Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ASSIMILATOR: a new tool to inform selection of associated genetic variants for functional studies.

ABSTRACT: Fine-mapping experiments from genome-wide association studies (GWAS) are underway for many complex diseases. These are likely to identify a number of putative causal variants, which cannot be separated further in terms of strength of genetic association due to linkage disequilibrium. The challenge will be selecting which variant to prioritize for subsequent expensive functional studies. A wealth of functional information generated from wet lab experiments now exists but cannot be easily interrogated by the user. Here, we describe a program designed to quickly assimilate this data called ASSIMILATOR and validate the method by interrogating two regions to show its effectiveness.http://www.medicine.manchester.ac.uk/musculoskeletal/research/arc/genetics/bioinformatics/assimilator/.

SUBMITTER: Martin P

PROVIDER: S-EPMC3008640 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

ASSIMILATOR: a new tool to inform selection of associated genetic variants for functional studies.

Martin Paul P Barton Anne A Eyre Stephen S

Bioinformatics (Oxford, England) 20110101 1

<h4>Motivation</h4>Fine-mapping experiments from genome-wide association studies (GWAS) are underway for many complex diseases. These are likely to identify a number of putative causal variants, which cannot be separated further in terms of strength of genetic association due to linkage disequilibrium. The challenge will be selecting which variant to prioritize for subsequent expensive functional studies. A wealth of functional information generated from wet lab experiments now exists but cannot ...[more]

PMID: 21177990

Similar Datasets

Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot.

Project description:BackgroundTetralogy of Fallot (TOF)-the most common cyanotic heart defect in newborns-has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes and could contribute to delineating pathomechanisms.MethodsUsing a clinically driven strategy, we reanalyzed exome sequencing data from 811 probands with TOF, to identify rare loss-of-function and other likely pathogenic variants in genes associated with congenital heart disease.ResultsWe confirmed a major contribution of likely pathogenic variants in FLT4 (VEGFR3 [vascular endothelial growth factor receptor 3]; n=14) and NOTCH1 (n=10) and identified 1 to 3 variants in each of 21 other genes, including ATRX, DLL4, EP300, GATA6, JAG1, NF1, PIK3CA, RAF1, RASA1, SMAD2, and TBX1. In addition, multiple loss-of-function variants provided support for 3 emerging congenital heart disease/TOF candidate genes: KDR (n=4), IQGAP1 (n=3), and GDF1 (n=8). In total, these variants were identified in 63 probands (7.8%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network (P=3.3×10-16), with VEGFR2 (vascular endothelial growth factor receptor 2; KDR) and NOTCH1 (neurogenic locus notch homolog protein 1) representing central nodes. Variants associated with arrhythmias/sudden death and heart failure indicated factors that could influence long-term outcomes.ConclusionsThe results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, with further evidence for KDR (VEGFR2) as a congenital heart disease/TOF gene and for VEGF (vascular endothelial growth factor) and Notch signaling as mechanisms in human disease. Harnessing the genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.

| S-EPMC8373675 | biostudies-literature

Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

Project description:This study presents a novel allograft model of high-risk, localised PCa. In characterising this model we have focused on its response to radiotherapy (RT).

2020-10-06 | GSE146790 | GEO

Functional Studies of Genetic Variants Associated with Human Diseases in Notch Signaling-Related Genes Using Drosophila.

Project description:Rare variants in the many genes related to Notch signaling cause diverse Mendelian diseases that affect myriad organ systems. In addition, genome- and exome-wide association studies have linked common and rare variants in Notch-related genes to common diseases and phenotypic traits. Moreover, somatic mutations in these genes have been observed in many types of cancer, some of which are classified as oncogenic and others as tumor suppressive. While functional characterization of some of these variants has been performed through experimental studies, the number of "variants of unknown significance" identified in patients with diverse conditions keeps increasing as high-throughput sequencing technologies become more commonly used in the clinic. Furthermore, as disease gene discovery efforts identify rare variants in human genes that have yet to be linked to a disease, the demand for functional characterization of variants in these "genes of unknown significance" continues to increase. In this chapter, we describe a workflow to functionally characterize a rare variant in a Notch signaling related gene that was found to be associated with late-onset Alzheimer's disease. This pipeline involves informatic analysis of the variant of interest using diverse human and model organism databases, followed by in vivo experiments in the fruit fly Drosophila melanogaster. The protocol described here can be used to study variants that affect amino acids that are not conserved between human and fly. By "humanizing" the almondex gene in Drosophila with mutant alleles and heterologous genomic rescue constructs, a missense variant in TM2D3 (TM2 Domain Containing 3) was shown to be functionally damaging. This, and similar approaches, greatly facilitate functional interpretations of genetic variants in the human genome and propel personalized medicine.

| S-EPMC9396741 | biostudies-literature

Functional characterization of genetic variants associated with upper digestive cancers

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-02-24 | GSE240214 | GEO

'Real time' genetic manipulation: a new tool for ecological field studies.

