scholarly journals RegTools: Integrated analysis of genomic and transcriptomic data for the discovery of splicing variants in cancer

2018 ◽  
Author(s):  
Kelsy C. Cotto ◽  
Yang-Yang Feng ◽  
Avinash Ramu ◽  
Zachary L. Skidmore ◽  
Jason Kunisaki ◽  
...  
Keyword(s):  
Sequence Data ◽  
Splice Variants ◽  
Tissue Expression ◽  
Integrated Analysis ◽  
Splice Isoforms ◽  
Transcriptomic Data ◽  
Dna And Rna ◽  
Splicing Variants ◽  
Integrate Analysis ◽  
Open Source Software Package

AbstractSomatic mutations in non-coding regions and even in exons may have unidentified regulatory consequences which are often overlooked in analysis workflows. Here we present RegTools (www.regtools.org), a free, open-source software package designed to integrate analysis of somatic variants from genomic data with splice junctions from transcriptomic data to identify variants that may cause aberrant splicing. RegTools was applied to over 9,000 tumor samples with both tumor DNA and RNA sequence data. We discovered 235,778 events where a variant significantly increased the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To characterize these somatic variants and their associated splice isoforms, we annotated them with the Variant Effect Predictor (VEP), SpliceAI, and Genotype-Tissue Expression (GTEx) junction counts and compared our results to other tools that integrate genomic and transcriptomic data. While certain events can be identified by the aforementioned tools, the unbiased nature of RegTools has allowed us to identify novel splice variants and previously unreported patterns of splicing disruption in known cancer drivers, such as TP53, CDKN2A, and B2M, as well as in genes not previously considered cancer-relevant, such as RNF145.

scholarly journals Differential Expression of BARD1 Isoforms in Melanoma

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 320
Author(s):  
Lorissa I. McDougall ◽  
Ryan M. Powell ◽  
Magdalena Ratajska ◽  
Chi F. Lynch-Sutherland ◽  
Sultana Mehbuba Hossain ◽  
...  
Keyword(s):  
Long Range ◽  
Patient Outcomes ◽  
Splice Variants ◽  
Significant Proportion ◽  
Nanopore Sequencing ◽  
Rna Seq ◽  
Splice Isoforms ◽  
Tissue Samples ◽  
Multiple Transcripts ◽  
Mrna Variants

Melanoma comprises <5% of cutaneous malignancies, yet it causes a significant proportion of skin cancer-related deaths worldwide. While new therapies for melanoma have been developed, not all patients respond well. Thus, further research is required to better predict patient outcomes. Using long-range nanopore sequencing, RT-qPCR, and RNA sequencing analyses, we examined the transcription of BARD1 splice isoforms in melanoma cell lines and patient tissue samples. Seventy-six BARD1 mRNA variants were identified in total, with several previously characterised isoforms (γ, φ, δ, ε, and η) contributing to a large proportion of the expressed transcripts. In addition, we identified four novel splice events, namely, Δ(E3_E9), ▼(i8), IVS10+131▼46, and IVS10▼176, occurring in various combinations in multiple transcripts. We found that short-read RNA-Seq analyses were limited in their ability to predict isoforms containing multiple non-contiguous splicing events, as compared to long-range nanopore sequencing. These studies suggest that further investigations into the functional significance of the identified BARD1 splice variants in melanoma are warranted.

scholarly journals Unveiling Crucivirus Diversity by Mining Metagenomic Data

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Ignacio de la Higuera ◽  
George W. Kasun ◽  
Ellis L. Torrance ◽  
Alyssa A. Pratt ◽  
Amberlee Maluenda ◽  
...  
Keyword(s):  
De Novo ◽  
Rna Viruses ◽  
Sequence Data ◽  
Ecosystem Dynamics ◽  
Capsid Proteins ◽  
Metagenomic Data ◽  
Dna Viruses ◽  
Rep Protein ◽  
Dna And Rna ◽  
Core Proteins

