Interpreting the CTCF-mediated sequence grammar of genome folding with AkitaV2
Fig 5
Pairwise nucleotide dependencies are largely additive in core CTCF motifs and their flanking sequences.
A) Pairwise mutagenesis. Mutation score for pairs of mutations in the 19bp core motifs +/- 15bp flanks for 100 strong CTCF sites. Mutation score is calculated as the difference between insertion scores for the mutant versus the unperturbed sequence. The heatmap shows the average mutation score for each pair of positions. B) Single-nucleotide saturation mutagenesis of the 19bp core motifs +/- 15bp flanks for the same sequences in A. The heatmap presents the average over all CTCF sites for each possible substitution. C) Predicted additive impact of pairwise mutagenesis. The predicted additive pairwise impact is the sum of the average single-nucleotide impacts (panel B). Note the shared color scale across panels A-C. D) Scatterplot of predicted additive and observed pairwise mutagenesis effects from panels A,B. For pairs of weak mutations, impacts are largely additive (up to mutation scores of -40). Higher impact mutations (i.e. more negative mutation scores) appear to saturate and diverge from this linear trend.