Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

Abstract

Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1–66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)—a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.

A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

“… 46 The new variant set from our analysis provide a much-needed boost in mapping precision. 8 , 46 , 47 …”

A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

“…51 The new variant set from our analysis provide a much-needed boost in mapping precision: prior mapping of these RI families was based on several hundred to tens of thousands markers. 8,51,52 The outbred N/NIH HS rats are another widely used rat genetic mapping population. 13 Our analysis is in agreement with Ramdas et al 22 in identifying 16 million variants in the progenitors.…”

“…51 The new variant set from our analysis provide a much-needed boost in mapping precision: prior mapping of these RI families was based on several hundred to tens of thousands markers. 8,51,52…”

Genetic Modulation of Protein Expression in Rat Brain

“…It has been used mainly to dissect loci genetic variants that modulate metabolic and cardiovascular diseases 23,[25][26][27] , but in recent work this family is increasingly being used to study the genetics of substance use disorders [28][29][30] . All members of the family have been fully sequenced, and high-density marker maps of all classes of DNA variants are now available for both forward and reverse genetic analyses 31,32 . There are also extensive transcriptomic data sets for several systems [33][34][35] , but now for the first time also for the brain 28 .…”