scholarly journals Hidden antibiotic resistance fitness costs revealed by GWAS-based epistasis analysis

2017 ◽  
Author(s):  
Maho Yokoyama ◽  
Maisem Laabei ◽  
Emily Stevens ◽  
Leann Bacon ◽  
Kate Heesom ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Association Studies ◽  
Resistance Mechanism ◽  
Resistance Mutation ◽  
Genomic Analysis ◽  
Resistant Mutant ◽  
Microbial Pathogens ◽  
Genome Wide Association Studies ◽  
Fitness Costs ◽  
Proteomic Approach

ABSTRACTUnderstanding how multi-drug resistant pathogens evolve is key to identifying means of curtailing their further emergence and dissemination. Fitness costs imposed on bacteria by resistance mechanisms are believed to hamper their dissemination in an antibiotic free environment, however, some have been reported to have little or no cost, which suggests there are few barriers preventing their global spread. One such apparently cost-free resistance mechanism acquired by the major human pathogen Staphylococcus aureus is to the clinically important antibiotic mupirocin, which is mediated by mutation of the highly-conserved and essential isoleucyl-tRNA synthethase (ileS) gene. In Genome Wide Association Studies (GWAS) on two genetically and geographically distinct MRSA lineages we have found this mutation to be associated with changes in bacterial virulence, driven through epistatic interactions with other loci. Given the potential dual effect of this mutation on both antibiotic resistance and virulence we adopted a proteomic approach and observed pleiotropic effects. This analysis revealed that the activity of the secretory apparatus of the PSM family of cytolytic toxins, the Pmt system, is affected in the mupirocin resistant mutant, which explains why it is less toxic. As an energetically costly activity, this reduction in toxicity masks the fitness costs associated with this resistance mutation, a cost that becomes apparent when toxin production is required. Given the widespread use of this antibiotic, and that this resistance often results from a single nucleotide substitution in the ileS gene, these hidden fitness costs provide an explanation for why this resistance mechanism is not more prevalent. This work also demonstrates how population-based genomic analysis of virulence and antibiotic resistance can contribute to uncovering hidden features of the biology of microbial pathogens.

scholarly journals Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

2020 ◽  
Vol 117 (34) ◽  
pp. 20753-20763 ◽  
Author(s):  
Lynn M. Williams ◽  
Fiona E. McCann ◽  
Marisa A. Cabrita ◽  
Thomas Layton ◽  
Adam Cribbs ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Association Studies ◽  
Genomic Analysis ◽  
Genome Wide Association Studies ◽  
Proteomic Profiling ◽  
Collagen Vi ◽  
Genome Wide ◽  
Fibrotic Diseases ◽  
Fibrotic Disorders ◽  
Fibrotic Disorder

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes,ACTA2andCOL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

Neuroblastoma: A Tough Nut to Crack

2016 ◽  
pp. e548-e557 ◽  
Author(s):  
Frank Speleman ◽  
Julie R. Park ◽  
Tara O. Henderson
Keyword(s):  
Clinical Trials ◽  
Late Effects ◽  
Association Studies ◽  
Genomic Analysis ◽  
The United States ◽  
Malignant Neoplasms ◽  
Genome Wide Association Studies ◽  
Second Malignant Neoplasms ◽  
Tumor In Childhood

Neuroblastoma, an embryonal tumor arising from neural crest–derived progenitor cells, is the most common solid tumor in childhood, with more than 700 cases diagnosed per year in the United States. In the past several decades, significant advances have been made in the treatment of neuroblastoma. Treatment advances reflect improved understanding of the biology of neuroblastoma. Although amplification of MYCN was discovered in the early 1980s, our understanding of neuroblastoma oncogenesis has advanced in the last decade as a result of high-throughput genomic analysis, exome and whole-genome sequencing, genome-wide association studies, and synthetic lethal drug screens. Our refined understanding of neuroblastoma biology and genetics is reflected in improved prognostic stratification and appropriate tailoring of therapy in recent clinical trials. Moreover, for high-risk neuroblastoma, a disease that was uniformly fatal 3 decades ago, recent clinical trials incorporating autologous hematopoietic transplant and immunotherapy utilizing anti-GD2 antibody plus cytokines have shown improved event-free and overall survival. These advances have resulted in a growing population of long-term survivors of neuroblastoma. Examination of the late effects and second malignant neoplasms (SMNs) in both older generations of survivors and more recently treated survivors will inform both design of future trials and surveillance guidelines for long-term follow-up. As a consequence of advances in understanding of the biology of neuroblastoma, successful clinical trials, and refined understanding of the late effects and SMNs of survivors, the promise of precision medicine is becoming a reality for patients with neuroblastoma.

scholarly journals A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

2021 ◽  
Author(s):  
Shweta Ramdas ◽  
Jonathan Judd ◽  
Sarah E Graham ◽  
Stavroula Kanoni ◽  
Yuxuan Wang ◽  
...  
Keyword(s):  
Association Studies ◽  
Density Lipoprotein ◽  
Genomic Analysis ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies ◽  
Functional Genomic ◽  
Selective Enrichment ◽  
Functional Genomic Analysis

AbstractA major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.

scholarly journals Genomic Analysis of Vavilov’s Historic Chickpea Landraces Reveals Footprints of Environmental and Human Selection

