WGS to identify candidate diabetes genes in congenic sBBM

The spontaneously diabetic BB rat was first described in 1978 and subjected to targeted breeding to clarify the genetics of the spontaneous eradication of the pancreatic islet beta cells. The original Diabetes Prone (DP) rat has since 1980 been subjected to marker-assisted cross-intercross breeding with inbred Diabetes Resistant (DR) rats to introgress DR DNA in order to dissect the mechanisms by which lymphopenia is induced to allow diabetes development by 50-70 days of age. The BB rat diabetes was early related to lymphopenia and found to segregate with diabetes as a single locus. The lymphopenia gene was cloned by position to demonstrate a frame-shift mutation in the Gimap5 gene resulting in a null allele of the anti-apoptotic Gimap5 protein. WGS is used to compare wild type rats with congenic rats homozygous for the mutated Gimap5 gene to disclose other potential diabetes genes. DNA of the sBBM line at Clinical Research Centre (CRC) at Lund University (Malmö, Sweden) was obtained from two individuals. One rat, sBBM DR.Gimap4-Gimap5-/Gimap4-Gimap5-, (animal ID sBBM 6 3:6) is homozygous for a frameshift mutation in the Gimap5 gene resulting in a null allele that is linked to the development of diabetes by 50-70 days of age. The other rat (animal ID 6 3:3) selected for sequence comparison is sBBM DR.Gimap4+Gimap5+/Gimap4+Gimap5+, denoted wildtype rat, which remains normal. Sequencing was performed by the SNP&SEQ Technology Platform in Uppsala. The facility is part of the National Genomics Infrastructure (NGI) Sweden and Science for Life Laboratory. The SNP&SEQ Platform is also supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation.