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<p>Gene expression is modulated jointly by transcriptional regulation and messenger RNA stability, yet the latter is often overlooked in studies on genetic variants. Here, leveraging metabolic labeling data (Bru/BruChase-seq) and a new computational pipeline, RNAtracker, we categorize genes as allele-specific RNA stability (asRS) or allele-specific RNA transcription events. We identify more than 5,000 asRS variants among 665 genes across a panel of 11 human cell lines. These variants directly overlap conserved microRNA target regions and allele-specific RNA-binding protein sites, illuminating mechanisms through which stability is mediated. Furthermore, we identified causal asRS variants using a massively parallel screen (MapUTR) for variants that affect post-transcriptional mRNA abundance, as well as through CRISPR prime editing approaches. Notably, asRS genes were enriched significantly among a multitude of immune-related pathways and contribute to the risk of several immune system diseases. This work highlights RNA stability as a critical, yet understudied mechanism linking genetic variation and disease.</p>

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Genetic variants affecting RNA stability influence complex traits and disease risk

  • 期刊论文

  • 发表日期：

    2025年9月5日

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  • Elaine Huang,
  • Ting Fu,
  • Ling Zhang,
  • Guanao Yan,
  • Ryo Yamamoto,
  • Sari Terrazas,
  • Thuy Linh Nguyen,
  • Carlos Gonzalez-Figueroa,
  • Armen Khanbabaei,
  • Jae Hoon Bahn,
  • Rajagopal Varada,
  • Kofi Amoah,
  • Jonatan Hervoso,
  • Michelle T. Paulsen,
  • Brian Magnuson,
  • Mats Ljungman,
  • Jingyi Jessica Li,
  • Xinshu Xiao

摘要

Gene expression is modulated jointly by transcriptional regulation and messenger RNA stability, yet the latter is often overlooked in studies on genetic variants. Here, leveraging metabolic labeling data (Bru/BruChase-seq) and a new computational pipeline, RNAtracker, we categorize genes as allele-specific RNA stability (asRS) or allele-specific RNA transcription events. We identify more than 5,000 asRS variants among 665 genes across a panel of 11 human cell lines. These variants directly overlap conserved microRNA target regions and allele-specific RNA-binding protein sites, illuminating mechanisms through which stability is mediated. Furthermore, we identified causal asRS variants using a massively parallel screen (MapUTR) for variants that affect post-transcriptional mRNA abundance, as well as through CRISPR prime editing approaches. Notably, asRS genes were enriched significantly among a multitude of immune-related pathways and contribute to the risk of several immune system diseases. This work highlights RNA stability as a critical, yet understudied mechanism linking genetic variation and disease.