Department of Genetics, Washington University School of Medicine, Saint Louis, United States.
Department of Medicine, Washington University School of Medicine, Saint Louis, United States.
Elife. 2022 Mar 31;11:e72989. doi: 10.7554/eLife.72989.
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 F 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 (F, F, F, F) 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 three imprinted and six 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 two genes, and , whose interaction associates with serum glucose levels across generations in high-fat-fed females. Single-cell RNAseq reveals that expression increases and expression decreases in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.
亲本来源效应在复杂性状中非常常见，包括代谢和神经性状。亲本来源效应可以被环境所修饰，但是这些基因-环境对表型的影响的结构仍然需要阐明。先前，在 LG/J 和 SM/J 近交系小鼠的高级互交的 F 代中，已经定位到了表现出代谢性状的特定上下文亲本来源效应的数量性状位点 (QTL)。然而，这些 QTL 没有富集已知的印迹基因，这表明需要另一种机制来解释这些亲本来源效应现象。我们提出，非印迹基因可以通过与印迹基因的相互作用，对代谢性状产生复杂的亲本来源效应。在这里，我们利用 LG/J 和 SM/J 近交系小鼠不同杂交水平（F、F、F、F）的小鼠群体的数据来检验这一假设。我们利用多个群体，并整合遗传、基因组和生理数据，利用正交证据来识别通过其传播亲本来源效应的基因网络。我们鉴定了一个由三个印迹基因和六个非印迹基因组成的网络，这些基因表现出亲本来源效应。这个上位性网络形成了一个营养响应途径，其中包含的基因共同提供与生长相关的细胞功能。我们关注两个基因 和 ，它们的相互作用在高脂肪喂养的雌性中与血清葡萄糖水平在各代之间相关联。单细胞 RNAseq 揭示，在脂肪生成轨迹中，前脂肪细胞中的 表达增加， 表达减少，这一结果与我们在批量白色脂肪组织中的观察结果一致。
