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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
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RNA splicing is a primary link between genetic variation and disease
Yang I Li1, Bryce van de Geijn2, Anil Raj1
1Department of Genetics, Stanford University, Stanford, CA, USA.
Science (New York, N.Y.)
|April 30, 2016
Summary
Genetic variants influencing complex traits often act in noncoding DNA. This study reveals that splicing QTLs significantly impact gene regulation and complex traits, comparable to expression QTLs.
Area of Science:
- Genetics
- Molecular Biology
- Genomics
Background:
- Noncoding variants are crucial for complex trait genetics but their mechanisms remain unclear.
- Understanding gene regulation pathways is essential for deciphering genetic contributions to disease.
Purpose of the Study:
- To quantify cis-acting genetic effects across all major gene regulation stages.
- To investigate the role of splicing quantitative trait loci (sQTLs) in human gene regulation and complex traits.
Main Methods:
- Analysis of Yoruba lymphoblastoid cell lines (LCLs).
- Quantification of genetic effects from chromatin to protein levels.
- Development and application of a novel method for detecting sQTLs.
Main Results:
- Approximately 65% of expression quantitative trait loci (eQTLs) primarily affect chromatin.
- The remaining eQTLs are enriched in transcribed regions.
- 2893 sQTLs were identified, with most having minimal impact on overall gene expression but significantly contributing to complex traits.
Conclusions:
- Genetic variation impacts human gene regulation through multiple mechanisms, including chromatin, gene expression, and splicing.
- Splicing QTLs represent a significant, previously underappreciated, mechanism linking genetic variation to complex traits.
- This study offers a comprehensive framework for understanding the genetic architecture of human gene regulation.
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