scholarly journals Alternative splicing of OAS1 alters the risk for severe COVID-19

2021 ◽  
Author(s):  
Jennifer Huffman ◽  
Guillaume Butler-Laporte ◽  
Atlas Khan ◽  
Theodore G. Drivas ◽  
Gina M. Peloso ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Splice Variant ◽  
African Ancestry ◽  
Protective Haplotype ◽  
Causal Variants ◽  
Risk Locus

A locus containing OAS1/2/3 has been identified as a risk locus for severe COVID-19 among Europeans ancestry individuals, with a protective haplotype of ~75 kilobases derived from Neanderthals. Here, we show that among several potentially causal variants at this locus, a splice variant of OAS1 occurs in people of African ancestry independently of the Neanderthal haplotype and confers protection against COVID-19 of a magnitude similar to that seen in individuals without African ancestry.

scholarly journals Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19

2022 ◽  
Author(s):  
Jennifer E. Huffman ◽  
Guillaume Butler-Laporte ◽  
Atlas Khan ◽  
Erola Pairo-Castineira ◽  
Theodore G. Drivas ◽  
...  
Keyword(s):  
Gene Flow ◽  
Fine Mapping ◽  
Splice Variant ◽  
Chromosomal Region ◽  
African Ancestry ◽  
European Ancestry ◽  
Effector Gene ◽  
Protective Haplotype ◽  
Risk Locus

AbstractThe OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.

Exon-1 skipping and intron-1 retaining by alternative splicing of the c-KIT gene encodes a novel splice variant in the skin of Merino sheep (Ovis aries)

2021 ◽  
Author(s):  
Siva Arumugam Saravanaperumal ◽  
Stefano Pallotti ◽  
Dario Pediconi ◽  
Carlo Renieri ◽  
Antonietta La Terza
Keyword(s):  
Alternative Splicing ◽  
Splice Variant ◽  
Ovis Aries ◽  
Merino Sheep ◽  
Intron 1 ◽  
Kit Gene ◽  
Exon 1

Characterization of three alternative splice variants associated with the Arabidopsis rhomboid protein gene At1g74130

Botany ◽  
2013 ◽  
Vol 91 (12) ◽  
pp. 840-849 ◽  
Author(s):  
Joshua Powles ◽  
Katharine Sedivy-Haley ◽  
Eric Chapman ◽  
Kenton Ko
Keyword(s):  
Alternative Splicing ◽  
Alternative Splice ◽  
Splice Variant ◽  
Serine Proteases ◽  
Transmembrane Domain ◽  
Splice Variants ◽  
Genes Encoding ◽  
Different Characteristics ◽  
Alternative Splice Variants

Rhomboid serine proteases are grouped into three main types — secretases, presenilin-like associated rhomboid-like (PARL) proteases, and “inactive” rhomboid proteins. Although the three rhomboid groups are distinct, the different types are likely to operate within the same cell or compartment, such as observed in the plastids of Arabidopsis. There are four distinct plastid rhomboid genes at play in Arabidopsis plastids, two for active types (At1g25290 and At5g25752) and two for inactive forms (At1g74130 and At1g74140). The number of working plastid rhomboids is further increased by alternative splicing, as reported for At1g25290. To understand how the plastid rhomboid system works, it is necessary to identify all rhomboid forms in play. To this end, this study was designed to examine the alternative splicing activities of At1g74130, one of the two genes encoding proteolytically “inactive” plastid rhomboids. The exon mapping and DNA sequencing results obtained here indicate the presence of three prominent alternative splice variants in the At1g74130 transcript population. The dominant splice variant, L, encodes the full-length protein. The other two splice variants, M and S, produce proteins lacking sections from the carboxyl transmembrane domain region. The splice variants M and S appear to be at levels with functional potential and appear to adjust relative to each other during development and in response to changes in the level of Tic40, a component of the plastid translocon. The splice variant proteins themselves exhibit different characteristics with respect to rhomboid protein–substrate interactions. These differences were observed in bacterial co-expression pull-down assays and in yeast mitochondrial studies. When considered together, the data suggest that the alternative splicing of At1g74130 bears functional significance in Arabidopsis and is likely to be part of a mechanism for diversifying plastid rhomboid function.

