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Tandem repeat sequence variation as causative cis-eQTLs for protein-coding gene expression variation: the case of
Christelle Borel1, Eugenia Migliavacca, Audrey Letourneau
1Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Human Mutation
|May 11, 2012
Summary
Copy-number variation in sequence repeats, specifically the dodecamer repeat in the CSTB gene promoter, strongly influences gene expression. This finding suggests polymorphic tandem repeats may explain many unknown gene expression regulators.
Area of Science:
- Genetics
- Molecular Biology
- Genomics
Background:
- Expression quantitative trait loci (eQTLs) are known to influence gene expression, but the specific causative variants are often unidentified.
- Copy-number variation (CNV) in sequence repeats is hypothesized to contribute to gene expression variability.
- Previous research linked a rare expansion of a repeat in the CSTB gene promoter to gene silencing and epilepsy.
Purpose of the Study:
- To investigate the role of repeat length variation in the CSTB gene promoter as a potential causative cis-eQTL.
- To determine the association between the c.-174CGGGGCGGGGCG repeat length and CSTB gene expression levels.
Main Methods:
- Genotyping of the dodecamer repeat length in 173 lymphoblastoid cell lines (LCLs) and fibroblast samples.
- Quantification of CSTB gene expression using quantitative real-time polymerase chain reaction (qRT-PCR).
- Analysis of single-nucleotide polymorphisms (SNPs) within a 2 Mb region surrounding the CSTB gene.
Main Results:
- A strong association was found between the c.-174CGGGGCGGGGCG repeat length and CSTB expression in LCLs (P = 3.14 × 10(-11)).
- The common two or three copy variation of the dodecamer repeat was identified as the strongest cis-eQTL for CSTB in LCLs.
- No significant association was observed in fibroblast samples.
Conclusions:
- Polymorphic tandem repeats, such as the dodecamer repeat in the CSTB promoter, can act as causative cis-eQTLs for gene expression variation.
- This study highlights the importance of considering repeat variations when investigating the genetic basis of gene expression.
- The findings suggest that CNVs in tandem repeats may explain a portion of the missing heritability in complex traits.
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