scholarly journals What’s Wrong in a Jump? Prediction and Validation of Splice Site Variants

2021 ◽  
Vol 4 (3) ◽  
pp. 62
Author(s):  
Giulia Riolo ◽  
Silvia Cantara ◽  
Claudia Ricci
Keyword(s):  
Splice Site ◽  
Splice Variants ◽  
Protein Isoforms ◽  
Specific Gene ◽  
Regulatory Sequences ◽  
Nucleotide Substitutions ◽  
Human Genes ◽  
Multiple Protein ◽  
Enhance Gene Expression ◽  
Key Steps

Alternative splicing (AS) is a crucial process to enhance gene expression driving organism development. Interestingly, more than 95% of human genes undergo AS, producing multiple protein isoforms from the same transcript. Any alteration (e.g., nucleotide substitutions, insertions, and deletions) involving consensus splicing regulatory sequences in a specific gene may result in the production of aberrant and not properly working proteins. In this review, we introduce the key steps of splicing mechanism and describe all different types of genomic variants affecting this process (splicing variants in acceptor/donor sites or branch point or polypyrimidine tract, exonic, and deep intronic changes). Then, we provide an updated approach to improve splice variants detection. First, we review the main computational tools, including the recent Machine Learning-based algorithms, for the prediction of splice site variants, in order to characterize how a genomic variant interferes with splicing process. Next, we report the experimental methods to validate the predictive analyses are defined, distinguishing between methods testing RNA (transcriptomics analysis) or proteins (proteomics experiments). For both prediction and validation steps, benefits and weaknesses of each tool/procedure are accurately reported, as well as suggestions on which approaches are more suitable in diagnostic rather than in clinical research.

scholarly journals Identification of embryo specific human isoforms using a database of predicted alternative splice forms

2006 ◽  
Vol 3 (1) ◽  
pp. 1-10
Author(s):  
Heike Pospisil
Keyword(s):  
Alternative Splice ◽  
Splice Site ◽  
Splice Variants ◽  
Main Idea ◽  
Protein Isoforms ◽  
Unequal Distribution ◽  
Interesting Candidate ◽  
Alternatively Spliced ◽  
Specific Alternative ◽  
Splice Forms

Abstract Alternative splicing is one of the most important mechanisms to generate a large number of mRNA and protein isoforms from a small number of genes. Its study became one of the hot topics in computational genome analysis. The repository EASED (Extended Alternatively Spliced EST Database, http://eased.bioinf.mdc-berlin.de/) stores a large collection of splice variants predicted from comparing the human genome against EST databases. It enables finding new unpublished splice forms that could be interesting candidate genes for stage specific, diseases specific or tissue specific splicing. The main idea behind selecting specific splice forms is to compare the number and the origin of ESTs confirming one isoform with the number and the origin of ESTs confirming the opposite isoform. A measure asDcs is introduced to take into account the unequal distribution of ESTs per splice site on one hand, and the possible uncertainties due to the relatively low quality of EST data on the other hand. First, the number of ESTs per splice site is scaled with a modified Hill function. The measure asDcs computes in the second step the distance of each pair of ESTs from equipartition. Equipartition exists if for every number of adult ESTs the same number of embryonic ESTs. The effect of several input parameters for the scaling of true EST values is analysed and can be reproduced on http://cardigan.zbh.uni-hamburg.de/asDcs. Some of the obtained best scoring hits for selected parameters (transcription factor P65, drebrin, and fetuin) have been already described in literature as been involved in embryonic development. This result shows the plausibility of this approach and looks promising for the identification of unplublished embryo specific alternative splice sites in human.

The role of p63 in epidermal morphogenesis and neoplasia

2010 ◽  
Vol 38 (1) ◽  
pp. 223-228 ◽  
Author(s):  
Simon S. McDade ◽  
Dennis J. McCance
Keyword(s):  
Transcription Factors ◽  
Splice Variants ◽  
Family Members ◽  
Protein Isoforms ◽  
Structural Homology ◽  
P53 Family ◽  
Multiple Protein ◽  
Proliferation And Differentiation ◽  
Epidermal Morphogenesis

