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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

pIgR-deficient NOD mice exhibit altered IgA levels and increased diabetes incidence.IgA concentration in fecal extracts (A) and serum (B) from female NOD and pIgR-deficient NOD mice are shown, mean values are represented by horizontal bars, and statistical significance is represented by ** P = 0.001. The cumulative incidence of diabetes was determined for age-matched female (C) and male (D) cohorts. The statistical significance of pairwise comparisons of diabetes incidence curves are (C) *** P = 7.6x10-6, (D) ** P = 0.001.
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pone.0121979.g001: pIgR-deficient NOD mice exhibit altered IgA levels and increased diabetes incidence.IgA concentration in fecal extracts (A) and serum (B) from female NOD and pIgR-deficient NOD mice are shown, mean values are represented by horizontal bars, and statistical significance is represented by ** P = 0.001. The cumulative incidence of diabetes was determined for age-matched female (C) and male (D) cohorts. The statistical significance of pairwise comparisons of diabetes incidence curves are (C) *** P = 7.6x10-6, (D) ** P = 0.001.

Mentions: To investigate the role of pIgR in the development of autoimmune diabetes, we generated a congenic mouse strain that contained the Pigr allele, derived from B6.Pigr-/- mice [27], on the NOD genetic background via serial backcrossing for ten generations. Disruption of Pigr on the NOD genetic background resulted in a significant reduction in IgA levels in fecal extracts (as a surrogate measure of IgA in mucosal secretions) compared with age-matched NOD mice that do not harbor the B6-derived Pigr allele (Fig 1A). Conversely, there was a significant increase in IgA levels in serum of pIgR-deficient NOD mice (Fig 1B). These results indicate that disruption of Pigr on the NOD genetic background has a similar effect upon IgA secretion as observed in B6.Pigr-/- mice [27]. Furthermore, both female and male pIgR-deficient NOD mice demonstrated increased diabetes incidences compared to age and gender-matched NOD mice, suggesting pIgR plays a role in the development of autoimmune diabetes (Fig 1C and 1D).


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)

pIgR-deficient NOD mice exhibit altered IgA levels and increased diabetes incidence.IgA concentration in fecal extracts (A) and serum (B) from female NOD and pIgR-deficient NOD mice are shown, mean values are represented by horizontal bars, and statistical significance is represented by ** P = 0.001. The cumulative incidence of diabetes was determined for age-matched female (C) and male (D) cohorts. The statistical significance of pairwise comparisons of diabetes incidence curves are (C) *** P = 7.6x10-6, (D) ** P = 0.001.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4383422&req=5

pone.0121979.g001: pIgR-deficient NOD mice exhibit altered IgA levels and increased diabetes incidence.IgA concentration in fecal extracts (A) and serum (B) from female NOD and pIgR-deficient NOD mice are shown, mean values are represented by horizontal bars, and statistical significance is represented by ** P = 0.001. The cumulative incidence of diabetes was determined for age-matched female (C) and male (D) cohorts. The statistical significance of pairwise comparisons of diabetes incidence curves are (C) *** P = 7.6x10-6, (D) ** P = 0.001.
Mentions: To investigate the role of pIgR in the development of autoimmune diabetes, we generated a congenic mouse strain that contained the Pigr allele, derived from B6.Pigr-/- mice [27], on the NOD genetic background via serial backcrossing for ten generations. Disruption of Pigr on the NOD genetic background resulted in a significant reduction in IgA levels in fecal extracts (as a surrogate measure of IgA in mucosal secretions) compared with age-matched NOD mice that do not harbor the B6-derived Pigr allele (Fig 1A). Conversely, there was a significant increase in IgA levels in serum of pIgR-deficient NOD mice (Fig 1B). These results indicate that disruption of Pigr on the NOD genetic background has a similar effect upon IgA secretion as observed in B6.Pigr-/- mice [27]. Furthermore, both female and male pIgR-deficient NOD mice demonstrated increased diabetes incidences compared to age and gender-matched NOD mice, suggesting pIgR plays a role in the development of autoimmune diabetes (Fig 1C and 1D).

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