scholarly journals GWAS of Depression Phenotypes in the Million Veteran Program and Meta-analysis in More than 1.2 Million Participants Yields 178 Independent Risk Loci

2020 ◽  
Author(s):  
Daniel F Levey ◽  
Murray B Stein ◽  
Frank R Wendt ◽  
Gita A Pathak ◽  
Hang Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Meta Analysis ◽  
African Ancestry ◽  
Genetic Correlations ◽  
Brain Regions ◽  
Self Report ◽  
European Ancestry ◽  
Causal Variants ◽  
Using Data ◽  
Genomic Risk

We report a large meta-analysis of depression using data from the Million Veteran Program (MVP), 23andMe Inc., UK Biobank, and FinnGen; including individuals of European ancestry (n=1,154,267; 340,591 cases) and African ancestry (n=59,600; 25,843 cases). We identified 223 and 233 independent SNPs associated with depression in European ancestry and transancestral analysis, respectively. Genetic correlations within the MVP cohort across electronic health records diagnosis, survey self-report of diagnosis, and a 2-item depression screen exceeded 0.81. Using transcriptome-wide association study (TWAS) we found significant associations for gene expression in several brain regions, including hypothalamus (NEGR1, p=3.19x10-25) and nucleus accumbens (DRD2, p=1.87x10-20). 178 genomic risk loci were fine-mapped to find likely causal variants. We identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our TWAS, including TRAF3. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.

Abstract 805: Differential Regulation Of Cytokine-induced Alternative Splicing Of The TF Gene By Serine/Arginine Rich Protein Kinases

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ursula Rauch ◽  
Andreas Eisenreich ◽  
Wolfgang Poller ◽  
Heinz-Peter Schultheiss
Keyword(s):  
Alternative Splicing ◽  
Protein Phosphorylation ◽  
Mrna Expression ◽  
Tissue Factor ◽  
Splice Variant ◽  
Sr Protein ◽  
Phosphorylation State ◽  
Post Induction ◽  
Tnf Α ◽  
Tf Gene

Background: Higher eukaryotes control gene expression and increase protein diversity by alternative splicing of pre-mRNA. The Cdc2-like kinase (Clk) family, DNA topoisomerase I (DNA topo I) or Akt kinase are involved in splicing control by regulating the phosphorylation state of serine/arginine rich (SR) proteins. We recently showed that alternatively spliced human tissue factor (asHTF), a soluble isoform of tissue factor (TF), the primary initiator of coagulation, is expressed in HUVECs in response to inflammatory cytokines. This study investigated the role of Clks, DNA topo I and the PI3K-Pathway in regulation of TF-splicing in TNF-α induced HUVECs. Methods: HUVECs were incubated with inhibitors of Clks, DNA-topo I or PI3K and were then stimulated with TNF-α. The SR protein phosphorylation state was determined 2 min post induction. The full length (fl) TF and asHTF mRNA were assessed 60 min post induction by Real-Time PCR. Proteins were measured 5 and 8 hours after stimulation by Western blots and the cell thrombogenicity was analyzed via a chromogenic assay. Results: TNF-α inceased the mRNA expression of asHTF and flTF in HUVECs. The Clk-inhibitor completely inhibited the TNF-α induced expression of asHTF and reduced flTF by 30 %. Inhibition of DNA topo I increased asHTF expression and reduced the flTF expression. Inhibition of the PI3K/Akt-pathway had no effect on TF mRNA expression. Reduced Clk-inhibition the TF activity by 50 % whereas DNA topo I inhibition significantly decreased the procoagulant TF activity 8 hours post TNF-α induction. The Clk- and DNA-topo I-inhibitors altered the SR-protein phosphorylation pattern post TNF-α-induction. Additionally resulted inhibition of Clks in the generation of a third TF mRNA-splice variant, TF-A. Conclusion: Selective inhibition of Clks or DNA topo I leads to alterations of SR-protein phosphorylation and affects the differential expression of TF isoforms, thereby modulating the thrombogenicity of HUVECs. The inhibition of Clks contributes to the generation of a third TF splice variant. The inhibition of these kinases gives new insights into the regulation of the TF gene splicing process, which may result in new therapeutic strategies for modulating cellular thrombogenicity.

