scholarly journals Deciphering the Genetic Architecture of Plant Virus Resistance by GWAS, State of the Art and Potential Advances

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3080
Author(s):  
Severine Monnot ◽  
Henri Desaint ◽  
Tristan Mary-Huard ◽  
Laurence Moreau ◽  
Valerie Schurdi-Levraud ◽  
...  
Keyword(s):  
Virus Resistance ◽  
Plant Virus ◽  
Association Studies ◽  
Effective Means ◽  
Genome Wide Association Studies ◽  
Polygenic Resistance ◽  
Gwas Result ◽  
Key Steps ◽  
The Impact ◽  
Plant Virus Resistance

Growing virus resistant varieties is a highly effective means to avoid yield loss due to infection by many types of virus. The challenge is to be able to detect resistance donors within plant species diversity and then quickly introduce alleles conferring resistance into elite genetic backgrounds. Until now, mainly monogenic forms of resistance with major effects have been introduced in crops. Polygenic resistance is harder to map and introduce in susceptible genetic backgrounds, but it is likely more durable. Genome wide association studies (GWAS) offer an opportunity to accelerate mapping of both monogenic and polygenic resistance, but have seldom been implemented and described in the plant–virus interaction context. Yet, all of the 48 plant–virus GWAS published so far have successfully mapped QTLs involved in plant virus resistance. In this review, we analyzed general and specific GWAS issues regarding plant virus resistance. We have identified and described several key steps throughout the GWAS pipeline, from diversity panel assembly to GWAS result analyses. Based on the 48 published articles, we analyzed the impact of each key step on the GWAS power and showcase several GWAS methods tailored to all types of viruses.

scholarly journals TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 513
Author(s):  
Grace H. Yang ◽  
Danielle A. Fontaine ◽  
Sukanya Lodh ◽  
Joseph T. Blumer ◽  
Avtar Roopra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Association Studies ◽  
Cell Cycle Gene ◽  
Genome Wide Association Studies ◽  
Β Cell ◽  
Nucleotide Incorporation ◽  
Damage Response ◽  
The Impact

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.

Abstract 13798: Ablation of the Hypertension Candidate Gene ATP2B1 Results in Increased Blood Pressure and Cardiac Hypertrophic Remodeling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sally K Hammad ◽  
Min Zi ◽  
Sukhpal Prehar ◽  
Robert Little ◽  
Ludwig Neyses ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Diastolic Pressure ◽  
Association Studies ◽  
Weight Ratio ◽  
Blood Pressure Regulation ◽  
Heart Weight ◽  
Genome Wide Association Studies ◽  
Pressure Regulation ◽  
The Impact

Introduction: Hypertension is a major risk factor for cardiac hypertrophy and heart failure. Genome wide association studies have recently identified single nucleotide polymorphisms in ATP2B1 , the gene encoding the calcium extrusion pump, plasma membrane calcium ATPase (PMCA1), as having a strong association with hypertension risk. Hypothesis: PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy. Aims: We aim to examine whether there is a functional link between PMCA1 and blood pressure regulation, and the development of hypertension. And to determine the impact this link may have on cardiac structure and function. Methods and Results: To study the role of PMCA1 we generated a global PMCA1 heterozygous knockout mouse (PMCA1 Ht ). PMCA1 Ht mice had 46% to 52% reduction in PMCA1 protein expression compared to the WT, in aorta, heart, kidney and brain. To study the mice under hypertensive stress conditions, 3 month old PMCA1 Ht and wild type (WT) mice were infused via minipump with angiotensin II (1mg/Kg/daily) or water as a control. Upon angiotensin treatment, PMCA1 Ht mice showed a significantly greater increase in systolic (62.24±3.05 mmHg) and diastolic pressure (52.68±4.67 mmHg), in comparison to the WT (33.37±2.91 mmHg and 23.94±4.56 mmHg, respectively), P<0.001, n=12. Moreover, PMCA1 Ht mice showed a significantly greater hypertrophic response as indicated by a greater heart weight to tibia length ratio, cardiomyocyte cell size (410±18.7 μm 2 ), compared to WT mice (340.4±9.8 μm 2 ), and increased expression of B-type natriuretic peptide (BNP), 2.36 ± 0.25 fold change, n =5-6, P< 0.01. Echocardiography showed no significant changes between PMCA1 Ht and WT mice, in heart rate, and in cardiac function, as indicated by fractional shortening and ejection fraction. In addition, PMCA1 Ht mice showed no sign of lung congestion as indicated by lung weight to body weight ratio. Conclusion: ATP2B1 deletion leads to increased blood pressure and cardiac hypertrophy. This provides functional evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.

