Multiomic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

We profiled the liver transcriptome, proteome, and metabolome from 347 individuals from 58 isogenic strains of the BXD mouse population across age (7 to 24 months) and diet (low or high fat) to link molecular variations to metabolic traits. Several hundred genes are affected by diet and/or age at the transcript and protein levels. Orthologs of two aging-associated genes, St7 and Ctsd, were knocked down in C. elegans, reducing longevity in wildtype and mutant long-lived strains. The multiomics data were analyzed as segregating gene networks according to each independent variable, providing causal insight into segregating edges. Candidate hits were cross-examined in an independent Diversity Outbred mouse liver dataset segregating for similar diets, with ~80-90% of diet-related candidate genes found in common across datasets. Together, we have developed a large multiomics resource for multivariate analysis of complex traits and demonstrate a methodology for moving from observational associations to causal connections. Overall design: RNA sequencing. About the cases used to generate this set of data: All animal care was handled according to the NIH's Guidelines for the Care and Use of Laboratory Animals and was also approved by the Animal Care and Use Committee of the University of Tennessee Health Science Center (UTHSC). 2157 mice from 89 strains of the BXD family (including parents and both F1s) were followed in the colony. 159 animals were males and 1998 animals were females. Animals were maintained in the UTHSC vivarium in Specific Pathogen-Free (SPF) housing throughout the longevity experiment. The housing environment was a 12-hour day/night cycle in 20–24°C temperature with housing cages of 145 in2 with up to 10 animals per cage. Diets were either Harlan Teklad 2018 (CD; 24% calories from protein, 18% from fat, 58% from carbohydrates) or Harlan Teklad 06414 (HFD; 18.3% calories from protein, 60.3% from fat, 21.4% from carbohydrates). Water was Memphis city municipal tap water. Food and water were ad libitum. All animals were followed from their point of entry into the colony (typically around 5 months of age) until death. Animals were checked daily for morbidity and were weighed approximately every 2-3 months throughout their lives. 662 animals were sacrificed at specific ages for tissue collection across cohort (i.e. diet, strain, sex, and age). These 662 animals were selected for tissue harvest with the following aims: 2 animals per strain, diet, and age, for a target of 4 age points, i.e. up to a target maximum of 16 sacrificed animals per strain (2 replicates * 2 diets * 4 ages). Transcriptomics were acquired for 291 individuals, which had targeted data generation for 1 animal of each of the 309 cohorts (i.e of the 662 individuals, just over half had a biological replicate which was age, diet, strain, and sex-matched). The target ages were 7, 12, 18, and 24 months of age. Roughly every 3 months for the duration of the experiment, ~40 animals were selected for sacrifice, with approximately 15 animals sacrificed per day over the course of 3 or 4 continuous days. Animals were removed from the aging colony the night prior to sacrifice, but retained access to food and water.