scholarly journals The genetic architecture of emerging fungicide resistance in populations of a global wheat pathogen

2020 ◽  
Author(s):  
Danilo Pereira ◽  
Bruce A. McDonald ◽  
Daniel Croll
Keyword(s):  
Fungicide Resistance ◽  
Genetic Architecture ◽  
Target Genes ◽  
Association Studies ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Resistance Mutations ◽  
Evolutionary Trajectory ◽  
Trade Offs

AbstractContaining fungal diseases often depends on the application of fungicidal compounds. Fungicides can rapidly lose effectiveness due to the rise of resistant individuals in populations. However, the lack of knowledge about resistance mutations beyond known target genes challenges investigations into pathways to resistance. We used whole-genome sequencing data and association mapping to reveal the multilocus genetic architecture of fungicide resistance in a global panel of 159 isolates of Parastagonospora nodorum, an important fungal pathogen of wheat. We found significant differences in azole resistance among global field populations. The populations evolved distinctive combinations of resistance alleles which can interact synergistically. We identified 34 significantly associated SNPs located in close proximity to genes associated with fungicide resistance in other fungi, including an MFS transporter. Using fungal colony growth rates and melanin production at different temperatures as fitness proxies, we found no evidence that resistance was constrained by genetic trade-offs. Our study demonstrates how genome-wide association studies of a global collection of pathogen strains can recapitulate the emergence of fungicide resistance. The distinct complement of resistance mutations found among populations illustrates how the evolutionary trajectory of fungicide adaptation can be complex and challenging to predict.

scholarly journals The Genetic Architecture of Emerging Fungicide Resistance in Populations of a Global Wheat Pathogen

2020 ◽  
Vol 12 (12) ◽  
pp. 2231-2244
Author(s):  
Danilo Pereira ◽  
Bruce A McDonald ◽  
Daniel Croll
Keyword(s):  
Fungicide Resistance ◽  
Genetic Architecture ◽  
Target Genes ◽  
Association Studies ◽  
Major Facilitator Superfamily ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Resistance Mutations ◽  
Evolutionary Trajectory ◽  
Trade Offs

Abstract Containing fungal diseases often depends on the application of fungicidal compounds. Fungicides can rapidly lose effectiveness due to the rise of resistant individuals in populations. However, the lack of knowledge about resistance mutations beyond known target genes challenges investigations into pathways to resistance. We used whole-genome sequencing data and association mapping to reveal the multilocus genetic architecture of fungicide resistance in a global panel of 159 isolates of Parastagonospora nodorum, an important fungal pathogen of wheat. We found significant differences in azole resistance among global field populations. The populations evolved distinctive combinations of resistance alleles which can interact when co-occurring in the same genetic background. We identified 34 significantly associated single nucleotide polymorphisms located in close proximity to genes associated with fungicide resistance in other fungi, including a major facilitator superfamily transporter. Using fungal colony growth rates and melanin production at different temperatures as fitness proxies, we found no evidence that resistance was constrained by genetic trade-offs. Our study demonstrates how genome-wide association studies of a global collection of pathogen strains can recapitulate the emergence of fungicide resistance. The distinct complement of resistance mutations found among populations illustrates how the evolutionary trajectory of fungicide adaptation can be complex and challenging to predict.

scholarly journals A high-quality reference panel reveals the complexity and distribution of structural genome changes in a human population

2016 ◽  
Author(s):  
Jayne Y. Hehir-Kwa ◽  
Tobias Marschall ◽  
Wigard P. Kloosterman ◽  
Laurent C. Francioli ◽  
Jasmijn A. Baaijens ◽  
...  
Keyword(s):  
Association Studies ◽  
Whole Genome Sequencing Data ◽  
Strong Linkage Disequilibrium ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Full Spectrum ◽  
Disease Phenotypes ◽  
Human Genomes ◽  
Genome Wide ◽  
Genome Variants

AbstractStructural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation.Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals. Our findings are essential for genome-wide association studies.

scholarly journals A high-resolution HLA reference panel capturing global population diversity enables multi-ethnic fine-mapping in HIV host response

