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  Identification of two novel candidate genes for insulin secretion by comparative genomics of multiple backcross populations

Schallschmidt, T., Lebek, S., Altenhofen, D., Damen, M., Schulte, Y., Knebel, B., et al. (2018). Identification of two novel candidate genes for insulin secretion by comparative genomics of multiple backcross populations. Genetics, 210(4), 1527-1542. doi:10.1534/genetics.118.301578.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-50AD-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-50AE-F
Genre: Journal Article

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 Creators:
Schallschmidt, Tanja , Author
Lebek, Sandra , Author
Altenhofen, Delsi , Author
Damen, Mareike, Author
Schulte, Yvonne , Author
Knebel, Birgit, Author
Herwig, Ralf1, Author              
Rasche, Axel1, Author              
Stermann, Torben, Author
Kamitz, Anne , Author
Hallahan, Nicole , Author
Jähnert, Markus , Author
Vogel, Heike, Author
Schürmann, Annette , Author
Chadt, Alexandra , Author
Al-Hasani, Hadi , Author
Affiliations:
1Bioinformatics (Ralf Herwig), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385701              

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Free keywords: candidate disease genes; diabetes; haplotypes; positional cloning; quantitative trait loci
 Abstract: To identify novel disease genes for type 2 diabetes (T2D) we generated two backcross populations of obese and diabetes-susceptible New Zealand Obese (NZO/HI) mice with the two lean mouse strains 129P2/OlaHsd and C3HeB/FeJ. Subsequent whole-genome linkage scans revealed 30 novel quantitative trait loci (QTL) for T2D-associated traits. The strongest association with blood glucose [12 cM, logarithm of the odds (LOD) 13.3] and plasma insulin (17 cM, LOD 4.8) was detected on proximal chromosome 7 (designated Nbg7p, NZO blood glucose on proximal chromosome 7) exclusively in the NZOxC3H crossbreeding, suggesting that the causal gene is contributed by the C3H genome. Introgression of the critical C3H fragment into the genetic NZO background by generating recombinant congenic strains and metabolic phenotyping validated the phenotype. For the detection of candidate genes in the critical region (30-46 Mb), we used a combined approach of haplotype and gene expression analysis to search for C3H-specific gene variants in the pancreatic islets, which appeared to be the most likely target tissue for the QTL. Two genes, Atp4a and Pop4, fulfilled the criteria from our candidate gene approaches. The knockdown of both genes in MIN6 cells led to decreased glucose-stimulated insulin secretion, indicating a regulatory role of both genes in insulin secretion, thereby possibly contributing to the phenotype linked to Nbg7p In conclusion, our combined- and comparative-cross analysis approach has successfully led to the identification of two novel diabetes susceptibility candidate genes, and thus has been proven to be a valuable tool for the discovery of novel disease genes.

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Language(s): eng - English
 Dates: 2018-10-162018-10-192018-12
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1534/genetics.118.301578
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Title: Genetics
Source Genre: Journal
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Publ. Info: Genetics Society of America
Pages: 16 Volume / Issue: 210 (4) Sequence Number: - Start / End Page: 1527 - 1542 Identifier: ISSN: 0016-6731
CoNE: https://pure.mpg.de/cone/journals/resource/954925400554