Rogers, Shozo Izui and Bernard J. Morley^3,*

^* Rheumatology Section and Department of Immunology, Imperial College, London, United Kingdom; and Department of Pathology and Immunology, Centre Medical Universitaire, Geneva, Switzerland

	Abstract

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The BXSB strain of recombinant inbred mice develops a spontaneous pathology that closely resembles the human disease systemic lupus erythematosus. Six non-MHC loci, Yaa, Bxs1–4, and Bxs6, have been linked to the development of aspects of the disease while a further locus, Bxs5, may be a BXSB-derived disease suppressor. Disease development is delayed in a substrain of BXSB, BXSB/MpJScr-long-lived (BXSB/ll). We compared the genetic derivation of BXSB/ll mice to the original strain, BXSB/MpJ, using microsatellite markers and single nucleotide polymorphisms across the genome. These differences were clustered and included two regions known to be important in the disease-susceptibility of these mice, Bxs5 and 6, as well as regions on chromosomes 5, 6, 9, 11, 12, and 13. We compared BXSB/ll to >20 strains including the BXSB parental SB/Le and C57BL/6 strains. This revealed that BXSB/ll is a separate recombinant inbred line derived from SB/Le and C57BL/6, but distinctly different from BXSB, that most likely arose due to residual heterozygosity in the BXSB stock. Despite the continued presence of the powerful disease-susceptibility locus Bxs3, BXSB/ll mice do not develop disease. We propose that the disappearance of the disease phenotype in the BXSB/ll mice is due to the inheritance of one or more suppressor loci in the differentially inherited intervals between the BXSB/ll and BXSB strains.

	Introduction

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The BXSB mouse has been extensively studied as a murine model of the human disease systemic lupus erythematosus (SLE).⁴ The spontaneous development of autoantibodies directed at nuclear components and commensurate glomerulonephritis result in 50% mortality in males at 5 mo of age (1). Disease is accelerated in male BXSB mice by a recently identified Y-linked autoimmune accelerator (Yaa) locus (2, 3, 4). Linkage analysis of BXSB mice has identified four genetic loci on chromosome 1 that are linked to the development of disease, Bxs1–4 (5, 6). A series of C57BL/10 (B10) congenic strains containing overlapping intervals from chromosome 1 has confirmed the presence of these loci and defined their individual and variable contributions to the disease phenotype (7, 8).

Kofler et al. (9) described a substrain of BXSB mice in which disease development was significantly delayed. This substrain was originally developed following the observation of occasional longevity in individual male BXSB/MpJScr mice. The offspring of BXSB/MpJScr mice were maintained until it could be determined retrospectively that the parental mouse was long-lived. The offspring were bred by brother-sister mating and selected for extended male survival. After six generations, the early mortality associated with SLE syndrome in BXSB male mice was abolished. In generations 6–12 suckling performance dropped and foster mothers were used (BALB/c). After the 12th generation fostering ceased.

The serum of BXSB/MpJScr-long-lived (BXSB/ll) mice (post-17th generation) was studied with regard to total IgG and antinuclear Abs (9). These studies showed that BXSB/ll had 50% male survival of >21 mo, with some males living until 30 mo of age. There was no significant glomerulonephritis in BXSB/ll mice until they developed the mesangial matrix increases associated with aging at 28 mo. At an age when BXSB mice develop increasing antinuclear Ab levels (3–5 mo), the level in BXSB/ll mice was reduced by 90% and serum IgG titers remained low.

To identify the genetic basis for the disappearance of disease, F₁ and F₂ crosses were performed by Kofler et al. (9) using BXSB/MpJScr and BXSB/ll in both directions. All F₁ mice were short-lived regardless of the direction of the cross, indicating that the long-lived phenotype was an autosomal recessive trait. Twenty-seven percent of the F₂ males lived for more than one year, resembling the BXSB/ll parents and leading the authors to conclude that a single spontaneous mutation was responsible for the survival differences between the two strains. We have previously studied microsatellite polymorphisms in the parental strains of BXSB, i.e., C57BL/6 (B6) and SB/Le, to determine the derivation of the strain (10). Given the imperative to identify a putative disease-suppressing ll gene, we initiated a study into the derivation of the BXSB/ll strain, using both microsatellite markers and single nucleotide polymorphisms (SNPs), to check that it was indeed a single gene mutation that we were searching for.