2020 ◽  
Author(s):  
Yang Luo ◽  
Masahiro Kanai ◽  
Wanson Choi ◽  
Xinyi Li ◽  
Kenichi Yamamoto ◽  
...  
Keyword(s):  
High Resolution ◽  
Fine Mapping ◽  
Association Studies ◽  
Population Group ◽  
Population Diversity ◽  
Reference Panel ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Hla Haplotypes

Defining causal variation by fine-mapping can be more effective in multi-ethnic genetic studies, particularly in regions such as the MHC with highly population-specific structure. To enable such studies, we constructed a large (N=21,546) high resolution HLA reference panel spanning five global populations based on whole-genome sequencing data. Expectedly, we observed unique long-range HLA haplotypes within each population group. Despite this, we demonstrated consistently accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in Admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT)). We jointly analyzed genome-wide association studies (GWAS) of HIV-1 viral load from EUR, AA and LAT populations. Our analysis pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide binding groove, explaining 12.9% of trait variance, and obviating effects of previously reported associations from population-specific HIV studies.

scholarly journals Genome-wide discovery of epistatic loci affecting antibiotic resistance using evolutionary couplings

2018 ◽  
Author(s):  
Benjamin Schubert ◽  
Rohan Maddamsetti ◽  
Jackson Nyman ◽  
Maha R. Farhat ◽  
Debora S. Marks
Keyword(s):  
Antibiotic Resistance ◽  
Statistical Power ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Vast Number ◽  
Genome Wide

ABSTRACTThe analysis of whole genome sequencing data should, in theory, allow the discovery of interdependent loci that cause antibiotic resistance. In practice, however, identifying this epistasis remains a challenge as the vast number of possible interactions erodes statistical power. To solve this problem, we extend a method that has been successfully used to identify epistatic residues in proteins to infer genomic loci that are strongly coupled and associated with antibiotic resistance. Our method reduces the number of tests required for an epistatic genome-wide association study and increases the likelihood of identifying causal epistasis. We discovered 38 loci and 250 epistatic pairs that influence the dose needed to inhibit growth for five different antibiotics in 1,102 isolates of Neisseria gonorrhoeae that were confirmed in an independent dataset of 495 isolates. Many known resistance-affecting loci were recovered; however, the majority of loci occurred in unreported genes, including murE which was associated with cefixime. About half of the novel epistasis we report involved at least one locus previously associated with antibiotic resistance, including interactions between gyrA and parC associated with ciprofloxacin. Still, many combinations involved unreported loci and genes. Our work provides a systematic identification of epistasis pairs affecting antibiotic resistance in N. gonorrhoeae and a generalizable method for epistatic genome-wide association studies.

scholarly journals A genetic and transcriptomic assessment of the KTN1 gene in Parkinson’s disease risk

2021 ◽  
Author(s):  
Anni Moore ◽  
Sara Bandres-Ciga ◽  
Cornelis Blauwendraat ◽  
Monica Diez-Fairen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Association Studies ◽  
Age At Onset ◽  
Brain Regions ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Increased Risk

AbstractParkinson’s disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. A recent finding has suggested an association between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson’s Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson’s disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to healthy individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

scholarly journals The MIR137 VNTR rs58335419 Is Associated With Cognitive Impairment in Schizophrenia and Altered Cortical Morphology

2020 ◽  
Author(s):  
Ebrahim Mahmoudi ◽  
Joshua R Atkins ◽  
Yann Quidé ◽  
William R Reay ◽  
Heath M Cairns ◽  
...  
Keyword(s):  
Association Studies ◽  
Variable Number Tandem Repeat ◽  
Variable Number ◽  
Brain Morphology ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Sequencing Data ◽  
Genome Wide ◽  
Cortical Morphology

Abstract Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide polymorphisms (SNPs) with functional implications for the microRNA’s expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.

