scholarly journals Junction-skipping regulation in complex disease

2019 ◽  
Author(s):  
Ruize Liu ◽  
Juha Karjalainen ◽  
Andrea Byrnes ◽  
Beryl B. Cummings ◽  
Padhraig Gormley ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Complex Disease ◽  
Single Gene ◽  
Complex Diseases ◽  
Mrna Isoforms ◽  
Complex Disorders ◽  
Genomic Variants ◽  
Disease Associations ◽  
Human Disorders ◽  
Credible Set

AbstractMultiple mRNA isoforms can be generated from a single gene locus through alternative splicing. Abnormality in alternative splicing has been linked to many human disorders. Here using RNA-seq data from 48 tissues from GTEx v7 release and summary statistics from GWAS of complex diseases and traits, we present a study to identify genomic variants regulating junction-skipping with the goal to understand their contribution to complex diseases and traits. For each tissue, we found 48 - 575 junction-skipping events regulated by genomic variants. We performed fine-mapping on both the junction-skipping association and 23 complex disease and trait associations and mapped them to 95% credible sets. We found 13 - 279 junction-skipping regulations were mapped to a credible set with ≤5 variants. On the genome-wide scale, we noted a clear disease-tissue specificity. Results from this approach provided critical insights into the functional mechanism of the genetic disease associations and contributed to our understanding of the genetic architecture of human complex disorders.

scholarly journals Deconstruction of Vulnerability to Complex Diseases: Enhanced Effect Sizes and Power of Intermediate Phenotypes

2007 ◽  
Vol 7 ◽  
pp. 124-130 ◽  
Author(s):  
David Goldman ◽  
Francesca Ducci
Keyword(s):  
Effect Size ◽  
Complex Disease ◽  
Complex Diseases ◽  
Effect Sizes ◽  
Complex Disorders ◽  
Large Samples ◽  
Intermediate Phenotypes ◽  
Genome Association ◽  
Whole Genome Association ◽  
Disease Loci

The deconstruction of vulnerability to complex disease with the help of intermediate phenotypes, including the heritable and disease-associated endophenotypes, is a legacy of Henri Begleiter. Systematic searches for genes influencing complex disorders, including bipolar disorder, have recently been completed using whole genome association (WGA), identifying a series of validated loci. Using this information, it is possible to compare effect sizes of disease loci discovered in very large samples to the effect sizes of replicated functional loci determining intermediate phenotypes that are of essential interest in psychiatric disorders. It is shown that the genes influencing intermediate phenotypes tend to have a larger effect size. Furthermore, the WGA results reveal that the number of loci of large effect size for complex diseases is limited, and yet multiple functional loci have already been identified for intermediate phenotypes relevant to psychiatric diseases, and without the benefit of WGA.

scholarly journals Truncated IRAG variants modulate cGMP-mediated inhibition of human colonic smooth muscle cell contraction

2011 ◽  
Vol 301 (6) ◽  
pp. C1445-C1457 ◽  
Author(s):  
Alexander von Werder ◽  
Martina Mayr ◽  
Günter Schneider ◽  
Daniela Oesterle ◽  
Ralph M. Fritsch ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Alternative Splicing ◽  
Smooth Muscle Cells ◽  
Single Gene ◽  
Muscle Cells ◽  
Acceptor Site ◽  
Human Tissues ◽  
Mrna Isoforms ◽  
Donor And Acceptor

