Population STARR-seq in preadipocytes pre/post differentiation

Transversions (Tv's) are more likely to alter the amino acid sequence of proteins than transitions (Ts's), and local deviations in the Ts:Tv ratio are indicative of evolutionary selection on genes. Whether the two different types of mutations have different effects in non-protein-coding sequences remains unknown. Here, we provide multiple lines of evidence demonstrating that Tv’s have larger impacts on regulatory DNA including analyses of transcription factor (TF) binding motifs, allele-specific TF binding, and genome-wide Tv density within accessible chromatin. Using massively parallel population-scale reporter assays, we also provide empirical evidence that Tv's have larger effects than Ts's on the activity of human gene regulatory elements. Understanding the features of functional non-coding variation will be valuable for revealing the genetic underpinnings of complex traits and diseases. STARR-seq libraries were generated from captured open chromatin regions at 3q25 in 760 individuals and transfected into HepG2 cells.