	Materials and Methods

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Mice

BXSB/MpJ mice were obtained from The Jackson Laboratory. BXSB/MpJScr-ll/ll mice were obtained from Dr. F. Dixon, Scripps Research Institute, La Jolla, CA. C57BL/10ScSn (B10) mice were originally obtained from Harlan Olac. All mice were bred and maintained at Imperial College (Hammersmith, U.K.).

Genomic DNA

Genomic DNA was prepared from liver samples by proteinase K digestion (Sigma-Aldrich) overnight at 55°C. Two phenol-chloroform extractions were performed followed by ethanol precipitation of genomic DNA. Pellets were resuspended in TE buffer (10 mM Tris-Cl (pH 7.5); 1 mM EDTA) and stored at 4°C before analysis. Genomic DNA was also obtained from Jackson Research Laboratories for all strains, while New Zealand Black (NZB) and New Zealand White (NZW) DNAs were provided by Dr. T. Vyse (Rheumatology Section, Imperial College).

Genotyping

Genotyping was conducted using microsatellite markers as described previously (5). Briefly, microsatellite markers were amplified by PCR and assessed using either 4% Metaphor gel electrophoresis (Flowgen Bioscience) or an ABI 377 automatic DNA sequencer (Applied Biosystems).

SNP typing

DNA samples were also submitted to our collaborators at the Wellcome Trust Centre for Human Genetics (Oxford, U.K.) CTC Mouse Strain Project for SNP typing using the Illumina platform (www.well.ox.ac.uk/mouse/INBREDS). A total of 13,374 SNPs were tested.

Autoantibody screening

Serum samples from mice were screened for anti-chromatin Abs, anti-ssDNA Abs, and anti-dsDNA Abs as described previously (6, 7).

Quantitative real-time PCR (qPCR)

qPCR was performed by using 12.5 µl of SYBR Green master mix (Applied Biosystems), 3.3 pmol of each primer and 5 µl of genomic DNA in a total reaction volume of 25 µl. Samples were tested in triplicate using a 96-well reaction optical plate (Applied Biosystems) and amplified on an Applied Biosystems 7500 fast real-time PCR system using standard reaction conditions (according to the manufacturer’s protocol). Data were analyzed using the manufacturer’s sequence detection software (version 1.7a). Primers for the control gene ubiquitin C-terminal hydroxylase (Ubc) and for TLR-7 (Tlr7) were as follows (where F is forward and R is reverse): UbcF, 5'-GTTACCACCAAGAAGGTCAAACAG-3'; UbcR, 5'-ATCACACCCAAGAACAAGCACAAG-3'; Tlr7e2i3F, 5'-CCACCAGACCTCTTGATTCC-3'; Tlr7e2i3R, 5'-GGACTACGGGCAAGTGTTGT-3'; Tlr7i6e6F, 5'-AGGGACGGAGGTGCTGTTTA-3'; Tlr7i6e6R, 5'-CGTGTCCACATCGAAACAC-3'; Tlr7e6F, 5'-GAGTCTTTGGGTTTCGATGG-3'; and Tlr7e6R, 5'-CAGCCTACGGAAGGAATCTG-3'. Tlr7 gene results were normalized to the control gene result for each strain. Statistical analysis of the results was performed using a Mann-Whitney U test.

	Results

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Microsatellite screening indicated regions of genetic difference between BXSB/ll and BXSB

We screened the BXSB/ll mice with 112 microsatellite markers, which we had previously identified as polymorphic, located throughout the genome between B10 and BXSB. B6 is one of the parental strains of the recombinant inbred BXSB and is closely related to B10; indeed, >90% of the microsatellites were identical in B6 and B10. We confirmed that these microsatellites were highly polymorphic among other strains. The markers were distributed so that at least 95% of the genome lay within 20 centimorgans of an informative marker. BXSB and B10 strains were also screened simultaneously as controls.