Nitric oxide (NO) induces relaxation of colonic smooth muscle cells predominantly by cGMP/cGMP-dependent protein kinase I (cGKI)-induced phosphorylation of the inositol 1,4,5-trisphosphate receptor (IP3R)-associated cGMP kinase substrate (IRAG), to block store-dependent calcium signaling. In the present study we analyzed the structure and function of the human IRAG/MRVI1 gene. We describe four unique first exon variants transcribed from individual promoters in diverse human tissues. Tissue-specific alternative splicing with exon skipping and alternative splice donor and acceptor site usage further increases diversity of IRAG mRNA variants that encode for NH2- and COOH-terminally truncated proteins. At the functional level, COOH-terminally truncated IRAG variants lacking both the cGKI phosphorylation and the IP3RI interaction site counteract cGMP-mediated inhibition of calcium transients and relaxation of human colonic smooth muscle cells. Since COOH-terminally truncated IRAG mRNA isoforms are widely expressed in human tissues, our results point to an important role of IRAG variants as negative modulators of nitric oxide/cGKI-dependent signaling. The complexity of alternative splicing of the IRAG gene impressively demonstrates how posttranscriptional processing generates functionally distinct proteins from a single gene.

scholarly journals Exploring complex disease gene relationships using simultaneous analysis

2014 ◽  
Author(s):  
Joseph D Romano ◽  
William G Tharp ◽  
Indra N Sarkar
Keyword(s):  
Alzheimer Disease ◽  
Phylogenetic Trees ◽  
Complex Disease ◽  
Disease Gene ◽  
Sequence Similarity ◽  
Single Gene ◽  
Genomic Data ◽  
Complex Diseases ◽  
Genetic Network ◽  
Automated Method

The characterization of complex diseases remains a great challenge for biomedical researchers due to the myriad interactions of genetic and environmental factors. Adaptation of phylogenomic techniques to increasingly available genomic data provides an evolutionary perspective that may elucidate important unknown features of complex diseases. Here an automated method is presented that leverages publicly available genomic data and phylogenomic techniques. The approach is tested with nine genes implicated in the development of Alzheimer Disease, a complex neurodegenerative syndrome. The developed technique, implemented through a suite of Ruby scripts entitled “ASAP2,” first compiles a list of sequence-similarity based orthologues using PSI-BLAST and a recursive NCBI BLAST+ search strategy, then constructs maximum parsimony phylogenetic trees for each set of nucleotide and protein sequences, and calculates phylogenetic metrics (partitioned Bremer support values, combined branch scores, and Robinson-Foulds distance) to provide an empirical assessment of evolutionary conservation within a given genetic network. This study demonstrates the potential for using automated simultaneous phylogenetic analysis to uncover previously unknown relationships among disease-associated genes that may not have been apparent using traditional, single-gene methods. Furthermore, the results provide the first integrated evolutionary history of an Alzheimer Disease gene network and identify potentially important co-evolutionary clustering around components of oxidative stress pathways.

scholarly journals Exploring complex disease gene relationships using simultaneous analysis

2014 ◽  
Author(s):  
Joseph D Romano ◽  
William G Tharp ◽  
Indra N Sarkar
Keyword(s):  
Alzheimer Disease ◽  
Phylogenetic Trees ◽  
Complex Disease ◽  
Disease Gene ◽  
Sequence Similarity ◽  
Single Gene ◽  
Genomic Data ◽  
Complex Diseases ◽  
Genetic Network ◽  
Automated Method

The characterization of complex diseases remains a great challenge for biomedical researchers due to the myriad interactions of genetic and environmental factors. Adaptation of phylogenomic techniques to increasingly available genomic data provides an evolutionary perspective that may elucidate important unknown features of complex diseases. Here an automated method is presented that leverages publicly available genomic data and phylogenomic techniques. The approach is tested with nine genes implicated in the development of Alzheimer Disease, a complex neurodegenerative syndrome. The developed technique, implemented through a suite of Ruby scripts entitled “ASAP2,” first compiles a list of sequence-similarity based orthologues using PSI-BLAST and a recursive NCBI BLAST+ search strategy, then constructs maximum parsimony phylogenetic trees for each set of nucleotide and protein sequences, and calculates phylogenetic metrics (partitioned Bremer support values, combined branch scores, and Robinson-Foulds distance) to provide an empirical assessment of evolutionary conservation within a given genetic network. This study demonstrates the potential for using automated simultaneous phylogenetic analysis to uncover previously unknown relationships among disease-associated genes that may not have been apparent using traditional, single-gene methods. Furthermore, the results provide the first integrated evolutionary history of an Alzheimer Disease gene network and identify potentially important co-evolutionary clustering around components of oxidative stress pathways.

