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Increased autoimmune diabetes in pIgR-deficient NOD mice is due to a "Hitchhiking" interval that refines the genetic effect of Idd5.4.

Simpfendorfer KR, Strugnell RA, Brodnicki TC, Wijburg OL - PLoS ONE (2015)

Bottom Line: However, the Pigr allele was encompassed by a relatively large "hitchhiking" genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes.The smallest B6-derived interval encompassing the Pigr allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4.This study provides another example of the potential hidden effects of "hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci.

View Article: PubMed Central - PubMed

Affiliation: The Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.

ABSTRACT
Selective breeding to introduce a gene mutation from one mouse strain onto the genetic background of another strain invariably produces "hitchhiking" (i.e. flanking) genomic intervals, which may independently affect a disease trait of interest. To investigate a role for the polymeric Ig receptor in autoimmune diabetes, a congenic nonobese diabetic (NOD) mouse strain was generated that harbors a Pigr allele derived from C57BL/6 (B6) mice. These pIgR-deficient NOD mice exhibited increased serum IgA along with an increased diabetes incidence. However, the Pigr allele was encompassed by a relatively large "hitchhiking" genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes. Additional congenic NOD mouse strains, harboring smaller B6-derived intervals, confirmed Idd5.4 independently of the other three known susceptibility loci on chromosome 1, and further localized Idd5.4 to an interval proximal to Pigr. Moreover, these congenic NOD mice showed that B6 mice harbor a more diabetogenic allele than NOD mice for this locus. The smallest B6-derived interval encompassing the Pigr allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4. This study provides another example of the potential hidden effects of "hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of mouse chromosome 1 and congenic intervals.Congenic strains names are abbreviated: R0 = NOD.B6-Chr1D1Mit48-D1Mit348Pigr-/-, R2 = NOD.B6-Chr1Pigr-D1Mit348Pigr-/-, R7 = NOD.B6-Chr1D1Mit48-D1Mit495. Diabetes incidence for congenic strains is described relative to NOD mice (>NOD or < NOD, based on Figs 1 and 3). Idd5.4a represents the B10-derived interval defined by Hunter et al. [25]; Idd5.4b represents the B6-derived interval, defined by the R7 congenic strain, that confers increased susceptibility to diabetes; IddX represents the B6-derived interval harboring the Pigr  allele, defined by the R2 congenic strain, that confers protection against diabetes. Marker and gene positions are based on NCBI Bld37, mm9.
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pone.0121979.g002: Schematic diagram of mouse chromosome 1 and congenic intervals.Congenic strains names are abbreviated: R0 = NOD.B6-Chr1D1Mit48-D1Mit348Pigr-/-, R2 = NOD.B6-Chr1Pigr-D1Mit348Pigr-/-, R7 = NOD.B6-Chr1D1Mit48-D1Mit495. Diabetes incidence for congenic strains is described relative to NOD mice (>NOD or < NOD, based on Figs 1 and 3). Idd5.4a represents the B10-derived interval defined by Hunter et al. [25]; Idd5.4b represents the B6-derived interval, defined by the R7 congenic strain, that confers increased susceptibility to diabetes; IddX represents the B6-derived interval harboring the Pigr allele, defined by the R2 congenic strain, that confers protection against diabetes. Marker and gene positions are based on NCBI Bld37, mm9.

Mentions: It is well known that flanking genomic intervals will accompany a gene mutation from a donor mouse strain (i.e. B6 in this study) when backcrossed onto the NOD genetic background as a result of linkage disequilibrium and recombination hotspots [10–12]. Donor-derived alleles within these so-called “hitchhiking” intervals may affect diabetes incidence independently of the introduced gene mutation. Nevertheless, only one such example for NOD mice has been published to date as far as we are aware. Kanagawa et al. showed that reduced diabetes incidence previously reported in NOD mice with a targeted mutation in the IFNγ receptor alpha chain was not due to the lack of the IFNγ receptor. Instead, the reduced diabetes incidence was due to another gene within the 129-derived "hitchhiking" interval that had been introduced along with the mutant Ifngr1 gene [30]. To determine the size of the “hitchhiking” B6-derived interval in our NOD.B6-Pigr-/- mice, genetic markers that were polymorphic between B6 and NOD mice on chromosome 1 were genotyped (Fig 2). In addition to the Pigr allele (~132.7 Mb), pIgR-deficient NOD mice harbored a B6-derived congenic interval between and including D1Mit48 (~90.5 Mb) and D1Mit348 (~134.3 Mb); this congenic strain was subsequently designated as NOD.B6-Chr1D1Mit48-D1Mit348Pigr-/- (henceforth abbreviated as NOD.B6-Chr1 R0). This B6-derived congenic interval also overlapped a large portion of the previously defined interval for Idd5.4, but not the intervals defined for the other three Idd5 sub-loci on chromosome 1 (Fig 2, [25,26]).


