Widespread site-dependent buffering of human regulatory polymorphism

Area of Science:

• Genomics
• Molecular Biology
• Epigenetics

Background:

• Thousands of genetic variants reside in non-coding DNA, regulating gene expression.
• Interpreting the functional impact of these variants on transcription factor binding is challenging.

Purpose of the Study:

• To analyze the heritable effects of genetic variation on the binding patterns of CTCF, a major sequence-specific regulator.
• To understand how genetic variability within transcription factor recognition sequences influences binding occupancy.

Main Methods:

• ChIP-seq was used to quantify CTCF occupancy across three generations in 12 individuals.
• Targeted resequencing of the CTCF-binding landscape was performed across all individuals.

Main Results:

• Hundreds of variants showed reproducible quantitative effects on CTCF occupancy.
• Variant effects were buffered by local DNA context, often rendering them silent.
• 40% of variants increasing CTCF occupancy were found at human-chimp divergence sites.

Conclusions:

• Predicting the functional consequences of regulatory DNA variation is constrained by complex buffering effects.
• Empirical functional genomic measurements are essential for site-specific prediction of variant impacts.
• The prevalence of variants increasing binding at divergence sites challenges assumptions about functional regulatory variants being primarily deleterious.