Identifying gene function and module connections by the integration of multi-species expression compendia

Li, Hao; Rukina, Daria; David, Fabrice; Li, Terytty Yang; Oh, Chang‐Myung; Gao, Arwen W.; Katsyuba, Elena; Sleiman, Maroun Bou; Komljenović, Andrea; Huang, Qingyao; Williams, Robert W.; Robinson‐Rechavi, Marc; Morgenthaler, Stephan; Auwerx, Johan

doi:10.1101/649079

Cited by 1 publication

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References 80 publications

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“…These indicate fully novel associations with mitochondrial function of unknown mechanism. To assist with annotating gene candidates beyond literature knowledge, we used GeneBridge, a tool have recently developed that performs literature mining and meta-analysis of GEO datasets [39] (Supplemental Table 4, sheet "26_", columns titled "GMAD").…”

Section: This Analysis Was Done For All 25 Pathways As a Function Of mentioning

confidence: 99%

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Multi-Omic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

Williams

Pfister

Roy

et al. 2020

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Systems biology approaches often use networks of gene expression and metabolite data to identify regulatory factors and pathways connected with phenotypic variance. Separating upstream causal mechanisms, downstream biomarkers, and incidental correlations remains a significant challenge, yet it is essential for designing mechanistic experiments. To address this, we first designed a population following 2157 individual mice from 89 isogenic strains of BXD mice across their lifespans to identify molecular interactions between genotype, environment, age (GxExA) and metabolic fitness. Each strain was separated into two cohorts, fed low fat (6% cal/fat) or high fat (60% cal/fat) diets. One-third of individuals (662) were sacrificed at ~6, 12, 18, or 24 months-of-age, with the remainder monitored until natural death. Transcriptome, proteome, and metabolome profiles were generated from liver samples. These multi-omic measurements were deconvolved into metabolic networks, where we observed varying network connectivity as a function of GxExA. The multiple independent study variables permitted causal inference analysis for the network variants using stability selection. This calculates the strength and directionality of the interactions between molecular measurements and metabolic networks as a function of age, diet, and genotype, and assigns each gene a score for its relative position to the target pathway. At 1% FDR, 94% of novel connections were stable across age and diet, such as the connection between Rdh11 with cholesterol biosynthesis and Mut with mitochondrial translation. 6% of discovered candidate genes were unstable, indicating a clear causal relationship between the segregating independent variable, the gene, and the pathway. For instance, age drives variation in proteasomal genes (e.g. Psmb3, Psmb4), which in turn drive changes in the mitochondrial ribosome. Conversely, COX7A2L malformation drives variation in OXPHOS genes, but both are downstream of changes in mitochondrial translation. Finally, we examined all data for connections with the longevity and known longevity-related pathways, identifying several dozen novel candidate genes. Specific C. elegans orthologs for the top two candidates, Ctsd and St7, were knocked down with RNAi and found to reduce longevity both in wildtype worms and in mutant long-lived strains.

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Section: This Analysis Was Done For All 25 Pathways As a Function Of mentioning

confidence: 99%

“…Notably, one of the top novel candidate genes associated with mitochondrial translation, Ddt, was also recently selected and validated as OXPHOS-related by our separate GMAD analysis and was shown to play a role in the electron transport chain [39].…”

Section: This Analysis Was Done For All 25 Pathways As a Function Of mentioning

confidence: 99%

Multi-Omic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

Williams

Pfister

Roy

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Identifying gene function and module connections by the integration of multi-species expression compendia

Cited by 1 publication

References 80 publications

Multi-Omic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

Multi-Omic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

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