title: Three interacting genomic loci incorporating two novel mutations underlie the evolution of diet-induced diabetes.
abstract: We investigated the pathophysiology of diet-induced diabetes in the Cohen diabetic rat (CDs/y) from its induction to its chronic phase, using a multi-layered integrated genomic approach. We identified by linkage analysis two diabetes-related quantitative trait loci on RNO4 and RNO13. We determined their functional contribution to diabetes by chromosomal substitution, using congenic and consomic strains. To identify within these loci genes of relevance to diabetes, we sequenced the genome of CDs/y and compared it to 25 other rat strains. Within the RNO4 locus, we detected a novel high impact deletion in theNdufa4gene that was unique to CDs/y. Within the RNO13 locus, we found multiple SNPs and INDELs that were unique to CDs/y but were unable to prioritize any of the genes. Genome wide screening identified a novel third locus not detected by linkage analysis that consisted of a novel high impact deletion on RNO11 that was unique to CDs/y and that involved theSdf2l1gene. Using co-segregation analysis, we investigated in silico the relative contribution to the diabetic phenotype and the interaction between the three genomic loci on RNO4, RNO11 and RNO13. We found that the RNO4 locus plays a major role during the induction of diabetes, whereas the genomic loci on RNO13 and RNO11, while interacting with the RNO4 locus, contribute more significantly to the diabetic phenotype during the chronic phase of the disease. The mechanisms whereby the mutations on RNO4 and 11 and the RNO13 locus contribute to the development of diabetes are under continuing investigation.
authors.affiliation: Laboratory for Molecular Medicine and Israeli Rat Genome Center, Barzilai University Medical Center, Ashkelon.|Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Yagil
authors.affiliation: The Nancy & Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Barak
authors.initials: B
authors.lastname: Markus
authors.affiliation: The Nancy & Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Refael
authors.initials: R
authors.lastname: Kohen
authors.affiliation: Laboratory for Molecular Medicine and Israeli Rat Genome Center, Barzilai University Medical Center, Ashkelon.|Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel.
authors.forename: Chana
authors.initials: C
authors.lastname: Yagil
keywords: Chromosomal substitution; Co-segregation analysis; Cohen Diabetic rat; Linkage analysis; Next generation sequencing; Sequence variations