Parent-of-origin effects propagate through networks to shape metabolic traits
- Washington University in Saint Louis, United States
- University of Utah, United States
- Loyola University Chicago, United States
Abstract
Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological traits. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these parent-of-origin effects phenomena. We propose that non-imprinted genes can generate complex parent-of-origin effects on metabolic traits through interactions with imprinted genes. Here, we employ data from mouse populations at different levels of intercrossing (F0, F1, F2, F16) of the LG/J and SM/J inbred mouse lines to test this hypothesis. Using multiple populations and incorporating genetic, genomic, and physiological data, we leverage orthogonal evidence to identify networks of genes through which parent-of-origin effects propagate. We identify a network comprised of 3 imprinted and 6 non-imprinted genes that show parent-of-origin effects. This epistatic network forms a nutritional responsive pathway and the genes comprising it jointly serve cellular functions associated with growth. We focus on 2 genes, Nnat and F2r, whose interaction associates with serum glucose levels across generations in high fat-fed females. Single-cell RNAseq reveals that Nnat expression increases and F2r expression decreases in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.
Data availability
Sequencing data are available through the NCBI-SRA under accession code PRJNA753198
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LG/J and SM/J hybrid RNAseqNCBI-SRA, PRJNA753198.
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Single-cell RNA-sequencing of white adipose tissue stromal cells during CL-induced adipogenesisEuropean Nucleotide Archive, PRJNA470640.
Article and author information
Author details
Juan F Macias-Velasco
Celine L St. Pierre
Clay F Semenkovich
Funding
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mouse colony was maintained at the Washington University School of Medicine and all experiments were approved by the Institutional Animal Care and Use Committee in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals. Protocol #20-0384
Copyright
© 2022, Macias-Velasco et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Parent-of-origin effects propagate through networks to shape metabolic traits
eLife 11:e72989.
https://doi.org/10.7554/eLife.72989
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