We identified five chromosomes where microsatellites indicated substantial differences spanning several megabases (Mb) between BXSB and BXSB/ll: chromosomes 1, 3, 5, 9, and 13 (Fig. 1). These specific intervals were then interrogated with a further 119 markers (data not shown). To account for the possibility that microsatellites may not show a difference between BXSB/ll and BXSB simply because the markers are not polymorphic, we tested several additional strains of mice: B6, SB/Le, C3H, NZW, NZB, AKR, BALB/c, DBA, and 129/Sv. For example, D5Mit133 was nonpolymorphic for all strains tested and thus was not informative with respect to the derivation of BXSB/ll, whereas D3Mit212 identified no BXSB/ll polymorphic size variation from BXSB but, as the other reference strains showed size variation, we assumed this was an informative result. All markers were homozygous within the BXSB/ll strain. Variation between BXSB and BXSB/ll was not contiguous in any of the regions, with informative markers showing BXSB-BXSB/ll-identical microsatellites interspersed with variant markers.

View larger version (19K): [in this window] [in a new window]   FIGURE 1. Microsatellite positions. Shown are the positions of 112 microsatellite markers across the genome that were used to screen BXSB/ll DNA on the basis of a size polymorphism between B10/B6 and BXSB mice. The scale in centimorgans is shown by the bars at the far left. BXSB disease associated loci (Bxs1–6) are indicated to the left of each chromosome. Microsatellite markers that showed a difference between BXSB and BXSB/ll are indicated by a thick horizontal bar, and the name of the markers are indicated in bold type.

SNP analysis confirmed genetic differences in 14 regions of the genome

In collaboration with J. Flint and R. Mott (Wellcome Trust Centre for Human Genetics), SNP data were generated for the BXSB and BXSB/ll DNA samples (www.well.ox.ac.uk/mouse/INBREDS). A total of 13,374 SNPs were typed and all SNPs were homozygous. Five hundred fifty-three SNPs were different between the two strains, and 23 SNPs failed to give a result in one or the other or both strains. Comparison of the SNP pattern revealed that there were 14 clusters of SNPs, lying on chromosomes 3, 5, 6, 9, 11, 12, and 13, that were different between the two strains (Fig. 2). These clusters suggested that the genetic difference between BXSB and BXSB/ll spanned 7.6% of the genome. Interestingly, chromosome 1 did not show any differential SNPs despite the differences that we had found in the microsatellite study. However, we did confirm the genetic differences between the strains that we had observed on chromosomes 3 (10.4% of the chromosome), 5 (28.1%), 9 (33.8%), and 13 (16.5%). Our microsatellite panel had not detected the 37.3% difference on chromosome 12 or the smaller differences on chromosome 6 (8.6%) or 11 (6.8%).

View larger version (17K): [in this window] [in a new window]   FIGURE 2. SNPs showing differences between BXSB and BXSB/ll. The left-hand side of each bar represents BXSB and the right-hand side represents BXSB/ll. SNPs are shown arranged in chromosomal order rather than distance, and thus the length of the bars is indicative of how many SNPs are present. SNPs were placed at 50 kb intervals and therefore this representation approximates physical distance. Gray bars are used to represent BXSB, whereas BXSB/ll differences are shown in pale gray. The 19 autosomes are shown.

BXSB/ll arose from C57BL/6 and SB/Le strains

We examined the hypothesis that BXSB/ll had arisen from BXSB by the introduction of a contaminating strain. To do this, we paired BXSB with each of the other strains and determined the probability that the BXSB/ll SNP pattern could be explained by inheritance from a combination of strains. To test this methodology, we first examined BXSB and demonstrated that 99.9% of SNPs could be explained by the combination of SB/Le and B6 (Table I). The difference was due to a failure of nine of 6592 informative SNPs to type (0.1%). The strain most closely related to B6, B10, in combination with SB/Le explained only 99.1% of the SNPs of BXSB. Thirty-four of 6051 informative SNPs did not type accounting for 0.6% of the difference. The remaining difference was due to the differences between B10 and B6.

