selective constraints in experimentally defined primate regulatory regions选择性约束定义实验灵长类动物监管区域.pdfVIP

Selective Constraints in Experimentally Defined Primate Regulatory Regions 1,2 3 1,2 Daniel J. Gaffney *, Ran Blekhman , Jacek Majewski ´ ´ ´ ´ ´ 1 McGill University, Montreal, Quebec, Canada, 2 Genome Quebec Innovation Centre, Montreal, Quebec, Canada, 3 Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America Abstract Changes in gene regulation may be important in evolution. However, the evolutionary properties of regulatory mutations are currently poorly understood. This is partly the result of an incomplete annotation of functional regulatory DNA in many species. For example, transcription factor binding sites (TFBSs), a major component of eukaryotic regulatory architecture, are typically short, degenerate, and therefore difficult to differentiate from randomly occurring, nonfunctional sequences. Furthermore, although sites such as TFBSs can be computationally predicted using evolutionary conservation as a criterion, estimates of the true level of selective constraint (defined as the fraction of strongly deleterious mutations occurring at a locus) in regulatory regions will, by definition, be upwardly biased in datasets that are a priori evolutionarily conserved. Here we investigate the fitness effects of regulatory mutations using two complementary datasets of human TFBSs that are likely to be relatively free of ascertainment bias with respect to evolutionary conservation but, importantly, are supported by experimental data. The first is a collection of almost .2,100 human TFBSs drawn from the literature in the TRANSFAC database, and the second is derived from several recent high-throughput chromatin immunopre