变异效应的综合多重分析揭示了儿茶酚- o -甲基转移酶基因表达的顺式调控决定因素

IF 4.6 1区 心理学 Q1 Medicine
Ian Hoskins, Shilpa Rao, Charisma Tante, Can Cenik
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引用次数: 0

摘要

变异效应的多重分析是分析罕见变异对基因表达和机体适应性影响的有力方法。然而,很少有研究整合了几种多重分析来绘制编码序列中基因表达的变异效应。在这里,我们开创了一种基于多聚体分析的多重分析方法,以大规模测量变异对翻译的影响,揭示单核苷酸变异增加和减少核糖体负荷。通过将高通量核糖体负载数据与多路mRNA和蛋白质丰度读数相结合,我们绘制了数千种儿茶酚- o -甲基转移酶(COMT)从RNA到蛋白质的顺式调控图景,并发现了许多改变COMT表达的编码变体。最后,我们训练了机器学习模型来绘制COMT基因表达变异效应的特征,并揭示了跨表达层的方向性和发散性影响。我们的分析揭示了COMT中数千种变异的表达表型,并强调了变异对单层和多层表达的影响。我们的发现促进了未来的研究,整合了几种多重检测来读取基因表达。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Integrated multiplexed assays of variant effect reveal cis-regulatory determinants of catechol-O-methyltransferase gene expression.

Multiplexed assays of variant effect are powerful methods to profile the consequences of rare variants on gene expression and organismal fitness. Yet, few studies have integrated several multiplexed assays to map variant effects on gene expression in coding sequences. Here, we pioneered a multiplexed assay based on polysome profiling to measure variant effects on translation at scale, uncovering single-nucleotide variants that increase and decrease ribosome load. By combining high-throughput ribosome load data with multiplexed mRNA and protein abundance readouts, we mapped the cis-regulatory landscape of thousands of catechol-O-methyltransferase (COMT) variants from RNA to protein and found numerous coding variants that alter COMT expression. Finally, we trained machine learning models to map signatures of variant effects on COMT gene expression and uncovered both directional and divergent impacts across expression layers. Our analyses reveal expression phenotypes for thousands of variants in COMT and highlight variant effects on both single and multiple layers of expression. Our findings prompt future studies that integrate several multiplexed assays for the readout of gene expression.

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期刊介绍: The Journal of Abnormal Psychology® publishes articles on basic research and theory in the broad field of abnormal behavior, its determinants, and its correlates. The following general topics fall within its area of major focus: - psychopathology—its etiology, development, symptomatology, and course; - normal processes in abnormal individuals; - pathological or atypical features of the behavior of normal persons; - experimental studies, with human or animal subjects, relating to disordered emotional behavior or pathology; - sociocultural effects on pathological processes, including the influence of gender and ethnicity; and - tests of hypotheses from psychological theories that relate to abnormal behavior.
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