Position-dependent variant effects reveal importance of context in genomic regulation

Variant effects in MPRAs are highly dependent on their position within the construct, with expression change magnitudes varying substantially based on placement.

• Why it matters: Understanding how variant position influences regulatory activity is crucial because it affects the accuracy of identifying causal variants and interpreting regulatory DNA function.
• What they did: The study used models predicting MPRA expression from DNA sequences to systematically analyze how shifting variant positions impacts regulatory activity, focusing on TF binding and promoter disruption.
• The result: Findings reveal that positional bias, driven by TF activity and Pol III promoter disruption, can lead to underestimating variant effects and missing causal variants in functional analyses.