Alternative transcriptional initiation (ATI) refers to the frequent observation that one gene has multiple transcription start sites (TSSs). Although this phenomenon is thought to be adaptive, the specific advantage is rarely known. Here, we propose that each gene has one optimal TSS and that ATI arises primarily from imprecise transcriptional initiation that could be deleterious. This error hypothesis predicts that (i) the TSS diversity of a gene reduces with its expression level; (ii) the fractional use of the major TSS increases, but that of each minor TSS decreases, with the gene expression level; and (iii) cis-elements for major TSSs are selectively constrained, while those for minor TSSs are not. By contrast, the adaptive hypothesis does not make these predictions a priori. Our analysis of human and mouse transcriptomes confirms each of the three predictions. These and other findings strongly suggest that ATI predominantly results from molecular errors, requiring a major revision of our understanding of the precision and regulation of transcription.
Bibliographical noteFunding Information:
This work was supported by US National Institutes of Health research grant GM120093 to JZ. CX and JP were supported in part by a grant from the Collaborative Genome Program (20140428) funded by the Ministry of Oceans and Fisheries, Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2019 Xu et al.