scholarly journals The Genetics of Circulating Resistin Level, A Biomarker for Cardiovascular Diseases, Is Informed by Mendelian Randomization and the Unique Characteristics of African Genomes

2020 ◽  
Author(s):  
Karlijn A.C. Meeks ◽  
Ayo P. Doumatey ◽  
Amy R. Bentley ◽  
Mateus H. Gouveia ◽  
Guanjie Chen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fine Mapping ◽  
Mendelian Randomization ◽  
African Ancestry ◽  
Resistance Index ◽  
Causal Variant ◽  
Transcriptomic Data ◽  
Causal Variants

Background - Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which GWAS consistently report variants within and near the coding gene ( RETN ). Here, we took advantage of the reduced linkage disequilibrium in African populations to infer genetic causality for circulating resistin levels by performing GWAS, whole-exome analysis, fine-mapping, Mendelian randomization and transcriptomic data analyses. Methods - GWAS and fine-mapping analyses for resistin were performed in 5621 African ancestry individuals, including 3754 continental Africans (AF) and 1867 African Americans (AA). Causal variants identified were subsequently used as an instrumental variable in Mendelian randomization analyses for homeostatic modelling (HOMA) derived insulin resistance index, BMI and type 2 diabetes. Results - The lead variant (rs3219175, in the promoter region of RETN ) for the single locus detected was the same for AF ( P -value 5.0×10 -111 ) and for AA (9.5×10 -38 ), respectively explaining 12.1% and 8.5% of variance in circulating resistin. Fine-mapping analyses and functional annotation revealed this variant as likely causal affecting circulating resistin levels as a cis -eQTL increasing RETN expression. Additional variants regulating resistin levels were upstream of RETN with genes PCP2 , STXBP2 and XAB2 showing the strongest association using integrative analysis of GWAS with transcriptomic data. Mendelian randomization analyses did not provide evidence for resistin increasing insulin resistance, BMI or type 2 diabetes risk in African-ancestry populations. Conclusions - Taking advantage of the fine-mapping resolution power of African genomes, we identified a single variant (rs3219175) as the likely causal variant responsible for most of the variability in circulating resistin levels. In contrast to findings in some other ancestry populations, we showed that resistin does not seem to increase insulin resistance and related cardiometabolic traits in African-ancestry populations.

The Nucleophosmin-1 Splice Variant Analysis Provides More Important Information On Prognosis Than NPM1 Mutational Status In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2563-2563
Author(s):  
Krzysztof Giannopoulos ◽  
Malgorzata Zajac ◽  
Anna Dolnik ◽  
Stephany Correa ◽  
Konstanze Dohner ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Splice Variant ◽  
Research Funding ◽  
Cellular Localization ◽  
Prognostic Significance ◽  
Splicing Variant ◽  
Mutational Status ◽  
Splicing Variants ◽  
Survival Differences ◽  
Median Expression