ABSTRACT The discovery of cruciviruses revealed the most explicit example of a common protein homologue between DNA and RNA viruses to date. Cruciviruses are a novel group of circular Rep-encoding single-stranded DNA (ssDNA) (CRESS-DNA) viruses that encode capsid proteins that are most closely related to those encoded by RNA viruses in the family Tombusviridae. The apparent chimeric nature of the two core proteins encoded by crucivirus genomes suggests horizontal gene transfer of capsid genes between DNA and RNA viruses. Here, we identified and characterized 451 new crucivirus genomes and 10 capsid-encoding circular genetic elements through de novo assembly and mining of metagenomic data. These genomes are highly diverse, as demonstrated by sequence comparisons and phylogenetic analysis of subsets of the protein sequences they encode. Most of the variation is reflected in the replication-associated protein (Rep) sequences, and much of the sequence diversity appears to be due to recombination. Our results suggest that recombination tends to occur more frequently among groups of cruciviruses with relatively similar capsid proteins and that the exchange of Rep protein domains between cruciviruses is rarer than intergenic recombination. Additionally, we suggest members of the stramenopiles/alveolates/Rhizaria supergroup as possible crucivirus hosts. Altogether, we provide a comprehensive and descriptive characterization of cruciviruses. IMPORTANCE Viruses are the most abundant biological entities on Earth. In addition to their impact on animal and plant health, viruses have important roles in ecosystem dynamics as well as in the evolution of the biosphere. Circular Rep-encoding single-stranded (CRESS) DNA viruses are ubiquitous in nature, many are agriculturally important, and they appear to have multiple origins from prokaryotic plasmids. A subset of CRESS-DNA viruses, the cruciviruses, have homologues of capsid proteins encoded by RNA viruses. The genetic structure of cruciviruses attests to the transfer of capsid genes between disparate groups of viruses. However, the evolutionary history of cruciviruses is still unclear. By collecting and analyzing cruciviral sequence data, we provide a deeper insight into the evolutionary intricacies of cruciviruses. Our results reveal an unexpected diversity of this virus group, with frequent recombination as an important determinant of variability.

Abstract 3155: Integrated analysis of genomic and transcriptomic data in esophageal squamous cell carcinoma.

2013 ◽  
Author(s):  
Yukie Sato-Kuwabara ◽  
Fabio Albuquerque Marchi ◽  
Clóvis Klock ◽  
Cristovam Scapulatempo ◽  
Felipe Coimbra ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Integrated Analysis ◽  
Transcriptomic Data

Molecular Characterization, Tissue Expression, and Mapping of a Novel Siglec-like Gene (SLG2) with Three Splice Variants

2001 ◽  
Vol 284 (4) ◽  
pp. 900-910 ◽  
Author(s):  
George M. Yousef ◽  
Michael H. Ordon ◽  
George Foussias ◽  
Eleftherios P. Diamandis
Keyword(s):  
Molecular Characterization ◽  
Splice Variants ◽  
Tissue Expression

Integrated Analysis of Transcriptomic Data Reveals Key Anti-CKD Targets and Anti-ESRD Targets

2020 ◽  
Vol 66 (07/2020) ◽  
Author(s):  
Zhi-Wei Sun ◽  
Ling-Lin Li ◽  
Jian-Zhong Tang ◽  
Yan-Ping Yang ◽  
Yan-Chun Geng ◽  
...  
Keyword(s):  
Integrated Analysis ◽  
Transcriptomic Data

scholarly journals Isoforms of renal Na-K-2Cl cotransporter NKCC2: expression and functional significance

2008 ◽  
Vol 295 (4) ◽  
pp. F859-F866 ◽  
Author(s):  
Hayo Castrop ◽  
Jurgen Schnermann
Keyword(s):  
Functional Significance ◽  
Splice Variants ◽  
Single Gene ◽  
Macula Densa ◽  
Full Length ◽  
Salt Transport ◽  
Thick Ascending Limb ◽  
Differential Splicing ◽  
Splice Isoforms ◽  
Variable Exon

The renal Na-K-2Cl cotransporter (NKCC2, BSC1) is selectively expressed in the apical membrane of cells of the thick ascending limb of the loop of Henle (TAL) and macula densa. NKCC2-dependent salt transport constitutes the major apical entry pathway for transepithelial salt reabsorption in the TAL. Although NKCC2 is encoded by a single gene ( Slc12a1), differential splicing of the NKCC2 pre-mRNA results in the formation of several alternate transcripts. Thus three full-length splice isoforms of NKCC2 differ in their variable exon 4, resulting in transcripts for NKCC2B, NKCC2A, and NKCC2F. In addition to full-length isoforms, variants with truncated COOH-terminal ends have been described. The various splice isoforms of NKCC2 differ in their localization along the TAL and in their transport characteristics. Data in the literature are reviewed to assess the principles of NKCC2 differential splicing, the localization of NKCC2 splice isoforms along the TAL in various species, and the functional characteristics of the splice isoforms. In addition, we discuss the functional significance of NKCC2 isoforms for TAL salt retrieval and for the specific salt sensor function of macula densa cells based on studies using isoform-specific NKCC2-knockout mice. We suggest that different NKCC2 splice variants cooperate in salt retrieval along the TAL and that the coexpression of two splice variants (NKCC2B and NKCC2A) in the macula densa cells facilitates efficient salt sensing over wide ranges of fluctuating salt concentrations.

