Alu insertion variants alter gene transcript levels

Area of Science:

• Genomics
• Molecular Biology
• Human Evolution

Background:

• Alu elements are abundant interspersed repeats in the human genome and a major source of structural variation.
• The regulatory impact of Alu insertions on gene expression is not fully understood, despite associations with expression quantitative trait loci (eQTLs).

Purpose of the Study:

• To directly assess the regulatory effects of polymorphic Alu insertions independently of other variants.
• To investigate whether Alu elements can introduce or disrupt gene regulatory functions.

Main Methods:

• Utilized ectopic luciferase reporter assays to screen 110 Alu insertion variants for regulatory effects.
• Employed CRISPR gene editing to create cell lines with different endogenous Alu genotypes.
• Analyzed reporter constructs with surrounding genomic context to differentiate regulatory mechanisms.

Main Results:

• Observed a range of regulatory effects, with some Alu insertions significantly up- or down-regulating gene expression.
• Identified three polymorphic Alu loci associated with breast cancer that showed significant regulatory activity in reporter assays.
• Demonstrated that Alu genotype can alter the expression of cancer-associated genes like PTHLH, RANBP9, and MYC.

Conclusions:

• Common polymorphic Alu elements can modulate gene transcript levels.
• Alu genotype represents a potential factor contributing to human disease risk, particularly in cancer.