Abstract Background The process of mRNA splicing has been reported to play an important role in human disease development and many cancer-related genes are regulated by alternative splicing. In addition, first analyses of alternative splicing in bone marrow of AML samples identified novel splice variants specific for AML patients in comparison to normal cells such NOTCH2, CD13 and FLT3. Recently, NPM1 mutations have been included as novel provisional entity within the WHO classification of AML. This new entity bears distinct genetic, pathological and clinical features. Of particular importance is the fact that mutations in NPM1 without concomitant FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations identifies a group of cytogenetically normal (CN) AML patients with favorable prognosis. Since splicing variants play an important role in cellular functioning and splicing factor mutations have been reported in myeloid tumors including AML, the current study focuses on the characterization of NPM1splicing variants expression as well as its impact on the biology and prognosis of AML patients. Methods For 104 samples (52 CN-AML and 52 patients samples with cytogenetic aberrations) qRT-PCR was performed. For sensitivity data normalization β-actin (ACTB)was analyzed. Quantity mean values for gene expression were calculated according to the Standard Curve method. In this first cohort of patients total expression of NPM1 (Rt) as well as levels of the three splicing variants of NPM1 were evaluated: R1 that translates exon 1 to 9 and 11 to 12, R2 which contains exons 1 to 10 and R3 that lacks exons 8 and 10. We found prognostic significance of the expression level of NPM1-R2, therefore we decided to validate the prognostic significance of the expression of NPM1-R2 in independent cohort of AML patients. We consolidated 104 patients previously analyzed with 87 patients from the new cohort and preformed the final analysis for NPM1-R2 in total 191 cases. The existence of NPM1-R2 at the protein level was evaluated with the use of Western Blot technique. The cellular localization of NPM-1 was assessed by immunohistochemistry and analyzed with the respect to NPM1-R2 expression. Results Total expression as well as expression of splicing variants R1 and R3 were significantly higher in 104 AML patients compared to healthy volunteers (HVs)with a median expression of 8.587 vs 0.928 (p= 0.001), 1.729 vs 0.5485 (p=0.014), and 2.535 vs 0.108 (p<0.0001), respectively. We evaluated the existence of NPM1-R2 at the protein in AML samples as well as AML cell line KG1. We found that the expression of R2 splicing variant was significantly higher in all AML patients compared to HVs with a median expression of 1.64 vs 0.33 (p= 0.009, n=191)). We have found no differences between groups of AML patients with and without NPM1 mutations (1.21 vs 0.82, p= 0.13). High R2 splicing variant expression was associated with longer OS when CN-AML patients were analyzed (880 vs 438 days, p= 0.028), but there was no association with OS in case of high or low R2 expression in all AML patients. Longer OS was observed in CN-AML patients with high R2 expression without concomitant FLT3-ITD mutations compared to the rest of groups (p<0.0001). Most importantly, in our cohort of CN-AML cases survival differences seen between the established ELN groups according to a NPM1/FLT3-ITD stratification were less impressive than between groups stratified according to R2 expression combined with FLT3-ITD mutational status. Conclusion Since the R2 splicing variant represents a truncated form of NPM1 gene due to the of the lack of exons 11 and 12 (coding for the domain responsible for nucleolar localization of the protein), this isoform mostly localizes in the nucleoplasm, and thus might also have a biological impact in the malignant cells. Most importantly, in our cohort of cases survival differences seen between the established ELN groups according to a NPM1/FLT3-ITD stratification were less impressive than between groups stratified according to R2 expression combined with FLT3-ITD mutational status. In summary, the expression of NPM1-R2 might be of biological importance for CN-AML patients. Moreover, R2 splice variant provides prognostic value for CN-AML patients and should be assessed in addition the NPM1 mutational status. Disclosures: Schlenk: Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Chugai: Research Funding; Ambit: Honoraria.

scholarly journals Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4

2019 ◽  
Author(s):  
Dylan M. Glubb ◽  
Wei Shi ◽  
Jonathan Beesley ◽  
Laura Fachal ◽  
Jayne-Louise Pritchard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Promoter Region ◽  
Risk Allele ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Enhancer Element ◽  
Causal Variants ◽  
Risk Locus