scholarly journals Position Specific Alternative Splicing and Gene Expression Profiles Along the Tonotopic Axis of Chick Cochlea

2021 ◽  
Vol 8 ◽  
Author(s):  
Heiyeun Koo ◽  
Jae Yeon Hwang ◽  
Sungbo Jung ◽  
Hyeyoung Park ◽  
Jinwoong Bok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Expression Profiles ◽  
Single Gene ◽  
Gene Expression Profiles ◽  
Binding Motif ◽  
Dependent Manner ◽  
Mrna Isoforms

Alternative splicing (AS) refers to the production of multiple mRNA isoforms from a single gene due to alternative selection of exons or splice sites during pre-mRNA splicing. It is a primary mechanism of gene regulation in higher eukaryotes and significantly expands the functional complexity of eukaryotic organisms, contributing to animal development and disease. Recent studies have shown that AS also influences functional diversity by affecting the transcriptomic and proteomic profiles in a position-dependent manner in a single organ. The peripheral hearing organ, the cochlea, is organized to detect sounds at different frequencies depending on its location along the longitudinal axis. This unique functional configuration, the tonotopy, is known to be facilitated by differential gene expression along the cochlear duct. We profiled transcriptome-wide gene expression and AS changes that occur within the different positions of chick cochlea. These analyses revealed distinct gene expression profiles and AS, including a splicing program that is unique to tonotopy. Changes in the expression of splicing factors PTBP3, ESRP1, and ESRP2 were demonstrated to contribute to position-specific AS. RNA-binding motif enrichment analysis near alternatively spliced exons provided further insight into the combinatorial regulation of AS at different positions by different RNA-binding proteins. These data, along with gene ontology (GO) analysis, represent a comprehensive analysis of the dynamic regulation of AS at different positions in chick cochlea.

Linking transcription, RNA polymerase II elongation and alternative splicing

2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Environmental Changes ◽  
Transcription Elongation ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Stepping Stones ◽  
Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

EHAI: Enhanced Human Microbe-Disease Association Identification

2020 ◽  
Vol 21 (11) ◽  
pp. 1078-1084
Author(s):  
Ruizhi Fan ◽  
Chenhua Dong ◽  
Hu Song ◽  
Yixin Xu ◽  
Linsen Shi ◽  
...  
Keyword(s):  
Microbial Community ◽  
Human Health ◽  
Complex Diseases ◽  
Disease Association ◽  
Computational Results ◽  
Computational Approaches ◽  
Disease Diagnostics ◽  
Disease Associations ◽  
Association Discovery ◽  
Biological Tool

: Recently, an increasing number of biological and clinical reports have demonstrated that imbalance of microbial community has the ability to play important roles among several complex diseases concerning human health. Having a good knowledge of discovering potential of microbe-disease relationships, which provides the ability to having a better understanding of some issues, including disease pathology, further boosts disease diagnostics and prognostics, has been taken into account. Nevertheless, a few computational approaches can meet the need of huge scale of microbe-disease association discovery. In this work, we proposed the EHAI model, which is Enhanced Human microbe- disease Association Identification. EHAI employed the microbe-disease associations, and then Gaussian interaction profile kernel similarity has been utilized to enhance the basic microbe-disease association. Actually, some known microbe-disease associations and a large amount of associations are still unavailable among the datasets. The ‘super-microbe’ and ‘super-disease’ were employed to enhance the model. Computational results demonstrated that such super-classes have the ability to be helpful to the performance of EHAI. Therefore, it is anticipated that EHAI can be treated as an important biological tool in this field.