Genetic Determinants of Peripheral Artery Disease

2021 ◽  
Vol 128 (12) ◽  
pp. 1805-1817
Author(s):  
Derek Klarin ◽  
Philip S. Tsao ◽  
Scott M. Damrauer
Keyword(s):  
Peripheral Artery Disease ◽  
Complex Disease ◽  
Association Studies ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Genetic Determinants ◽  
Peripheral Artery ◽  
Common Complex Disease ◽  
Artery Disease

Peripheral artery disease—atherosclerosis of the abdominal aorta and lower extremity vascular bed—is a complex disease with both environmental and genetic determinants. Unmitigated disease is associated with major functional decline and can lead to chronic limb-threatening ischemia, amputation, and increased mortality. Over the last 10 years, major advances have been made in identifying the genetic basis of this common, complex disease. In this review, we provide an overview of the primary types of genetic analyses performed for peripheral artery disease, including heritability and linkage studies, and more recently biobank-based genome-wide association studies. Looking forward, we highlight areas of future study including efforts to identify causal peripheral artery disease genes, rare variant and structural variant analyses using whole-exome and whole-genome sequencing data, and the need to include individuals of diverse genetic ancestries.

scholarly journals Inherited platelet disorders: toward DNA-based diagnosis

Blood ◽  
2016 ◽  
Vol 127 (23) ◽  
pp. 2814-2823 ◽  
Author(s):  
Claire Lentaigne ◽  
Kathleen Freson ◽  
Michael A. Laffan ◽  
Ernest Turro ◽  
Willem H. Ouwehand
Keyword(s):  
High Throughput Sequencing ◽  
Rare Variants ◽  
Association Studies ◽  
Genetic Diagnosis ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Increased Risk ◽  
Risk Of Malignancy ◽  
Platelet Disorders

Abstract Variations in platelet number, volume, and function are largely genetically controlled, and many loci associated with platelet traits have been identified by genome-wide association studies (GWASs).1 The genome also contains a large number of rare variants, of which a tiny fraction underlies the inherited diseases of humans. Research over the last 3 decades has led to the discovery of 51 genes harboring variants responsible for inherited platelet disorders (IPDs). However, the majority of patients with an IPD still do not receive a molecular diagnosis. Alongside the scientific interest, molecular or genetic diagnosis is important for patients. There is increasing recognition that a number of IPDs are associated with severe pathologies, including an increased risk of malignancy, and a definitive diagnosis can inform prognosis and care. In this review, we give an overview of these disorders grouped according to their effect on platelet biology and their clinical characteristics. We also discuss the challenge of identifying candidate genes and causal variants therein, how IPDs have been historically diagnosed, and how this is changing with the introduction of high-throughput sequencing. Finally, we describe how integration of large genomic, epigenomic, and phenotypic datasets, including whole genome sequencing data, GWASs, epigenomic profiling, protein–protein interaction networks, and standardized clinical phenotype coding, will drive the discovery of novel mechanisms of disease in the near future to improve patient diagnosis and management.

scholarly journals Elevated plasma levels of CXCL16 in severe COVID-19 patients

2021 ◽  
Author(s):  
Sandra P. Smieszek ◽  
Vasilios M. Polymeropoulos ◽  
Christos M. Polymeropoulos ◽  
Bartlomiej P. Przychodzen ◽  
Gunther Birznieks ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Association Studies ◽  
Plasma Concentrations ◽  
Hospitalized Patients ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Genome Wide ◽  
Targeted Treatments ◽  
Severe Manifestation

AbstractGenome-wide association studies have recently identified 3p21.31, with lead variant pointing to the CXCR6 gene, as the strongest thus far reported susceptibility risk locus for severe manifestation of COVID-19. In order the determine its role, we measured plasma levels of Chemokine (C□X□C motif) ligand 16 (CXCL16) in the plasma of COVID-19 hospitalized patients. CXCL16 interacts with CXCR6 promoting chemotaxis or cell adhesion. The CXCR6/CXCL16 axis mediates homing of T cells to the lungs in disease and hyper-expression is associated with localised cellular injury. To characterize the CXCR6/CXCL16 axis in the pathogenesis of severe COVID-19, plasma concentrations of CXCL16 collected at baseline from 115 hospitalized COVID-19 patients participating in ODYSSEY COVID-19 clinical trial were assessed together with a set of controls. We report elevated levels of CXCL16 in a cohort of COVID-19 hospitalized patients. Specifically, we report significant elevation of CXCL16 plasma levels in association with severity of COVID-19 (as defined by WHO scale) (P-value<0.02). Our current study is the largest thus far study reporting CXCL16 levels in COVID-19 hospitalized patients (with whole-genome sequencing data available). The results further support the significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19 and warrants further studies to understand which patients would benefit most from targeted treatments.

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