The p53 family of transcription factors is made up of p53, p63 and p73, which share significant structural homology. In particular, transcriptional complexity and the expression of multiple protein isoforms are an emergent trait of all family members. p63 is the evolutionarily eldest member of the p53 family and the various isoforms have critical roles in the development of stratifying epithelia. Recent results have uncovered additional splice variants, adding to the complexity of the transcriptional architecture of p63. These observations and the emerging extensive interplay between p63 and p53 in development, proliferation and differentiation underline the importance of considering all isoforms and family members in studies of the function of p53 family members.

scholarly journals APPRIS principal isoforms and MANE Select transcripts in clinical variant interpretation

2021 ◽  
Author(s):  
Fernando Pozo ◽  
Jose Manuel Rodriguez ◽  
Jesus Vazquez ◽  
Michael L. Tress
Keyword(s):  
Splice Variants ◽  
Cellular Protein ◽  
Protein Isoforms ◽  
Variant Interpretation ◽  
Splice Isoforms ◽  
Pathogenic Variants ◽  
Pathogenic Mutations ◽  
Multiple Protein ◽  
Clinical Variant ◽  
Almost All

AbstractMost coding genes are able to generate multiple alternatively spliced transcripts. Determining which of these transcript variants produces the main protein isoform, and which of a gene’s multiple splice variants are functionally important, is crucial in comparative genomics and essential for clinical variant interpretation.Here we show that the principal isoforms chosen by APPRIS and the MANE Select variants provide the best approximations of the main cellular protein isoforms. Principal isoforms are predicted from conservation and from protein features, and MANE transcripts are chosen from the consensus between teams of expert manual curators. APPRIS principal isoforms coincide in over 94% of coding genes with MANE Select transcripts and the two methods are particularly discriminating when they agree on the main splice variant. Where the two methods agree, the splice variants coincide with the main isoform detected in proteomics experiments in 98.2% of genes with multiple protein isoforms.We also find that almost all ClinVar pathogenic mutations map to MANE Select or APPRIS principal isoforms. Where APPRIS and MANE agree on the main isoform, 99.93% of validated pathogenic variants map to principal rather than alternative exons. MANE Plus Clinical transcripts cover most validated pathogenic mutations in alternative coding exons. TRIFID functional importance scores are particularly useful for distinguishing clinically important alternative isoforms: the highest scoring TRIFID isoforms are more than 300 times more likely to have validated pathogenic mutations.We find that APPRIS, MANE and TRIFID are important for determining the biological relevance of splice isoforms and should be an essential part of clinical variant interpretation.

Evolutionary Relationships of Major Histocompatibility Complex Class I Genes in Simian Primates

Genetics ◽  
2004 ◽  
Vol 166 (4) ◽  
pp. 1897-1907
Author(s):  
Hiromi Sawai ◽  
Yoshi Kawamoto ◽  
Naoyuki Takahata ◽  
Yoko Satta
Keyword(s):  
Major Histocompatibility Complex ◽  
Distinct Group ◽  
Gene Organization ◽  
Class I ◽  
Phylogenetic Position ◽  
Specific Gene ◽  
New World Monkeys ◽  
Major Histocompatibility ◽  
Nucleotide Substitutions ◽  
Histocompatibility Complex

Abstract New World monkeys (NWMs) occupy a critical phylogenetic position in elucidating the evolutionary process of major histocompatibility complex (MHC) class I genes in primates. From three subfamilies of Aotinae, Cebinae, and Atelinae, the 5′-flanking regions of 18 class I genes are obtained and phylogenetically examined in terms of Alu/LINE insertion elements as well as the nucleotide substitutions. Two pairs of genes from Aotinae and Atelinae are clearly orthologous to human leukocyte antigen (HLA) -E and -F genes. Of the remaining 14 genes, 8 belong to the distinct group B, together with HLA-B and -C, to the exclusion of all other HLA class I genes. These NWM genes are classified into four groups, designated as NWM-B1, -B2, -B3, and -B4. Of these, NWM-B2 is orthologous to HLA-B/C. Also, orthologous relationships of NWM-B1, -B2, and -B3 exist among different families of Cebidae and Atelidae, which is in sharp contrast to the genus-specific gene organization within the subfamily Callitrichinae. The other six genes belong to the distinct group G. However, a clade of these NWM genes is almost equally related to HLA-A, -J, -G, and -K, and there is no evidence for their orthologous relationships to HLA-G. It is argued that class I genes in simian primates duplicated extensively in their common ancestral lineage and that subsequent evolution in descendant species has been facilitated mainly by independent loss of genes.

