Genetic variants affecting RNA stability influence complex traits and disease risk
Elaine Huang1, Ting Fu2, Ling Zhang2
1Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.
Nature Genetics
|September 5, 2025
Summary
Genetic variants influencing messenger RNA stability (asRS) are identified, revealing new insights into gene regulation and immune disease risk. This study emphasizes RNA stability
Area of Science:
- Molecular Biology
- Genetics
- Bioinformatics
Background:
- Gene expression is regulated by both transcription and mRNA stability.
- The role of mRNA stability in genetic variation is often overlooked.
- Understanding allele-specific regulation is crucial for disease research.
Purpose of the Study:
- To identify and characterize allele-specific RNA stability (asRS) variants.
- To explore the mechanisms underlying mRNA stability regulation.
- To investigate the link between asRS variants and immune-related diseases.
Main Methods:
- Utilized metabolic labeling data (Bru/BruChase-seq) and the RNAtracker computational pipeline.
- Categorized genes into allele-specific RNA stability or transcription events.
- Employed massively parallel screening (MapUTR) and CRISPR prime editing to identify causal asRS variants.
Main Results:
- Identified over 5,000 asRS variants in 665 genes across 11 human cell lines.
- Found overlap of asRS variants with microRNA target regions and RNA-binding protein sites.
- asRS genes are significantly enriched in immune-related pathways and linked to immune disease risk.
Conclusions:
- RNA stability is a critical mechanism linking genetic variation to disease.
- This study highlights the underappreciated role of mRNA stability in genetic studies.
- The findings provide a new perspective on the genetic basis of immune disorders.
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