Identifying deleterious noncoding variation through gain and loss of CTCF binding activity

Area of Science:

• Genomics
• Epigenetics
• Bioinformatics

Background:

• CCCTC binding factor (CTCF) regulates gene expression by binding to thousands of genomic sites.
• Genetic variations within CTCF binding sites (CBSs) contribute to phenotypic diversity, but identifying functionally significant variants in whole-genome sequencing data is challenging.

Purpose of the Study:

• To develop a hypothesis-driven framework for identifying and prioritizing CBS variants within the gnomAD database.
• To assess the functional impact of single-nucleotide variations (SNVs) that disrupt CTCF binding.

Main Methods:

• Synthesized CTCF binding patterns across 1,063,878 loci and 214 biological contexts to create a binding activity summary.
• Correlated binding activity with nucleotide conservation and CTCF binding motifs.
• Evaluated allelic binding predictions for 1,253,329 SNVs disrupting CBSs using binding activity and the mutability-adjusted proportion of singletons (MAPS) metric.

Main Results:

• High CTCF binding activity strongly correlates with conserved nucleotides and high-quality CTCF binding motifs.
• A significant positive relationship exists between the MAPS metric and the loss of CTCF binding at loci with high in vitro activity.
• A subset of 339,380 loss of CTCF binding variants is observed as infrequently as missense variants.

Conclusions:

• The developed framework effectively identifies and prioritizes rare, noncoding variants that disrupt CTCF binding.
• These variants are nominated for further functional investigation.
• The study provides a model for prioritizing variations in other transcription factor binding sequences.