Project description:Genetic linkage analyses in rodents have unveiled numerous genomic loci contributing to a diverse array of traits, such as susceptibility to addictive behaviors and hypertension. To investigate the genetic basis of trait variation in rodents, genetic reference populations, such as the HXB/BXH recombinant inbred (RI) rat panel, have been extensively utilized. The HXB/BXH panel serves as a well-established rat model to dissect genetic variants that modulate metabolic and cardiovascular diseases. The panel has accumulated a wealth of comprehensive genotypic data, transcriptomic profiles, and phenotypic data, enabling integrative analyses to understand the pathway from genomic loci to traits. The parental strains of the HXB/BXH rat panel, SHR/OlaIpcv (SHR) and BN-Lx/Cub (BN-Lx) strains, have been completely sequenced, and sequence variants between them have been well-defined. Integrating genomics, transcriptomics, and proteomics data from these two inbred strains, have successfully identified splice events, genetic variants, and RNA editing. However, there remains a lack of proteome-wide profiling across all 30 HXB/BXH RI strains, and the genetic regulation of protein expression remains largely unexplored.
Project description:Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain and is dysregulated in metabolic and neurodegenerative diseases, but the molecular relationships between neural stem cells activity, adult neurogenesis and global metabolism are largely unknown. We applied unbiased systems genetics to reveal genetic correlations between adult neurogenesis and metabolism of peripheral tissues in a genetic reference population of 30 HXB/BXH recombinant inbred (RI) strains, derived from a cross between spontaneously hypertensive (SHR/OlaIpcv) and Brown Norway (BN-Lx/Cub) rats. We measured the rates of precursor cell proliferation, survival of new neurons, and gene expression profiles in the hippocampi of RI and parental strains and combined them with published metabolic phenotypes to reveal a “neuro-metabolic” quantitative trait locus (QTL) for serum glucose and neuronal survival, which was further narrowed down to the Tti2 (Telo2 interacting protein 2) gene, which is a regulator of activity and stability of PIKK kinases. To validate Tti2 as a causal QTL gene, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- rats showed decreased hippocampal neurogenesis and hallmarks of dysglycemia when compared to wild-type littermates. Here we present gene expression profiling of hippocampus, liver, soleus muscle and peritoneal fat in SHR-Tti2 heterozygous rats and wild-type SHR control littermates. Our findings suggest that Tti2 may represent a direct molecular link between glucose metabolism and structural brain plasticity.
Project description:BXH/HXB rat recombinant inbred (RI) strains are derived from the spontaneously hypertensive rat (SHR/Ola) and the Brown Norway congenic strains carrying the polydactylyl-luxate mutation (BN-Lx). Tissue from the apex of left ventricle of the heart was disected from 128 RI SHR/Ola and BN-Lx parental strains, RNA was extracted and labelled and hybridised to Affymetrix Rat Genome 230 2.0 Arrays.