scholarly journals Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Guiomar Martín ◽  
Yamile Márquez ◽  
Federica Mantica ◽  
Paula Duque ◽  
Manuel Irimia
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Alternative Splicing ◽  
Stress Responses ◽  
Target Genes ◽  
Intron Retention ◽  
Single Gene ◽  
Exon Skipping ◽  
Environmental Response ◽  
Biotic Stresses

Abstract Background Alternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing. Results We generate a massive resource for Arabidopsis thaliana, PastDB, comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets reveals that A. thaliana shows high levels of AS, similar to fruitflies, and that, compared to animals, disproportionately uses AS for stress responses. We identify core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that is tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, are overrepresented across regulated AS sets in A. thaliana, being also largely involved in modulating gene expression through NMD and uORF inclusion. Conclusions Non-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana.

scholarly journals Multiple Sclerosis Biomarker Discoveries by Proteomics and Metabolomics Approaches

2021 ◽  
Vol 16 ◽  
pp. 117727192110133
Author(s):  
Ameneh Jafari ◽  
Amirhesam Babajani ◽  
Mostafa Rezaei-Tavirani
Keyword(s):  
Multiple Sclerosis ◽  
Complex Disease ◽  
Biomarker Discovery ◽  
Response To Treatment ◽  
Inflammatory Disorder ◽  
Protein Marker ◽  
Complex Disorders ◽  
New Information ◽  
The Central Nervous System ◽  
Monitoring Treatment

Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS) resulting in demyelination and axonal loss in the brain and spinal cord. The precise pathogenesis and etiology of this complex disease are still a mystery. Despite many studies that have been aimed to identify biomarkers, no protein marker has yet been approved for MS. There is urgently needed for biomarkers, which could clarify pathology, monitor disease progression, response to treatment, and prognosis in MS. Proteomics and metabolomics analysis are powerful tools to identify putative and novel candidate biomarkers. Different human compartments analysis using proteomics, metabolomics, and bioinformatics approaches has generated new information for further clarification of MS pathology, elucidating the mechanisms of the disease, finding new targets, and monitoring treatment response. Overall, omics approaches can develop different therapeutic and diagnostic aspects of complex disorders such as multiple sclerosis, from biomarker discovery to personalized medicine.

scholarly journals Neuroinflammation as a Common Denominator of Complex Diseases (Cancer, Diabetes Type 2, and Neuropsychiatric Disorders)

2021 ◽  
Vol 22 (11) ◽  
pp. 6138
Author(s):  
Serena Asslih ◽  
Odeya Damri ◽  
Galila Agam
Keyword(s):  
Cell Activation ◽  
Neuronal Degeneration ◽  
Complex Diseases ◽  
Diabetes Type 2 ◽  
Neuropsychiatric Disorders ◽  
Diabetes Type ◽  
Common Denominator ◽  
Cancer Type ◽  
Complex Disorders

The term neuroinflammation refers to inflammation of the nervous tissue, in general, and in the central nervous system (CNS), in particular. It is a driver of neurotoxicity, it is detrimental, and implies that glial cell activation happens prior to neuronal degeneration and, possibly, even causes it. The inflammation-like glial responses may be initiated in response to a variety of cues such as infection, traumatic brain injury, toxic metabolites, or autoimmunity. The inflammatory response of activated microglia engages the immune system and initiates tissue repair. Through translational research the role played by neuroinflammation has been acknowledged in different disease entities. Intriguingly, these entities include both those directly related to the CNS (commonly designated neuropsychiatric disorders) and those not directly related to the CNS (e.g., cancer and diabetes type 2). Interestingly, all the above-mentioned entities belong to the same group of “complex disorders”. This review aims to summarize cumulated data supporting the hypothesis that neuroinflammation is a common denominator of a wide variety of complex diseases. We will concentrate on cancer, type 2 diabetes (T2DM), and neuropsychiatric disorders (focusing on mood disorders).

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