scholarly journals Complex Expression of the UL136 Gene of Human Cytomegalovirus Results in Multiple Protein Isoforms with Unique Roles in Replication

2014 ◽  
Vol 88 (24) ◽  
pp. 14412-14425 ◽  
Author(s):  
K. Caviness ◽  
L. Cicchini ◽  
M. Rak ◽  
M. Umashankar ◽  
F. Goodrum
Keyword(s):  
Human Cytomegalovirus ◽  
Protein Isoforms ◽  
Multiple Protein ◽  
Complex Expression

Identification of Gαs messenger ribonucleic acid splice variants in human granulosa cells

1997 ◽  
Vol 18 (1) ◽  
pp. 27-35 ◽  
Author(s):  
G N Europe-Finner ◽  
E Cartwright ◽  
J Bellinger ◽  
H J Mardon ◽  
D H Barlow ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Ovarian Function ◽  
Splice Variants ◽  
Consensus Sequence ◽  
Phosphorylation Site ◽  
Follicular Development ◽  
Protein Isoforms ◽  
Mrna Isoforms ◽  
Messenger Ribonucleic Acid

ABSTRACT Granulosa cells are essential for follicular development and corpus luteum formation and their functions are regulated by gonadotrophins through G protein-coupled receptors. The dominant second messenger pathway involves the stimulation of cyclic AMP formation by Gαs-linked receptors. In this paper we have investigated the expression of Gαs mRNA splice variants in relation to expression of Gαs protein isoforms in granulosa cells obtained from patients undergoing in vitro fertilization. We have carried out ribonuclease protection assays using cRNA riboprobes which are capable of detecting all Gαs mRNA isoforms as well as quantifying total amounts of Gαs mRNA. Granulosa cells express the message for Gαs-Large and Gαs-Small and the presence of two distinct protein products was confirmed by immunoblotting using the antibody RM/1. Moreover, the data show that a significant fraction of Gαs-Large and Gαs-Small mRNAs contain an extra CAG codon. This should generate proteins with an extra serine residue, resulting in Gαs variants with the consensus sequence of a protein kinase C phosphorylation site. These results highlight the possible interaction between different signalling pathways in the control of cAMP production and the need to investigate the relationship between Gαs variants and different adenylyl cyclase isozymes in patients with normal and abnormal ovarian function.

scholarly journals Loss of critical developmental and human disease-causing genes in 58 mammals

2019 ◽  
Author(s):  
Yatish Turakhia ◽  
Heidi I. Chen ◽  
Amir Marcovitz ◽  
Gill Bejerano
Keyword(s):  
Evolutionary Biology ◽  
Large Scale ◽  
Gene Annotation ◽  
Synonymous Substitution ◽  
Specific Gene ◽  
High Confidence ◽  
Protein Coding ◽  
Congenital Diseases ◽  
Manual Curation ◽  
Human Genes

Gene losses provide an insightful route for studying the morphological and physiological adaptations of species, but their discovery is challenging. Existing genome annotation tools and protein databases focus on annotating intact genes and do not attempt to distinguish nonfunctional genes from genes missing annotation due to sequencing and assembly artifacts. Previous attempts to annotate gene losses have required significant manual curation, which hampers their scalability for the ever-increasing deluge of newly sequenced genomes. Using extreme sequence erosion (deletion and non-synonymous substitution) as an unambiguous signature of loss, we developed an automated approach for detecting high-confidence protein-coding gene loss events across a species tree. Our approach relies solely on gene annotation in a single reference genome, raw assemblies for the remaining species to analyze, and the associated phylogenetic tree for all organisms involved. Using the hg38 human assembly as a reference, we discovered over 500 unique human genes affected by such high-confidence erosion events in different clades across 58 mammals. While most of these events likely have benign consequences, we also found dozens of clade-specific gene losses that result in early lethality in outgroup mammals or are associated with severe congenital diseases in humans. Our discoveries yield intriguing potential for translational medical genetics and for evolutionary biology, and our approach is readily applicable to large-scale genome sequencing efforts across the tree of life.

scholarly journals SAM68: Signal Transduction and RNA Metabolism in Human Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Paola Frisone ◽  
Davide Pradella ◽  
Anna Di Matteo ◽  
Elisa Belloni ◽  
Claudia Ghigna ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Nuclear Export ◽  
Cell Biology ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Human Cancer ◽  
Rna Metabolism ◽  
Regulatory Sequences

