Genetic analysis of autoimmune type 1 diabetes mellitus in mice

Todd, John A.; Aitman, Timothy J.; Cornall, Richard J.; Ghosh, Soumitra; Hall, '; Hearne, C M; Knight, A M; Love, Jennifer M.; McAleer, Marcia A.; Prins, Jan–Bas

doi:10.1038/351542a0

Cited by 474 publications

(233 citation statements)

References 35 publications

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“…For example, they could affect the efficiency of signal transduction via the IL-12 receptor or modulate the regulatory role of the IL-12p40 homodimer, by augmenting or preventing its interaction with the IL-12 receptor ␤1 chain and consequently the biological action of the IL-12p75 heterodimer. No T1D susceptibility gene has as yet been mapped to the vicinity of Il12b in backcrosses of NOD mice with B6 19,20 or F2 crosses to NOR. 18 For example, the Idd4 gene 19 is on mouse chromosome 11 but was mapped to a region over 20 cM distal to the reported location 14 of Il12b.…”

Section: Discussionmentioning

confidence: 99%

“…No T1D susceptibility gene has as yet been mapped to the vicinity of Il12b in backcrosses of NOD mice with B6 19,20 or F2 crosses to NOR. 18 For example, the Idd4 gene 19 is on mouse chromosome 11 but was mapped to a region over 20 cM distal to the reported location 14 of Il12b. However, the B6 backcrosses would not have detected a NOD-dominant gene effect, while in the NOR crosses a potentially protective effect of the NOR allele may not be sufficiently strong to be detected in the presence of all the other susceptibility alleles shared between the NOD and NOR strains.…”

Section: Discussionmentioning

confidence: 99%

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Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

et al. 2002

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

et al. 2002

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“…In the 1990s, with the availability of genome-wide marker sets, it became possible for the first time to map the chromosomal location of genetic effects that contribute to quantitative variation (Lander and Botstein 1989;Hilbert et al 1991;Jacob et al 1991;Todd et al 1991). The methods adopted depended on the organism: Mouse and fly geneticists could use inbred strains, thereby considerably simplifying the genetics.…”

Section: Genetic Architecture: Many Loci Of Small Effectmentioning

confidence: 99%

Genetic architecture of quantitative traits in mice, flies, and humans

Flint¹,

Mackay²

2009

Genome Res.

407

364

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We compare and contrast the genetic architecture of quantitative phenotypes in two genetically well-characterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, with that found in our own species from recent successes in genome-wide association studies. We show that the current model of large numbers of loci, each of small effect, is true for all species examined, and that discrepancies can be largely explained by differences in the experimental designs used. We argue that the distribution of effect size of common variants is the same for all phenotypes regardless of species, and we discuss the importance of epistasis, pleiotropy, and gene by environment interactions. Despite substantial advances in mapping quantitative trait loci, the identification of the quantitative trait genes and ultimately the sequence variants has proved more difficult, so that our information on the molecular basis of quantitative variation remains limited. Nevertheless, available data indicate that many variants lie outside genes, presumably in regulatory regions of the genome, where they act by altering gene expression. As yet there are very few instances where homologous quantitative trait loci, or quantitative trait genes, have been identified in multiple species, but the availability of high-resolution mapping data will soon make it possible to test the degree of overlap between species.Recent successes in mapping quantitative trait loci (QTLs) that contribute to phenotypic variation in humans and model organisms make it possible to address important questions about the genetic architecture of quantitative phenotypes, such as the likely number of loci, their mode of genetic action, and interaction with each other and with the environment. An understanding of the genetic architecture of quantitative traits is not only important in its own right, it will also inform studies that seek to proceed to the identification of the quantitative trait genes (QTGs) and the quantitative trait nucleotide (QTN) variants, the functional changes in DNA sequence that contribute to trait variation.In this work we use examples from two genetically wellcharacterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, to discuss how an understanding of the genetic architecture of quantitative phenotypes in model organisms informs mapping experiments in human genetics. In our discussion of the latter, we draw upon the recent successful application of genome-wide association studies (GWAS) to both quantitative phenotypes (such as height and weight) and disease phenotypes (assuming that the genetic architecture of common disease is similar, if not identical, to that of quantitative phenotypes).Genetic architecture has been the subject of a number of recent reviews, most of which deal with information from a single model organism (Mackay 2004) or review a small number of phenotypes (Kendler and Greenspan 2006). Here, our purpose is different. We tackle three relate...

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“…Idd5 was originally identified as a 34-cM interval on chromosome 1 that affected susceptibility to both spontaneous and cyclophosphamide-induced diabetes (40) as well as to peri-insulitis (41,42). Analysis of recently developed Idd5 congenic strains in which portions of the C57BL/10 (B10) genome were introgressed into the NOD background suggested presence of two loci, Idd5.1 and Idd5.2, each conferring protection from insulitis and T1D ( (43,44); Fig.…”

Section: Idd5mentioning

confidence: 99%

Sex-Specific Effect of Insulin-Dependent Diabetes 4 on Regulation of Diabetes Pathogenesis in the Nonobese Diabetic Mouse

Ivakine

Fox

Paterson

et al. 2005

The Journal of Immunology

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Many human autoimmune diseases are more frequent in females than males, and their clinical severity is affected by sex hormone levels. A strong female bias is also observed in the NOD mouse model of type I diabetes (T1D). In both NOD mice and humans, T1D displays complex polygenic inheritance and T cell-mediated autoimmune pathogenesis. The identities of many of the insulin-dependent diabetes (Idd) loci, their influence on specific stages of autoimmune pathogenesis, and sex-specific effects of Idd loci in the NOD model are not well understood. To address these questions, we analyzed cyclophosphamide-accelerated T1D (CY-T1D) that causes disease with high and similar frequencies in male and female NOD mice, but not in diabetes-resistant animals, including the nonobese diabetes-resistant (NOR) strain. In this study we show by genetic linkage analysis of (NOD × NOR) × NOD backcross mice that progression to severe islet inflammation after CY treatment was controlled by the Idd4 and Idd9 loci. Congenic strains on both the NOD and NOR backgrounds confirmed the roles of Idd4 and Idd9 in CY-T1D susceptibility and revealed the contribution of a third locus, Idd5. Importantly, we show that the three loci acted at distinct stages of islet inflammation and disease progression. Among these three loci, Idd4 alleles alone displayed striking sex-specific behavior in CY-accelerated disease. Additional studies will be required to address the question of whether a sex-specific effect of Idd4, observed in this study, is also present in the spontaneous model of the disease with striking female bias.

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Genetic analysis of autoimmune type 1 diabetes mellitus in mice

Cited by 474 publications

References 35 publications

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

Genetic architecture of quantitative traits in mice, flies, and humans

Sex-Specific Effect of Insulin-Dependent Diabetes 4 on Regulation of Diabetes Pathogenesis in the Nonobese Diabetic Mouse

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