Fig. 1

Process of scoring TFBS-SNP impact and identifying a TF’s “binding change SNPs.” a We build a STAP model to predict TF binding at a DNA segment, separately for every available motif from ENCODE, FactorBook, and HOCOMOCO that represents the TF. For a given sequence, each motif-specific STAP model outputs a score indicating the occupancy of the TF on the sequence. An SVM model then combines STAP scores from all motifs of the TF to compute a combined score of the TF’s binding to the sequence; this is called the “MOP” score. b “Delta-MOP” score of a SNP is defined as the absolute value of the difference between the MOP scores of the major and minor allele sequences, constructed from the 501-bp sequence centered on the SNP location. In this example, SNP rs6717613 (G->A) is found to have a Delta-MOP score of 0.45 for the TF ATF2, which is the difference of MOP scores between the major and minor alleles (0.29 and 0.74 respectively). MOP scores were based on combining scores for six different ATF2 motifs (logos shown). The Delta-MOP score in this example can be qualitatively understood in terms of matches of the core binding site (top) to each of the six ATF2 motifs, whose STAP scores are shown separately for the two alleles (bottom). The core site’s match to motifs ATF2-1, ATF2-2, and ATF-6 changes in strength between the two alleles. For instance, the SNP falls on the 10th position of motif ATF2-1, which prefers an “A,” and the change from “G” (major allele) to “A” (minor allele) is interpreted as a change in strength of motif match. On the other hand, the core site does not have a strong match to ATF2-3 or ATF2-4, in either allelic form, while motif ATF2-5 overlaps the core site but not the SNP position. The Delta-MOP score combines these different pieces of information in a principled manner to compute an overall score of the impact of rs6717613 on ATF2 binding