Contribution of unfixed transposable element insertions to human regulatory variation

Area of Science:

• Genomics
• Molecular Biology
• Population Genetics

Background:

• Thousands of unfixed transposable element (TE) insertions exist in the human population with largely unknown effects on genome function.
• Previous studies suggest associations between TE insertions and mRNA levels of nearby genes, but biological significance and mechanisms remain unclear.

Purpose of the Study:

• To investigate the impact of unfixed TE insertions on genome function across different human cell types.
• To identify TE-expression quantitative trait loci (eQTL) and understand their mechanisms of gene regulation.

Main Methods:

• Performed TE-eQTL analysis in 444 lymphoblastoid cell lines (LCL) and 289 induced pluripotent stem cells.
• Utilized a new set of genotypes for 2743 polymorphic TE insertions.
• Analyzed chromatin accessibility QTL in a subset of LCL.

Main Results:

• Identified 211 and 176 TE-eQTL acting in cis in LCL and stem cells, respectively.
• Found that approximately 18% of TE-eQTL were shared across cell types with correlated effects.
• Demonstrated that unfixed TEs modulate enhancer activity and DNA accessibility, and potentially affect gene expression post-transcriptionally.

Conclusions:

• Unfixed TEs exert broad and diverse cis-regulatory effects in the human population.
• These TEs likely contribute to phenotypic variation through their influence on gene regulation.
• The study highlights the significant role of mobile genetic elements in shaping genome function and human traits.