A Variant Noncoding Region Regulates Prrx1 and Predisposes to Atrial Arrhythmias

2021 ◽  
Author(s):  
Fernanda M Bosada ◽  
Mathilde R Rivaud ◽  
Jae-Sun Uhm ◽  
Sander Verheule ◽  
Karel van Duijvenboden ◽  
...  
Keyword(s):  
Sodium Current ◽  
Association Studies ◽  
Noncoding Region ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Atrial Cardiomyocytes ◽  
The Impact ◽  
Lineage Specific Gene

Rationale: Atrial Fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. Genome-wide association studies have identified AF-associated common variants across 100+ genomic loci, but the mechanism underlying the impact of these variant loci on AF susceptibility in vivo has remained largely undefined. One such variant region, highly associated with AF, is found at 1q24, close to PRRX1, encoding the Paired Related Homeobox 1 transcription factor. Objective: To identify the mechanistic link between the variant region at 1q24 and AF predisposition. Methods and Results: The mouse orthologue of the noncoding variant genomic region (R1A) at 1q24 was deleted using CRISPR genome editing. Among the genes sharing the topologically associated domain with the deleted R1A region (Kifap3, Prrx1, Fmo2, Prrc2c), only the broadly expressed gene Prrx1 was downregulated in mutants, and only in cardiomyocytes. Expression and epigenetic profiling revealed that a cardiomyocyte lineage-specific gene program (Mhrt, Myh6, Rbm20, Tnnt2, Ttn, Ckm) was upregulated in R1A-/- atrial cardiomyocytes, and that Mef2 binding motifs were significantly enriched at differentially accessible chromatin sites. Consistently, Prrx1 suppressed Mef2-activated enhancer activity in HL-1 cells. Mice heterozygous or homozygous for the R1A deletion were susceptible to atrial arrhythmia induction, had atrial conduction slowing and more irregular RR intervals. Isolated R1A-/- mouse left atrial cardiomyocytes showed lower action potential upstroke velocities and sodium current, as well as increased systolic and diastolic calcium concentrations compared to controls. Conclusions: The noncoding AF variant region at 1q24 modulates Prrx1 expression in cardiomyocytes. Cardiomyocyte-specific reduction of Prrx1 expression upon deletion of the noncoding region leads to a profound induction of a cardiac lineage-specific gene program and to propensity for AF. These data indicate that AF-associated variants in humans may exert AF predisposition through reduced PRRX1 expression in cardiomyocytes.

scholarly journals Boosting GWAS using biological networks: A study on susceptibility to familial breast cancer

2021 ◽  
Vol 17 (3) ◽  
pp. e1008819
Author(s):  
Héctor Climente-González ◽  
Christine Lonjou ◽  
Fabienne Lesueur ◽  
Dominique Stoppa-Lyonnet ◽  
Nadine Andrieu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Biological Networks ◽  
Familial Breast Cancer ◽  
Association Studies ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Functional Relationships ◽  
Network Methods ◽  
The Impact

