Title: Evolution of Genomic Binding Landscapes by Global Selection 

Abstract: Genomic composition with respect to short motifs impacts the ability of transcription factors to locate and bind their target sites. Using in vitro measurements of binding strengths on all 8-mer nucleotide words from a large collection of transcription factors, in multiple species, we discover a clear signal of evolutionary selection to reduce the large number of weak binding sites genome-wide. This evolutionary process, which we call global selection, has a distinct hallmark in that similar words experience similar evolutionary pressure. By analyzing this hallmark in genomes, and controlling for mutational biases, we show that global selection exists in all domains of life, and operates through tiny selective steps, shaping genomic binding landscapes over timescales spanning millions of generations. Our findings introduce a fundamentally new view on genomic evolution, in which molecular diversity that is effectively neutral over shorter timescales provides raw material for global selection acting over much longer timescales.