Divergent Transcription: A Driving Force for New Gene Origination?

Computational and Systems Biology Graduate Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell (Impact Factor: 32.24). 11/2013; 155(5):990-996. DOI: 10.1016/j.cell.2013.10.048
Source: PubMed


The mammalian genome is extensively transcribed, a large fraction of which is divergent transcription from promoters and enhancers that is tightly coupled with active gene transcription. Here, we propose that divergent transcription may shape the evolution of the genome by new gene origination.

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    • "These non-coding transcripts aregenerated by divergent promoters and are typically under the surveillance of the exosome[26,29]. Their expression can significantly enrich the transcriptome during spermatogenesis, potentially impacting evolution of new genes[67]. uaRNA expression appears to be associated with open chromatin around the TSS and correlates with the expression of sense transcripts. It is not clear, however, why they are not eliminated by the nuclear exosome. "
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    ABSTRACT: Background: Most mammalian genes display alternative cleavage and polyadenylation (APA). Previous studies have indicated preferential expression of APA isoforms with short 3' untranslated regions (3'UTRs) in testes. Results: By deep sequencing of the 3' end region of poly(A) + transcripts, we report widespread shortening of 3'UTR through APA during the first wave of spermatogenesis in mouse, with 3'UTR size being the shortest in spermatids. Using genes without APA as a control, we show that shortening of 3'UTR eliminates destabilizing elements, such as U-rich elements and transposable elements, which appear highly potent during spermatogenesis. We additionally found widespread regulation of APA events in introns and exons that can affect the coding sequence of transcripts and global activation of antisense transcripts upstream of the transcription start site, suggesting modulation of splicing and initiation of transcription during spermatogenesis. Importantly, genes that display significant 3'UTR shortening tend to have functions critical for further sperm maturation, and testis-specific genes display greater 3'UTR shortening than ubiquitously expressed ones, indicating functional relevance of APA to spermatogenesis. Interestingly, genes with shortened 3'UTRs tend to have higher RNA polymerase II and H3K4me3 levels in spermatids as compared to spermatocytes, features previously known to be associated with open chromatin state. Conclusions: Our data suggest that open chromatin may create a favorable cis environment for 3' end processing, leading to global shortening of 3'UTR during spermatogenesis. mRNAs with shortened 3'UTRs are relatively stable thanks to evasion of powerful mRNA degradation mechanisms acting on 3'UTR elements. Stable mRNAs generated in spermatids may be important for protein production at later stages of sperm maturation, when transcription is globally halted.
    Full-text · Article · Dec 2016 · BMC Biology
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    • "Several recent studies have advanced our understanding of new gene origins, their influence on genetic systems (including developmental networks), and the resulting effects on phenotypic evolution. Regarding origins, a study in mouse embryonic stem cells revealing pervasive bidirectional transcription suggested to the authors that opposite strand transcription could provide a robust source for new genes (Almada et al. 2013; Wu and Sharp 2013). Regarding genetic systems, studies of new genes in Drosophila (those present in just a few species) showed that they can quickly become essential for viability, male fertility, and foraging behavior (Chen et al. 2010; Chen, Ni, et al. 2012; Chen, Spletter, et al. 2012). "
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    ABSTRACT: Uncovering how a new gene acquires its function and understanding how the function of a new gene influences existing genetic networks are important topics in evolutionary biology. Here we demonstrate nonconservation for the embryonic functions of Drosophila Bonus and its newest vertebrate relative TIF1-γ/TRIM33. We showed previously that TIF1-γ/TRIM33 functions as an ubiquitin ligase for the Smad4 signal transducer and antagonizes the Bone Morphogenetic Protein (BMP) signaling network underlying vertebrate dorsal-ventral axis formation. Here we show that Bonus functions as an agonist of the Decapentaplegic (Dpp) signaling network underlying dorsal-ventral axis formation in flies. The absence of conservation for the roles of Bonus and TIF1-γ/TRIM33 reveals a shift in the dorsal-ventral patterning networks of flies and mice, systems that were previously considered wholly conserved. The shift occurred when the new gene TIF1-γ/TRIM33 replaced the function of the ubiquitin ligase Nedd4L in the lineage leading to vertebrates. Evidence of this replacement is our demonstration that Nedd4 performs the function of TIF1-γ/TRIM33 in flies during dorsal-ventral axis formation. The replacement allowed vertebrate Nedd4L to acquire novel functions as a ubiquitin ligase of vertebrate-specific Smad proteins. Overall our data reveals that the architecture of the Dpp/BMP dorsal-ventral patterning network continued to evolve in the vertebrate lineage, after separation from flies, via the incorporation of new genes.
    Full-text · Article · May 2014 · Molecular Biology and Evolution
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    • "RPL36aL is transcribed from a site some 1545 bp upstream, within <100 bp of the divergent initiation site of the MGAT2 gene. Since it is now clear that most promoters drive divergent transcription (Seila et al. 2009), we suggest that RPL36aL has been " fixed " in the " on " position, an example of a recent prediction (Wu and Sharp 2013). Excision of a 1422 nt intron from the 5 ′ UTR leaves the translation initiation site intact. "
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    ABSTRACT: The torrent of RNA-seq data becoming available not only furnishes an overview of the entire transcriptome but also provides tools to focus on specific areas of interest. Our focus on the synthesis of ribosomes asked whether the abundance of mRNAs encoding ribosomal proteins (RPs) matched the equimolar need for the RPs in the assembly of ribosomes. We were at first surprised to find, in the mapping data of ENCODE and other sources, that there were nearly 100-fold differences in the level of the mRNAs encoding the different RPs. However, after correcting for the mapping ambiguities introduced by the presence of more than 2000 pseudogenes derived from RP mRNAs, we show that for 80%-90% of the RP genes, the molar ratio of mRNAs varies less than threefold, with little tissue specificity. Nevertheless, since the RPs are needed in equimolar amounts, there must be sluggish or regulated translation of the more abundant RP mRNAs and/or substantial turnover of unused RPs. In addition, seven of the RPs have subsidiary genes, three of which are pseudogenes that have been "rescued" by the introduction of promoters and/or upstream introns. Several of these are transcribed in a tissue-specific manner, e.g., RPL10L in testis and RPL3L in muscle, leading to potential variation in ribosome structure from one tissue to another. Of the 376 introns in the RP genes, a single one is alternatively spliced in a tissue-specific manner.
    Full-text · Article · May 2014 · RNA
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