Genome-wide association studies (GWAS) explore the genetic causes of complex diseases. However, classical approaches ignore the biological context of the genetic variants and genes under study. To address this shortcoming, one can use biological networks, which model functional relationships, to search for functionally related susceptibility loci. Many such network methods exist, each arising from different mathematical frameworks, pre-processing steps, and assumptions about the network properties of the susceptibility mechanism. Unsurprisingly, this results in disparate solutions. To explore how to exploit these heterogeneous approaches, we selected six network methods and applied them to GENESIS, a nationwide French study on familial breast cancer. First, we verified that network methods recovered more interpretable results than a standard GWAS. We addressed the heterogeneity of their solutions by studying their overlap, computing what we called the consensus. The key gene in this consensus solution was COPS5, a gene related to multiple cancer hallmarks. Another issue we observed was that network methods were unstable, selecting very different genes on different subsamples of GENESIS. Therefore, we proposed a stable consensus solution formed by the 68 genes most consistently selected across multiple subsamples. This solution was also enriched in genes known to be associated with breast cancer susceptibility (BLM, CASP8, CASP10, DNAJC1, FGFR2, MRPS30, and SLC4A7, P-value = 3 × 10−4). The most connected gene was CUL3, a regulator of several genes linked to cancer progression. Lastly, we evaluated the biases of each method and the impact of their parameters on the outcome. In general, network methods preferred highly connected genes, even after random rewirings that stripped the connections of any biological meaning. In conclusion, we present the advantages of network-guided GWAS, characterize their shortcomings, and provide strategies to address them. To compute the consensus networks, implementations of all six methods are available at https://github.com/hclimente/gwas-tools.

scholarly journals Quantitative Proteomics of Human Heart Samples Collected In Vivo Reveal the Remodeled Protein Landscape of Dilated Left Atrium Without Atrial Fibrillation

2020 ◽  
Vol 19 (7) ◽  
pp. 1132-1144
Author(s):  
Nora Linscheid ◽  
Pi Camilla Poulsen ◽  
Ida Dalgaard Pedersen ◽  
Emilie Gregers ◽  
Jesper Hastrup Svendsen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Mitral Valve ◽  
Protein Expression ◽  
High Resolution Mass Spectrometry ◽  
Association Studies ◽  
Genomic Research ◽  
Genome Wide Association Studies ◽  
History Of ◽  
The Impact

Genetic and genomic research has greatly advanced our understanding of heart disease. Yet, comprehensive, in-depth, quantitative maps of protein expression in hearts of living humans are still lacking. Using samples obtained during valve replacement surgery in patients with mitral valve prolapse (MVP), we set out to define inter-chamber differences, the intersect of proteomic data with genetic or genomic datasets, and the impact of left atrial dilation on the proteome of patients with no history of atrial fibrillation (AF).We collected biopsies from right atria (RA), left atria (LA) and left ventricle (LV) of seven male patients with mitral valve regurgitation with dilated LA but no history of AF. Biopsy samples were analyzed by high-resolution mass spectrometry (MS), where peptides were pre-fractionated by reverse phase high-pressure liquid chromatography prior to MS measurement on a Q-Exactive-HF Orbitrap instrument. We identified 7,314 proteins based on 130,728 peptides. Results were confirmed in an independent set of biopsies collected from three additional individuals. Comparative analysis against data from post-mortem samples showed enhanced quantitative power and confidence level in samples collected from living hearts. Our analysis, combined with data from genome wide association studies suggested candidate gene associations to MVP, identified higher abundance in ventricle for proteins associated with cardiomyopathies and revealed the dilated LA proteome, demonstrating differential representation of molecules previously associated with AF, in non-AF hearts.This is the largest dataset of cardiac protein expression from human samples collected in vivo. It provides a comprehensive resource that allows insight into molecular fingerprints of MVP and facilitates novel inferences between genomic data and disease mechanisms. We propose that over-representation of proteins in ventricle is consequent not to redundancy but to functional need, and conclude that changes in abundance of proteins known to associate with AF are not sufficient for arrhythmogenesis.

scholarly journals Pyk2 overexpression in postsynaptic neurons blocks amyloid β1–42-induced synaptotoxicity in microfluidic co-cultures

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Devrim Kilinc ◽  
Anaïs-Camille Vreulx ◽  
Tiago Mendes ◽  
Amandine Flaig ◽  
Diego Marques-Coelho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Genetic Risk ◽  
Association Studies ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
The Impact

Abstract Recent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer’s disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer’s disease, deciphering the impact of Alzheimer’s risk genes on synapse formation and maintenance is of great interest. In this article, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid β peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein. Co-culture with cells overexpressing mutated amyloid precursor protein exposed the synapses of primary hippocampal neurons to amyloid β1–42 molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of amyloid β suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta—an Alzheimer’s disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimer’s disease brains at gene expression and protein levels—selectively in postsynaptic neurons is protective against amyloid β1–42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically relevant model of Alzheimer’s disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments.

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