| Autor: |
Tyler AL, Mahoney JM, Keller MP, Baker CN, Gaca M, Srivastava A, Gerdes Gyuricza I, Braun MJ, Rosenthal NA, Attie AD, Churchill GA, Carter GW |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 27. Date of Electronic Publication: 2024 Sep 27. |
| DOI: |
10.1101/2024.09.26.613931 |
| Abstrakt: |
Although many genes are subject to local regulation, recent evidence suggests that complex distal regulation may be more important in mediating phenotypic variability. To assess the role of distal gene regulation in complex traits, we combined multi-tissue transcriptomes with physiological outcomes to model diet-induced obesity and metabolic disease in a population of Diversity Outbred mice. Using a novel high-dimensional mediation analysis, we identified a composite transcriptome signature that summarized genetic effects on gene expression and explained 30% of the variation across all metabolic traits. The signature was heritable, interpretable in biological terms, and predicted obesity status from gene expression in an independently derived mouse cohort and multiple human studies. Transcripts contributing most strongly to this composite mediator frequently had complex, distal regulation distributed throughout the genome. These results suggest that trait-relevant variation in transcription is largely distally regulated, but is nonetheless identifiable, interpretable, and translatable across species. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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