Genome-wide association studies have revealed a locus at 8p12 that is associated with breast cancer risk. Fine-mapping of this locus identified 16 candidate causal variants (CCVs). However, as these variants are intergenic, their function is unclear. To map chromatin looping from this risk locus to a previously identified candidate target gene, DUSP4, we performed chromatin conformation capture analyses in normal and tumoral breast cell lines. We identified putative regulatory elements, containing CCVs, that loop to the DUSP4 promoter region. Using reporter gene assays, we found that the risk allele of CCV rs7461885 reduced the activity of a DUSP4 enhancer element, consistent with the function of DUSP4 as a tumor suppressor gene. Furthermore, the risk allele of CCV rs12155535, located in another DUSP4 enhancer element, was negatively correlated with looping of this element to the DUSP4 promoter region, suggesting that this allele would be associated with reduced expression. These findings provide the first evidence that CCV risk alleles downregulate DUSP4 expression, suggesting that this gene is a regulatory target of the 8p12 breast cancer risk locus.

scholarly journals Splice variants’ role in mediating different disease states in tissue requiring ion transduction through calcium channel for function

2017 ◽  
Author(s):  
Wenfa Ng
Keyword(s):  
Alternative Splicing ◽  
Calcium Channel ◽  
Alternative Splice ◽  
Splice Variant ◽  
Splice Variants ◽  
Energetic Cost ◽  
Hypoxic Stress ◽  
Tissue Samples ◽  
Hek 293 ◽  
Selection Of

Structure informs function, and this may be the evolutionary reason why alternative splicing, which is capable of generating different variants of the same protein, arise. But, given the energetic cost of generating different splice variants for testing their capability at a specific task, which incurs cellular functional uncertainty; as well as the exertion of differing physiological effects on cells that may translate into diseased states, what is the evolutionary advantage of this process? Additionally, what are the factors that select a specific variant for a presented task? Using heart tissue samples exposed to hypoxia stress as model system, this research idea entails the illumination of single nucleotide polymorphisms (SNP) of the calcium channel transporter, Cav 1.2 gene in the population through gene sequencing followed by bioinformatic analysis for alternative splice sites. This would be followed by a scan for alternative splice variants through colony polymerase chain reaction using universal primers for Cav 1.2 gene. Confirmation of splice variant identity through Western blot laid the stage for subsequent efforts at cloning and expressing the variant gene in HEK 293 cells lacking endogenous expression of Cav 1.2, for biophysical characterization of calcium conduction through patch clamp electrophysiology. In parallel, structural elucidation efforts necessitate the purification of the calcium channel via hydrophobic interaction or reversed phase liquid chromatography after its heterologous expression in a bacterial host. But, biophysical and biochemical characterization does not speak of the signaling and metabolic pathways laying the path to generation of the splice variant(s). Hence, discovery approaches such as RNA-seq and mass spectrometry proteomics could uncover the molecular mysteries at the transcript and protein level that help guide the selection of specific splice variant in response to hypoxic stress, where HIF is a candidate pathway. Implementing this approach from the retrospective angle of examining diseased human tissue samples provide one important facet for uncovering possible mechanisms driving the generation of a splice variant. However, the complementary prospective approach of identifying the molecular basis and processes for responding to hypoxia in a cell line such as HEK 293 would help provide confirmatory evidence in understanding the key drivers of physiological response to lack of oxygen at the cellular level. Collectively, this research route would illuminate both the nucleotide informational basis of alternative splicing in calcium channel Cav 1.2 as well as identify the molecular mechanisms enabling the selection of specific splice variants useful for conferring, at the cell and tissue level, ability to withstand hypoxic stress without significant negative effects on cell function. Interested readers can expand on the ideas presented.

scholarly journals Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): a novel function for the viral EBNA-LP protein

2021 ◽  
Vol 49 (18) ◽  
pp. 10657-10676
Author(s):  
Evelyne Manet ◽  
Hélène Polvèche ◽  
Fabrice Mure ◽  
Paulina Mrozek-Gorska ◽  
Florian Roisné-Hamelin ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
B Lymphocytes ◽  
Splice Variant ◽  
Epstein Barr Virus ◽  
Human Herpesvirus ◽  
Splicing Regulation ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
The Impact

Abstract Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides—besides transcription—an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP—together with the RBM4 splicing factor—in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.

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