Optimized high-throughput screening of non-coding variants identified from genome-wide association studies
Tunc Morova1, Yi Ding2, Chia-Chi F Huang1
1Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
Nucleic Acids Research
|December 22, 2022
Summary
A new method, snpSTARRseq, efficiently tests how genetic variants in non-coding DNA affect gene regulation. This approach identified functional variants in prostate cancer risk regions, offering insights into disease mechanisms.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Most disease-associated genetic variants are in non-coding DNA.
- These variants can alter gene expression by affecting transcription factor binding to enhancers.
Purpose of the Study:
- To develop a high-throughput method for functionally testing non-coding genetic variants.
- To investigate the impact of single nucleotide polymorphisms (SNPs) on enhancer activity.
Main Methods:
- Developed snpSTARRseq, a novel high-throughput assay for enhancer activity.
- Utilized advanced sequencing and bioinformatics for improved signal-to-noise ratio.
- Tested hundreds to thousands of variants per locus.
Main Results:
- Interrogated prostate cancer (PCa) risk loci, finding 35% of SNPs altered enhancer activity.
- Integrated data with chromosomal looping to identify interacting genes for 20 PCa GWAS risk regions.
- snpSTARRseq correlated strongly with in vivo allelic-imbalance studies, unlike in silico methods.
Conclusions:
- snpSTARRseq is an effective tool for functional interrogation of non-coding variants.
- Provides a framework for understanding the mechanisms of GWAS-identified risk regions.
- Enhances the functional characterization of genetic variants in disease.
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