Complex Selection on Human Polyadenylation Signals Revealed by Polymorphism and Divergence Data

Kainov, Yaroslav A.; Aushev, Vasily N.; Naumenko, Sergey; Tchevkina, Elena M.; Bazykin, Georgii A.

doi:10.1093/gbe/evw137

Cited by 9 publications

(8 citation statements)

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“…Our in silico analysis revealed that the poly(A) cleavage site of NTO2 is located within a canonical CA element, with a GU-rich region starting 13 nt downstream from the TES. The NTO3 has a CTTAAA poly(A) signal [ 68 ] starting 20 nt upstream from its TES, with a cleavage site in a homopolymer C run and with a consensus GU-rich region starting 25 nt downstream from the TES. The NTO4 has an ATATAA poly(A) signal [ 69 ] starting 24 nt upstream the TES, the cleavage site being marked by a consensus CA signal, followed by a GU-rich region 33 nt downstream.…”

Section: Resultsmentioning

confidence: 99%

Long-read sequencing uncovers a complex transcriptome topology in varicella zoster virus

et al. 2018

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BackgroundVaricella zoster virus (VZV) is a human pathogenic alphaherpesvirus harboring a relatively large DNA molecule. The VZV transcriptome has already been analyzed by microarray and short-read sequencing analyses. However, both approaches have substantial limitations when used for structural characterization of transcript isoforms, even if supplemented with primer extension or other techniques. Among others, they are inefficient in distinguishing between embedded RNA molecules, transcript isoforms, including splice and length variants, as well as between alternative polycistronic transcripts. It has been demonstrated in several studies that long-read sequencing is able to circumvent these problems.ResultsIn this work, we report the analysis of the VZV lytic transcriptome using the Oxford Nanopore Technologies sequencing platform. These investigations have led to the identification of 114 novel transcripts, including mRNAs, non-coding RNAs, polycistronic RNAs and complex transcripts, as well as 10 novel spliced transcripts and 25 novel transcription start site isoforms and transcription end site isoforms. A novel class of transcripts, the nroRNAs are described in this study. These transcripts are encoded by the genomic region located in close vicinity to the viral replication origin. We also show that the ORF63 exhibits a complex structural variation encompassing the splice sites of VZV latency transcripts. Additionally, we have detected RNA editing in a novel non-coding RNA molecule.ConclusionsOur investigations disclosed a composite transcriptomic architecture of VZV, including the discovery of novel RNA molecules and transcript isoforms, as well as a complex meshwork of transcriptional read-throughs and overlaps. The results represent a substantial advance in the annotation of the VZV transcriptome and in understanding the molecular biology of the herpesviruses in general.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5267-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Long-read sequencing uncovers a complex transcriptome topology in varicella zoster virus

et al. 2018

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“…We used the number of pseudo-PASs as a proxy for the expected number of PASs under no selection, where pseudo-PASs are PAS hexamers identified from the complementary sequence of the region of mRNA where PASs are searched. We were able to test these predictions in humans, thanks to a recent study that computationally identified all PASs and pseudo-PASs in human genes (Kainov et al, 2016). The mean number of PASs per gene in the 21,458 human genes examined is 1.87, significantly lower than the mean number of pseudo-PASs per gene (3.85; P < 10 −125 , paired t -test).…”

Section: Resultsmentioning

confidence: 99%

“…The PAS hexamers and pseudo-PASs in human genes, as well as human SNP densities, were acquired from Kainov et al (2016). Briefly, Kainov et al downloaded the PAS hexamers from PAS.db2 (Lee et al, 2007) and converted the genomic coordinates of PASs from hg17 to hg19 using liftOver from UCSC.…”

Section: Star Methodsmentioning

confidence: 99%

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Alternative Polyadenylation of Mammalian Transcripts Is Generally Deleterious, Not Adaptive

Zhang

2018

Cell Systems

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Alternative polyadenylation (APA) produces from the same gene multiple mature RNAs with varying 3' ends. Although APA is commonly believed to generate beneficial functional diversity and be adaptive, we hypothesize that most genes have one optimal polyadenylation site and that APA is caused largely by deleterious polyadenylation errors. The error hypothesis, but not the adaptive hypothesis, predicts that, as the expression level of a gene increases, its polyadenylation diversity declines, relative use of the major (presumably optimal) polyadenylation site increases, and that of each minor (presumably nonoptimal) site decreases. It further predicts that the number of polyadenylation signals per gene is smaller than the random expectation and that polyadenylation signals for major but not minor sites are under purifying selection. All of these predictions are confirmed in mammals, suggesting that numerous defective RNAs are produced in normal cells, many phenotypic variations at the molecular level are nonadaptive, and cellular life is noisier than is appreciated.

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“…Transcription termination can also occur anywhere from the 3′ end of the mRNA by readthrough transcription ( Proudfoot 1989 ; Dye and Proudfoot 1999 ; Richard and Manley 2009 ), which generates the mRNA 3′ end polymorphism ( de Klerk and ‘t Hoen 2015 ; Kainov et al 2016 ; Nourse et al 2020 ). In yeast, various transcript boundaries are present ( Gullerova and Proudfoot 2008 ; Pelechano et al 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Regulation of closely juxtaposed proto-oncogene c-fms and HMGXB3 gene expression by mRNA 3′ end polymorphism in breast cancer cells

Woo

Chambers

2021

RNA

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Sense-antisense mRNA pairs generated by convergent transcription is a way of gene regulation. c-fms gene is closely juxtaposed to the HMGXB3 gene in the opposite orientation, in chromosome 5. The intergenic region (IR) between c-fms and HMGXB3 genes is 162 bp. We found that a small portion (∼4.18%) of HMGXB3 mRNA is transcribed further downstream, including the end of the c-fms gene generating antisense mRNA against c-fms mRNA. Similarly, a small portion (∼1.1%) of c-fms mRNA is transcribed further downstream, including the end of the HMGXB3 gene generating antisense mRNA against the HMGXB3 mRNA. Insertion of the strong poly(A) signal sequence in the IR results in decreased c-fms and HMGXB3 antisense mRNAs, resulting in up-regulation of both c-fms and HMGXB3 mRNA expression. miR-324-5p targets HMGXB3 mRNA 3′ UTR, and as a result, regulates c-fms mRNA expression. HuR stabilizes c-fms mRNA, and as a result, down-regulates HMGXB3 mRNA expression. UALCAN analysis indicates that the expression pattern between c-fms and HMGXB3 proteins are opposite in vivo in breast cancer tissues. Together, our results indicate that the mRNA encoded by the HMGXB3 gene can influence the expression of adjacent c-fms mRNA, or vice versa.

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Complex Selection on Human Polyadenylation Signals Revealed by Polymorphism and Divergence Data

Cited by 9 publications

References 57 publications

Long-read sequencing uncovers a complex transcriptome topology in varicella zoster virus

Long-read sequencing uncovers a complex transcriptome topology in varicella zoster virus

Alternative Polyadenylation of Mammalian Transcripts Is Generally Deleterious, Not Adaptive

Regulation of closely juxtaposed proto-oncogene c-fms and HMGXB3 gene expression by mRNA 3′ end polymorphism in breast cancer cells

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