Increased autoimmune diabetes in pIgR-deficient NOD mice is due to a "Hitchhiking" interval that refines the genetic effect of Idd5.4.

Simpfendorfer KR, Strugnell RA, Brodnicki TC, Wijburg OL - PLoS ONE (2015)

Schematic diagram of mouse chromosome 1 and congenic intervals.Congenic strains names are abbreviated: R0 = NOD.B6-Chr1D1Mit48-D1Mit348Pigr-/-, R2 = NOD.B6-Chr1Pigr-D1Mit348Pigr-/-, R7 = NOD.B6-Chr1D1Mit48-D1Mit495. Diabetes incidence for congenic strains is described relative to NOD mice (>NOD or < NOD, based on Figs 1 and 3). Idd5.4a represents the B10-derived interval defined by Hunter et al. [25]; Idd5.4b represents the B6-derived interval, defined by the R7 congenic strain, that confers increased susceptibility to diabetes; IddX represents the B6-derived interval harboring the Pigr  allele, defined by the R2 congenic strain, that confers protection against diabetes. Marker and gene positions are based on NCBI Bld37, mm9.
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Related In: Results  -  Collection

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pone.0121979.g002: Schematic diagram of mouse chromosome 1 and congenic intervals.Congenic strains names are abbreviated: R0 = NOD.B6-Chr1D1Mit48-D1Mit348Pigr-/-, R2 = NOD.B6-Chr1Pigr-D1Mit348Pigr-/-, R7 = NOD.B6-Chr1D1Mit48-D1Mit495. Diabetes incidence for congenic strains is described relative to NOD mice (>NOD or < NOD, based on Figs 1 and 3). Idd5.4a represents the B10-derived interval defined by Hunter et al. [25]; Idd5.4b represents the B6-derived interval, defined by the R7 congenic strain, that confers increased susceptibility to diabetes; IddX represents the B6-derived interval harboring the Pigr allele, defined by the R2 congenic strain, that confers protection against diabetes. Marker and gene positions are based on NCBI Bld37, mm9.
Mentions: It is well known that flanking genomic intervals will accompany a gene mutation from a donor mouse strain (i.e. B6 in this study) when backcrossed onto the NOD genetic background as a result of linkage disequilibrium and recombination hotspots [10–12]. Donor-derived alleles within these so-called “hitchhiking” intervals may affect diabetes incidence independently of the introduced gene mutation. Nevertheless, only one such example for NOD mice has been published to date as far as we are aware. Kanagawa et al. showed that reduced diabetes incidence previously reported in NOD mice with a targeted mutation in the IFNγ receptor alpha chain was not due to the lack of the IFNγ receptor. Instead, the reduced diabetes incidence was due to another gene within the 129-derived "hitchhiking" interval that had been introduced along with the mutant Ifngr1 gene [30]. To determine the size of the “hitchhiking” B6-derived interval in our NOD.B6-Pigr-/- mice, genetic markers that were polymorphic between B6 and NOD mice on chromosome 1 were genotyped (Fig 2). In addition to the Pigr allele (~132.7 Mb), pIgR-deficient NOD mice harbored a B6-derived congenic interval between and including D1Mit48 (~90.5 Mb) and D1Mit348 (~134.3 Mb); this congenic strain was subsequently designated as NOD.B6-Chr1D1Mit48-D1Mit348Pigr-/- (henceforth abbreviated as NOD.B6-Chr1 R0). This B6-derived congenic interval also overlapped a large portion of the previously defined interval for Idd5.4, but not the intervals defined for the other three Idd5 sub-loci on chromosome 1 (Fig 2, [25,26]).

Bottom Line: However, the Pigr allele was encompassed by a relatively large "hitchhiking" genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes.The smallest B6-derived interval encompassing the Pigr allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4.This study provides another example of the potential hidden effects of "hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci.

View Article: PubMed Central - PubMed

Affiliation: The Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.

ABSTRACT
Selective breeding to introduce a gene mutation from one mouse strain onto the genetic background of another strain invariably produces "hitchhiking" (i.e. flanking) genomic intervals, which may independently affect a disease trait of interest. To investigate a role for the polymeric Ig receptor in autoimmune diabetes, a congenic nonobese diabetic (NOD) mouse strain was generated that harbors a Pigr allele derived from C57BL/6 (B6) mice. These pIgR-deficient NOD mice exhibited increased serum IgA along with an increased diabetes incidence. However, the Pigr allele was encompassed by a relatively large "hitchhiking" genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes. Additional congenic NOD mouse strains, harboring smaller B6-derived intervals, confirmed Idd5.4 independently of the other three known susceptibility loci on chromosome 1, and further localized Idd5.4 to an interval proximal to Pigr. Moreover, these congenic NOD mice showed that B6 mice harbor a more diabetogenic allele than NOD mice for this locus. The smallest B6-derived interval encompassing the Pigr allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4. This study provides another example of the potential hidden effects of "hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci.

No MeSH data available.


Related in: MedlinePlus