The Y chromosome accelerator gene, Yaa is intact in BXSB/ll mice

We previously developed BXSB chromosome 1 congenic strains on a C57BL/10ScSn background and demonstrated that Yaa is sufficient to break tolerance. Furthermore, both Bxs4 and Bxs3 intervals on chromosome 1 are sufficient in the context of Yaa to cause the development of severe autoimmune disease. In the BXSB/ll strain, chromosome 1 was apparently intact and followed the same inheritance pattern as BXSB, yet there was no disease. We considered whether this was due to the loss of Yaa. SNPs and microsatellites specific for the Y chromosome are rare. We therefore performed a cross between BXSB and BXSB/ll in both directions to demonstrate that Yaa was still present. We tested sera from (BXSB x BXSB/ll)F₁ and (BXSB/ll x BXSB)F₁ mice at 2 and 3 mo for anti-chromatin, anti-ssDNA, and anti-dsDNA Abs (Fig. 3). There was no significant difference in any autoantibody between the two F₁ crosses and the BXSB parental strain.

View larger version (6K): [in this window] [in a new window]   FIGURE 3. Autoantibody levels. Mice were analyzed at 2–3 mo of age for serum anti-chromatin (A), anti-ssDNA (B), and anti-dsDNA (C) autoantibodies. Each data point represents a single mouse. The median level is indicated by a horizontal bar. Mouse strains were compared using Mann-Whitney U test.

We have therefore demonstrated both functionally and structurally that Yaa is present in the BXSB/ll strain and excluded this explanation for disease resistance. Both F₁ crosses showed comparable disease; hence the loss of autoimmunity is a recessive trait in which the proven effect of powerful chromosome 1 disease-associated loci is suppressed. Thus, we propose that in one or more of the intervals that have been differentially inherited in the BXSB/ll strain there is a disease suppressor gene or genes.

The genetic differences arose from either the C57BL/6 or SB/Le strain

The SB/Le parental strain does not develop the accelerated autoimmunity seen in BXSB despite containing the Yaa gene (12). We examined the derivation of the clusters of different SNPs between BXSB and BXSB/ll (Fig. 4). There is a single interval on chromosome 3 (78.6–95.2 Mb), four clusters on chromosome 5 (3.6–14.3, 26.2–31.8, 73.0–79.5, and 106.5–114.3 Mb), one interval on chromosome 6, (128.1–140.6 Mb), three clusters on chromosome 9 (13.3–31.1, 57.0–76.1, and 94.1–99.1 Mb), a single interval on chromosome 11 (89.9–98.3 Mb), two intervals on chromosome 12 (7.3–14.9 and 68.2–103.3 Mb) and three clusters on chromosome 13 (31.4–39.4, 70.4–73.6, and 106.8–114.5 Mb). In each cluster/interval the SNP derivation for BXSB/ll could be wholly attributed to SB/Le or B6.

View larger version (13K): [in this window] [in a new window]   FIGURE 4. Derivation analysis of the chromosomes where SNPs were clustered. The cluster regions have been enlarged for each chromosome. The left-hand bar of each set represents BXSB and the right-hand bar represents BXSB/ll chromosomes. Uninformative SNPs are shown as white bars, gray indicates SNPs matching SB/Le, and black indicates SNPs matching B6. Differences between B6 and B10 lying within each cluster are shown by the boxes on the right-hand side of each enlarged section. BXSB disease-associated loci (Bxs5 and 6) are indicated to the left of each chromosome.

	Discussion

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Kofler et al. (9) suggested a spontaneous mutation resulting in the presence of a single recessive gene capable of abrogating disease susceptibility in the BXSB model of SLE. Identification of such a gene would have been an important advance in our understanding of the genetic basis of lupus. However, our study of the derivation of the BXSB/ll strain indicates that the explanation is more complex. We have confirmed that the effect is recessive and that a functional Yaa is still present using an F₁ cross of BXSB/ll mice and by genomic qPCR. The potential loss of Bxs6 could provide a partial explanation as to why the BXSB/ll strain does not develop the disease observed in the parental BXSB strain. However, BXSB/ll levels of gp70 and the gp70 immune complex were comparable to those in BXSB (J. Rankin, S. Izui, and B. J. Morley, manuscript in preparation). Thus, we suspect that the Bxs6 locus is still present in BXSB/ll.