Alterations in expression and/or activity of splicing factors as well as mutations incis-acting splicing regulatory sequences contribute to cancer phenotypes. Genome-wide studies have revealed more than 15,000 tumor-associated splice variants derived from genes involved in almost every aspect of cancer cell biology, including proliferation, differentiation, cell cycle control, metabolism, apoptosis, motility, invasion, and angiogenesis. In the past decades, several RNA binding proteins (RBPs) have been implicated in tumorigenesis. SAM68 (SRC associated in mitosis of 68 kDa) belongs to the STAR (signal transduction and activation of RNA metabolism) family of RBPs. SAM68 is involved in several steps of mRNA metabolism, from transcription to alternative splicing and then to nuclear export. Moreover, SAM68 participates in signaling pathways associated with cell response to stimuli, cell cycle transitions, and viral infections. Recent evidence has linked this RBP to the onset and progression of different tumors, highlighting misregulation of SAM68-regulated splicing events as a key step in neoplastic transformation and tumor progression. Here we review recent studies on the role of SAM68 in splicing regulation and we discuss its contribution to aberrant pre-mRNA processing in cancer.

scholarly journals Herpes simplex virus ICP27 regulates alternative pre-mRNA polyadenylation and splicing in a sequence-dependent manner

2016 ◽  
Vol 113 (43) ◽  
pp. 12256-12261 ◽  
Author(s):  
Shuang Tang ◽  
Amita Patel ◽  
Philip R. Krause
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Splice Site ◽  
Alternative Polyadenylation ◽  
Common Mechanism ◽  
Specific Gene ◽  
Dependent Manner ◽  
Splice Sites ◽  
Cellular Genes ◽  
Simplex Virus

The herpes simplex virus (HSV) infected cell culture polypeptide 27 (ICP27) protein is essential for virus infection of cells. Recent studies suggested that ICP27 inhibits splicing in a gene-specific manner via an unknown mechanism. Here, RNA-sequencing revealed that ICP27 not only inhibits splicing of certain introns in <1% of cellular genes, but also can promote use of alternative 5′ splice sites. In addition, ICP27 induced expression of pre-mRNAs prematurely cleaved and polyadenylated from cryptic polyadenylation signals (PAS) located in intron 1 or 2 of ∼1% of cellular genes. These previously undescribed prematurely cleaved and polyadenylated pre-mRNAs, some of which contain novel ORFs, were typically intronless, <2 Kb in length, expressed early during viral infection, and efficiently exported to cytoplasm. Sequence analysis revealed that ICP27-targeted genes are GC-rich (as are HSV genes), contain cytosine-rich sequences near the 5′ splice site, and have suboptimal splice sites in the impacted intron, suggesting that a common mechanism is shared between ICP27-mediated alternative polyadenylation and splicing. Optimization of splice site sequences or mutation of nearby cytosines eliminated ICP27-mediated splicing inhibition, and introduction of C-rich sequences to an ICP27-insensitive splicing reporter conferred this phenotype, supporting the inference that specific gene sequences confer susceptibility to ICP27. Although HSV is the first virus and ICP27 is the first viral protein shown to activate cryptic PASs in introns, we suspect that other viruses and cellular genes also encode this function.

scholarly journals Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Anna Di Matteo ◽  
Elisa Belloni ◽  
Davide Pradella ◽  
Ambra Cappelletto ◽  
Nina Volf ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Human Cancer ◽  
Single Gene ◽  
Predictive Biomarkers ◽  
Protein Isoforms ◽  
Therapeutic Interventions ◽  
Cancer Therapies ◽  
Functional Changes ◽  
Splicing Regulators ◽  
Multiple Protein

AbstractAlternative splicing (AS) is a pervasive molecular process generating multiple protein isoforms, from a single gene. It plays fundamental roles during development, differentiation and maintenance of tissue homeostasis, while aberrant AS is considered a hallmark of multiple diseases, including cancer. Cancer-restricted AS isoforms represent either predictive biomarkers for diagnosis/prognosis or targets for anti-cancer therapies. Here, we discuss the contribution of AS regulation in cancer angiogenesis, a complex process supporting disease development and progression. We consider AS programs acting in a specific and non-redundant manner to influence morphological and functional changes involved in cancer angiogenesis. In particular, we describe relevant AS variants or splicing regulators controlling either secreted or membrane-bound angiogenic factors, which may represent attractive targets for therapeutic interventions in human cancer.

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