Thousands of large-scale RNA sequencing experiments yield a comprehensive new human gene list and reveal extensive transcriptional noise

Pertea, Mihaela; Shumate, Alaina; Pertea, Geo; Varabyou, Ales; Chang, Yu Chi; Madugundu, Anil K.; Pandey, Akhilesh; Salzberg, Steven L.

doi:10.1101/332825

Cited by 40 publications

(32 citation statements)

References 54 publications

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“…We discovered 8.4 to 22Mb of novel transcription across all tissues, consistent with previous reports that annotation remains incomplete 26,27 . Novel ERs predominantly fell into intragenic regions suggesting we were improving the annotation of known genes rather than discovering new genes (Figure 2a).…”

Section: Novel Transcription Is Widespread Across All Human Tissues Asupporting

confidence: 90%

Incomplete annotation of disease-associated genes is limiting our understanding of Mendelian and complex neurogenetic disorders

Zhang

Guelfi

García-Ruiz

et al. 2018

Preprint

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Although the increasing use of whole-exome and whole-genome sequencing have improved the yield of genetic testing for Mendelian disorders, an estimated 50% of patients still leave the clinic without a genetic diagnosis.This can be attributed in part to our lack of ability to accurately interpret the genetic variation detected through next-generation sequencing. Variant interpretation is fundamentally reliant on accurate and complete gene annotation, however numerous reports and discrepancies between gene annotation databases reveals that the knowledge of gene annotation remains far from comprehensive. Here, we detect and validate transcription in an annotation-agnostic manner across all 41 different GTEx tissues, then connect novel transcription to known genes, ultimately improving the annotation of 63% of the known OMIM-morbid genes. We find the majority of novel transcription to be tissue-specific in origin, with brain tissues being most susceptible to misannotation.Furthermore, we find that novel transcribed regions tend to be poorly conserved, but are significantly depleted for genetic variation within humans, suggesting they are functionally significant and potentially have humanspecific functions. We present our findings through an online platform vizER, which enables individual genes to be visualised and queried for evidence of misannotation. We also release all tissue-specific transcriptomes in a BED format for ease of integration with whole-genome sequencing data. We anticipate that these resources will improve the diagnostic yield for a wide range of Mendelian disorders.

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Section: Novel Transcription Is Widespread Across All Human Tissues Asupporting

confidence: 90%

Incomplete annotation of disease-associated genes is limiting our understanding of Mendelian and complex neurogenetic disorders

Zhang

Guelfi

García-Ruiz

et al. 2018

Preprint

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“…The transcription of unannotated genome sequence is evidenced by transcriptomic studies in which raw reads do not align to known genes (Wu and Knudson, 2018;Pertea et al, 2018b;Delcourt et al, 2018;Struhl, 2007;Lu et al, 2017). Many dismiss this genome expression as "noise" (Pertea et al, 2018b,a;Consortium et al, 2012;Barroso et al, 2018;Lloréns-Rico et al, 2016), However, some of this sequence are translated (Wu and Knudson, 2018;Carvunis et al, 2012;Smith et al, 2014;Olexiouk et al, 2017;Hsu et al, 2016;Ruiz-Orera et al, 2015;Chew et al, 2013), and several functional genes have been identified from it (Ji et al, 2015;Andrews and Rothnagel, 2014).…”

Section: Introductionmentioning

confidence: 99%

Landscape of the Dark Transcriptome Revealed through Re-mining Massive RNA-Seq Data

Jing

Singh

Arendsee

et al. 2019

Preprint

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The “dark transcriptome” can be considered the multitude of sequences that are transcribed but not annotated as genes. We evaluated expression of 6,692 annotated genes and 29,354 unannotated ORFs in the Saccharomyces cerevisiae genome across diverse environmental, genetic and developmental conditions (3,457 RNA-Seq samples). Over 48% of the transcribed ORFs have translation evidence. Phylostratigraphic analysis infers most of these transcribed ORFs would encode species-specific proteins (“orphan-ORFs”); hundreds have mean expression comparable to annotated genes. These data reveal unannotated ORFs most likely to be protein-coding genes. We partitioned a co-expression matrix by Markov Chain Clustering; the resultant clusters contain 2,468 orphan-ORFs. We provide the aggregated RNA-Seq yeast data with extensive metadata as a project in MetaOmGraph, a tool designed for interactive analysis and visualization. This approach enables reuse of public RNA-Seq data for exploratory discovery, providing a rich context for experimentalists to make novel, experimentally-testable hypotheses about candidate genes.

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“…Over 500 million years of evolution from hydra to humans, the total number of ORFs have been thought to remain the same at around 30,000. With the advent of deep sequencing strategies in both genomics and proteomics fields, we are now discovering nORFs that have remained undiscovered or 'hidden' 1,2,5,6 . These nORFs are pervasive throughout the genome and are observed in both the coding and non coding regions 1,7 .…”

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confidence: 99%

Proteins encoded by Novel ORFs have increased disorder but can be biochemically regulated and harbour pathogenic mutations

Jagannathan

Meena

Bhayankaram

et al. 2019

Preprint

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Recent advances in proteogenomics indicate that protein or protein-like products can be encoded by previously uncharacterized Open Reading Frames (ORFs) that we define as Novel Open Reading Frames (nORFs) 1 , 2 . Although it is yet unclear if these protein or protein-like products could possess any significant biological function hopes have been raised to target them for anticancer and antimicrobial therapy 3,4 . In this study, we used computational tools to systematically investigate these novel protein sequences for their propensities toward structural disorder, post-translational modifications (PTM) and mutational densities. We found that these novel proteins have significantly higher disorder and similar PTM frequencies compared to known proteins. Although these regions were found to harbour deleterious mutations, we did not observe any correlation between the pathogenicity of mutations and their location (ordered/disordered) within these novel proteins. This study suggests that these nORFs encode an important class of proteins, that could undergo sequence, structural or regulatory changes during complex diseases, and hence warrant further study. Significance:Certain noncoding regions of the genome are known to make protein-like products. These protein-like products have significantly expanded the number of the cellular proteome but we dont know whether they are capable of performing biological functions. Here in this study, we have investigated all such putative protein-like products and analyzed whether they can form structures, whether hey harbour mutations, and whether they can be regulated by biochemical regulatory processes. Results from this study indicate that indeed these protein-like proteins can perform and be involved in all the above processes.

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Thousands of large-scale RNA sequencing experiments yield a comprehensive new human gene list and reveal extensive transcriptional noise

Cited by 40 publications

References 54 publications

Incomplete annotation of disease-associated genes is limiting our understanding of Mendelian and complex neurogenetic disorders

Incomplete annotation of disease-associated genes is limiting our understanding of Mendelian and complex neurogenetic disorders

Landscape of the Dark Transcriptome Revealed through Re-mining Massive RNA-Seq Data

Proteins encoded by Novel ORFs have increased disorder but can be biochemically regulated and harbour pathogenic mutations

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