Chromosome 1 and particularly the Bxs3 interval (165.9–199.3 Mb) were found to be intact. We have studied B10 mice congenic for the Bxs3 interval and have shown that this locus is sufficiently powerful to be able to direct the early onset of autoantibodies and glomerulonephritis in a nonautoimmune prone mouse (7). The equivalent intervals from both the NZM strain (Sle1) and the NZB (Nba2) interval, when coupled to Yaa, also produce a moderately severe lupus-like phenotype (12, 14). We therefore propose that one or more suppressor genes must lie in the regions that were inherited differently in BXSB/ll.

The parental SB/Le mouse strain is a model for Chediak-Higashi syndrome (15). However, this strain, while developing some lymphadenopathy, does not develop autoimmunity. In our work in BXSB mice all of the disease-associated loci that we identified lie in regions derived from the SB/Le parental strain. This leads to the possibility that there are suppressor loci present in SB/Le that were lost when the recombinant inbred BXSB strain was developed and must therefore lie in regions that were derived from B6 in the BXSB strain. In the BXSB/ll strain these SB/Le regions may have been retained. There are seven clusters that are SB/Le-derived in BXSB/ll but B6-derived in BXSB, two each on chromosomes 5 and 13 and one each on chromosomes 6, 9, and 12. Any of these intervals may therefore contain an SB/Le-derived disease suppressor locus and are strong candidates for further investigation.

Loci capable of suppressing the lupus phenotype have previously been identified in the NZW mouse (16). These loci, termed Sles1–4 are located on chromosomes 17, 4, 3, and 9, respectively. Two of these, Sles3 and Sles4, therefore map to the same chromosomes as BXSB/ll:BXSB differences. Sles3 lies at 78.5 Mb on chromosome 3 in an interval that is SB/Le-derived in BXSB and B6-derived in BXSB/ll. Sles3 is a B6-derived suppressor locus. Sles4 at 9.1 Mb lies slightly centromeric of the cluster that we identified at 13.3 Mb in a region where the SNP typing was noninformative. This was also originally identified as a B6-derived suppressor, and our analysis indicated that BXSB/ll inherited the B6 interval at this cluster. Thus, in addition to SB/Le-derived intervals we have identified two strong candidate intervals for a B6-derived suppressor.

It was originally proposed that a spontaneous mutation had occurred in the BXSB parental line and that a single suppressor gene accounted for the suppression of the disease phenotype in BXSB/ll. We have shown that this is unlikely to be true. BXSB/ll should be considered as a second recombinant inbred strain derived from B6 and SB/Le. Several loci probably affect the abrogation of disease, including the loss of Bxs6, the presence of SB/Le-derived suppressors, and possibly the presence of a B6-derived suppressor. This study has identified the most likely regions where these powerful suppressors lie and provides an exciting model in which to study disease suppression and then use this information to devise novel therapeutic strategies.

	Acknowledgments

 
We thank our collaborators at Wellcome Trust Centre for Human Genetics, Oxford, U.K., for inviting us to submit material to the Wellcome-CTC Mouse Strain SNP Genotype project. We thank A. E. Bygrave for technical help with the anti-chromatin assay.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Arthritis Research Campaign (U.K.) (to B.J.M.) and from the Swiss National Foundation for Scientific Research (to S.I.).

² M.E.K.H. and L.G. contributed equally to this manuscript.

³ Address correspondence and reprint requests to Prof. Bernard J. Morley, Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, U.K. E-mail address: b.morley{at}imperial.ac.uk

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; B6, C57BL/6; BXSB/ll, BXSB/MpJScr-long-lived; B10, C57BL/10; Mb, megabase; NZB, New Zealand Black; NZW, New Zealand White; qPCR, quantitative real-time PCR; SNP, single nucleotide polymorphism; Yaa, Y chromosome accelerator of autoimmunity.

Received for publication March 15, 2006. Accepted for publication June 1, 2007.

	References

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