Project description:Field experiments with transgenic plants often reveal the functional significance of genetic traits that are important for the performance of the plants in their natural environments. Until now, only constitutive overexpression, ectopic expression and gene silencing methods have been used to analyze gene-related phenotypes in natural habitats. These methods do not allow sufficient control over gene expression for the study of ecological interactions in real time, of genetic traits that play essential roles in development, or of dose-dependent effects. We applied the sensitive dexamethasone (DEX)-inducible pOp6/LhGR expression system to the ecological model plant Nicotiana attenuata and established a lanolin-based DEX application method to facilitate ectopic gene expression and RNA interference-mediated gene silencing in the field and under challenging conditions (e.g. high temperature, wind and UV radiation). Fully established field-grown plants were used to silence phytoene desaturase and thereby cause photobleaching only in specific plant sectors, and to activate expression of the cytokinin (CK) biosynthesis gene isopentenyl transferase (ipt). We used ipt expression to analyze the role of CKs in both the glasshouse and the field to understand resistance to the native herbivore Tupiocoris notatus, which attacks plants at small spatial scales. By spatially restricting ipt expression and elevating CK levels in single leaves, damage by T. notatus increased, demonstrating the role of CKs in this plant-herbivore interaction at a small scale. As the arena of most ecological interactions is highly constrained in time and space, these tools will advance the genetic analysis of dynamic traits that matter for plant performance in nature.

| S-EPMC4190501 | biostudies-literature

Functional Studies of Deafness-Associated Pendrin and Prestin Variants.

Project description:Pendrin and prestin are evolutionary-conserved membrane proteins that are essential for normal hearing. Dysfunction of these proteins results in hearing loss in humans, and numerous deafness-associated pendrin and prestin variants have been identified in patients. However, the pathogenic impacts of many of these variants are ambiguous. Here, we report results from our ongoing efforts to experimentally characterize pendrin and prestin variants using in vitro functional assays. With previously established fluorometric anion transport assays, we determined that many of the pendrin variants identified on transmembrane (TM) 10, which contains the essential anion binding site, and on the neighboring TM9 within the core domain resulted in impaired anion transport activity. We also determined the range of functional impairment in three deafness-associated prestin variants by measuring nonlinear capacitance (NLC), a proxy for motor function. Using the results from our functional analyses, we also evaluated the performance of AlphaMissense (AM), a computational tool for predicting the pathogenicity of missense variants. AM prediction scores correlated well with our experimental results; however, some variants were misclassified, underscoring the necessity of experimentally assessing the effects of variants. Together, our experimental efforts provide invaluable information regarding the pathogenicity of deafness-associated pendrin and prestin variants.

| S-EPMC10931795 | biostudies-literature

DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes.

Project description:The additional sex combs-like (ASXL) gene family-encoded by ASXL1, ASXL2, and ASXL3-is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina's Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath's epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes.

| S-EPMC9177544 | biostudies-literature

Functional characterization of genetic variants associated with upper digestive cancers [HiChIP]

Project description:Using H3K27ac HiChIP assays to link genetic variants to target genes in upper digestive cancers

2024-02-25 | GSE235431 | GEO

Massively parallel functional dissection of schizophrenia associated non-coding genetic variants

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-16 | GSE225817 | GEO

Genetic Variants Associated With Resilience in Human and Animal Studies.

Project description:Resilience is broadly defined as the ability to maintain or regain functioning in the face of adversity and is influenced by both environmental and genetic factors. The identification of specific genetic factors and their biological pathways underpinning resilient functioning can help in the identification of common key factors, but heterogeneities in the operationalisation of resilience have hampered advances. We conducted a systematic review of genetic variants associated with resilience to enable the identification of general resilience mechanisms. We adopted broad inclusion criteria for the definition of resilience to capture both human and animal model studies, which use a wide range of resilience definitions and measure very different outcomes. Analyzing 158 studies, we found 71 candidate genes associated with resilience. OPRM1 (Opioid receptor mu 1), NPY (neuropeptide Y), CACNA1C (calcium voltage-gated channel subunit alpha1 C), DCC (deleted in colorectal carcinoma), and FKBP5 (FKBP prolyl isomerase 5) had both animal and human variants associated with resilience, supporting the idea of shared biological pathways. Further, for OPRM1, OXTR (oxytocin receptor), CRHR1 (corticotropin-releasing hormone receptor 1), COMT (catechol-O-methyltransferase), BDNF (brain-derived neurotrophic factor), APOE (apolipoprotein E), and SLC6A4 (solute carrier family 6 member 4), the same allele was associated with resilience across divergent resilience definitions, which suggests these genes may therefore provide a starting point for further research examining commonality in resilience pathways.

| S-EPMC9163442 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data