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It is now well established that noncoding regulatory variants play a central role in the genetics of common diseases and in evolution. However, until recently, we have known little about the mechanisms by which most regulatory variants act. For instance, what types of functional elements in DNA, RNA, or proteins are most often affected by regulatory variants? Which stages of gene regulation are typically altered? How can we predict which variants are most likely to impact regulation in a given cell type? Recent studies, in many cases using quantitative trait loci (QTL)-mapping approaches in cell lines or tissue samples, have provided us with considerable insight into the properties of genetic loci that have regulatory roles. Such studies have uncovered novel biochemical regulatory interactions and led to the identification of previously unrecognized regulatory mechanisms. We have learned that genetic variation is often directly associated with variation in regulatory activities (namely, we can map regulatory QTLs, not just expression QTLs [eQTLs]), and we have taken the first steps towards understanding the causal order of regulatory events (for example, the role of pioneer transcription factors). Yet, in most cases, we still do not know how to interpret overlapping combinations of regulatory interactions, and we are still far from being able to predict how variation in regulatory mechanisms is propagated through a chain of interactions to eventually result in changes in gene expression profiles.
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