Toxicogenomic markers for corticosteroid treatment in beef cattle: Integrated analysis of transcriptomic data

2015 ◽  
Vol 77 ◽  
pp. 1-11 ◽  
Author(s):  
Sara Pegolo ◽  
Barbara Di Camillo ◽  
Clara Montesissa ◽  
Francesca Tiziana Cannizzo ◽  
Bartolomeo Biolatti ◽  
...  
Keyword(s):  
Beef Cattle ◽  
Corticosteroid Treatment ◽  
Integrated Analysis ◽  
Transcriptomic Data

scholarly journals Two novel phosphatidylinositol-4-phosphate 5-kinase type Iγ splice variants expressed in human cells display distinctive cellular targeting

2009 ◽  
Vol 422 (3) ◽  
pp. 473-482 ◽  
Author(s):  
Nicholas J. Schill ◽  
Richard A. Anderson
Keyword(s):  
Amino Acids ◽  
Splice Variant ◽  
Protein Targeting ◽  
Splice Variants ◽  
Human Cells ◽  
Subcellular Targeting ◽  
Splice Isoforms ◽  
Messenger Molecules ◽  
Phosphatidylinositol 4

The generation of various phosphoinositide messenger molecules at distinct locations within the cell is mediated via the specific targeting of different isoforms and splice variants of phosphoinositide kinases. The lipid messenger PtdIns(4,5)P2 is generated by several of these enzymes when targeted to distinct cellular compartments. Several splice variants of the type Iγ isoform of PIPK (PtdIns4P 5-kinase), which generate PtdIns(4,5)P2, have been identified, and each splice variant is thought to serve a unique functional role within cells. Here, we have identified two novel C-terminal splice variants of PIPKIγ in human cells consisting of 700 and 707 amino acids. These two splice variants are expressed in multiple tissue types and display PIPK activity in vitro. Interestingly, both of these novel splice variants display distinct subcellular targeting. With the addition of these two new splice isoforms, there are minimally five PIPKIγ splice variants that have been identified in mammals. Therefore, we propose the use of the HUGO (Human Genome Organization) nomenclature in the naming of the splice isoforms. PIPKIγ_i4 (700 amino acids) is present in the nucleus, a targeting pattern that has not been previously observed in any PIPKIγ splice variant. PIPKIγ_i5 (707 amino acids) is targeted to intracellular vesicle-like structures, where it co-localizes with markers of several types of endosomal compartments. As occurs with other PIPKIγ splice variants, the distinctive C-terminal sequences of PIPKIγ_i4 and PIPKIγ_i5 may facilitate association with unique protein targeting factors, thereby localizing the kinases to their appropriate cellular subdomains for the site-specific generation of PtdIns(4,5)P2.

scholarly journals Evidence for Transcriptome-wide RNA Editing Among Sus scrofa PRE-1 SINE Elements

2017 ◽  
Author(s):  
Scott A. Funkhouser ◽  
Juan P. Steibel ◽  
Ronald O. Bates ◽  
Nancy E. Raney ◽  
Darius Schenk ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Transcriptional Regulation ◽  
Rna Editing ◽  
High Throughput ◽  
Sus Scrofa ◽  
Sequence Data ◽  
Rna Sequences ◽  
Editing Event ◽  
Coding Regions ◽  
Dna And Rna

AbstractBackgroundRNA editing by ADAR (adenosine deaminase acting on RNA) proteins is a form of transcriptional regulation that is widespread among humans and other primates. Based on high-throughput scans used to identify putative RNA editing sites, ADAR appears to catalyze a substantial number of adenosine to inosine transitions within repetitive regions of the primate transcriptome, thereby dramatically enhancing genetic variation beyond what is encoded in the genome.ResultsHere, we demonstrate the editing potential of the pig transcriptome by utilizing DNA and RNA sequence data from the same pig. We identified a total of 8550 mismatches between DNA and RNA sequences across three tissues, with 75% of these exhibiting an A-to-G (DNA to RNA) discrepancy, indicative of a canonical ADAR-catalyzed RNA editing event. When we consider only mismatches within repetitive regions of the genome, the A-to-G percentage increases to 94%, with the majority of these located within the swine specific SINE retrotransposon PRE-1. We also observe evidence of A-to-G editing within coding regions that were previously verified in primates.ConclusionsThus, our high-throughput evidence suggests that pervasive RNA editing by ADAR can exist outside of the primate lineage to dramatically enhance genetic variation in pigs.

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