(A) Relative frequency of DNA-binding changes observed for variants
at DNA-contacting residues. “Both” comprises residues at which
variants changed DNA binding affinity and specificity either simultaneously in
one protein or separately across different proteins. (B) Overlap
between DBDPs affecting DNA-contacting residues in zf-C2H2, Fork_head, HLH, and
Homeobox Pfam domains (blue) or predicted as “probably
damaging” by PolyPhen-2 and “damaging” by SIFT
(green). (C) Number of sequence-specific TFs
for which DBDPs were identified and their evaluation, as in (B).
(D) Minor allele frequencies (ExAC v0.2) of nsSNPs.
(E) Histogram of DBD variants per individual (1000 Genomes
Project Phase 3), annotated as in C. (F) Fraction of
DNA-contacting residues per TF altered by at least one nsSNP (ExAC), for genes
tolerant of homozygous or compound heterozygous LoF mutations versus genes for
which LoF-tolerance was not observed (21). (G) Fraction of variable DNA-contacting residues
(ExAC) in TFs with versus without at least one co-expressed paralog.