2020 ◽  
Vol 21 (11) ◽  
pp. 3952 ◽  
Author(s):  
Alena Sokolkova ◽  
Sergey V. Bulyntsev ◽  
Peter L. Chang ◽  
Noelia Carrasquilla-Garcia ◽  
Anna A. Igolkina ◽  
...  
Keyword(s):  
Association Studies ◽  
Genomic Analysis ◽  
Phenotypic Traits ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Multiple Traits ◽  
Phenotypic Data ◽  
Genome Wide ◽  
Bioclimatic Variables ◽  
Modern Breeding

A defining challenge of the 21st century is meeting the nutritional demands of the growing human population, under a scenario of limited land and water resources and under the specter of climate change. The Vavilov seed bank contains numerous landraces collected nearly a hundred years ago, and thus may contain ‘genetic gems’ with the potential to enhance modern breeding efforts. Here, we analyze 407 landraces, sampled from major historic centers of chickpea cultivation and secondary diversification. Genome-Wide Association Studies (GWAS) conducted on both phenotypic traits and bioclimatic variables at landraces sampling sites as extended phenotypes resulted in 84 GWAS hits associated to various regions. The novel haploblock-based test identified haploblocks enriched for single nucleotide polymorphisms (SNPs) associated with phenotypes and bioclimatic variables. Subsequent bi-clustering of traits sharing enriched haploblocks underscored both non-random distribution of SNPs among several haploblocks and their association with multiple traits. We hypothesize that these clusters of pleiotropic SNPs represent co-adapted genetic complexes to a range of environmental conditions that chickpea experienced during domestication and subsequent geographic radiation. Linking genetic variation to phenotypic data and a wealth of historic information preserved in historic seed banks are the keys for genome-based and environment-informed breeding intensification.

scholarly journals Large-Scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew

2021 ◽  
Author(s):  
Xiang-Zhen Kong ◽  
Merel Postema ◽  
Dick Schijven ◽  
Amaia Carrión Castillo ◽  
Antonietta Pepe ◽  
...  
Keyword(s):  
Large Scale ◽  
Right Hemisphere ◽  
Association Studies ◽  
Genomic Analysis ◽  
Population Level ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Imaging Data ◽  
Physical And Mental Health ◽  
Human Connectome Project

Abstract The human cerebral hemispheres show a left–right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here, we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, UK Biobank (N = 39 678), Human Connectome Project (N = 1113), and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional gray and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed single nucleotide polymorphisms-based heritabilities of 4–13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in genome-wide association studies for either skew. There was evidence for a significant genetic correlation between horizontal brain skew and autism, which requires future replication. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.

scholarly journals Integrative genomic analysis of blood pressure and related phenotypes in rats

2021 ◽  
Author(s):  
Fumihiko Takeuchi ◽  
Yi-Qiang Liang ◽  
Masato Isono ◽  
Michiko Tajima ◽  
Zong Hu Cui ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Target Genes ◽  
Association Studies ◽  
Genomic Analysis ◽  
Pharmacological Intervention ◽  
Genome Wide Association Studies ◽  
Causal Pathways ◽  
Genome Wide ◽  
Wistar Kyoto

Despite remarkable progress made in human genome-wide association studies, there remains a substantial gap between statistical evidence for genetic associations and functional comprehension of the underlying mechanisms governing these associations. As a means of bridging this gap, we performed genomic analysis of blood pressure (BP) and related phenotypes in spontaneously hypertensive rats (SHR) and their sub-strain, stroke-prone SHR (SHRSP), both of which are unique genetic models of severe hypertension and cardiovascular complications. By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (max n=1,415), fine congenic mapping (max n=8,704), pharmacological intervention and comparative analysis with transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY); e.g., inter-strain BP differences between SHRSP and WKY could be largely explained by an aggregate of BP changes in seven SHRSP-derived consomic strains. We identified 26 potential target genes, including rat homologues of human TWAS loci, for the tested traits. In this study, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein-kinin/renin-angiotensin systems (KKS/RAS), where the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogues. In combination with a pharmacological intervention, we provide in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, in a rat polygenic hypertension model.

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 Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus

2021 ◽  
Vol 12 ◽  
Author(s):  
Robert E. Weber ◽  
Stephan Fuchs ◽  
Franziska Layer ◽  
Anna Sommer ◽  
Jennifer K. Bender ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Genetic Variants ◽  
Association Studies ◽  
Rapid Development ◽  
Genome Wide Association ◽  
Resistant Isolate ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Resistance Traits

BackgroundAs next generation sequencing (NGS) technologies have experienced a rapid development over the last decade, the investigation of the bacterial genetic architecture reveals a high potential to dissect causal loci of antibiotic resistance phenotypes. Although genome-wide association studies (GWAS) have been successfully applied for investigating the basis of resistance traits, complex resistance phenotypes have been omitted so far. For S. aureus this especially refers to antibiotics of last resort like daptomycin and ceftaroline. Therefore, we aimed to perform GWAS for the identification of genetic variants associated with DAP and CPT resistance in clinical S. aureus isolates.Materials/methodsTo conduct microbial GWAS, we selected cases and controls according to their clonal background, date of isolation, and geographical origin. Association testing was performed with PLINK and SEER analysis. By using in silico analysis, we also searched for rare genetic variants in candidate loci that have previously been described to be involved in the development of corresponding resistance phenotypes.ResultsGWAS revealed MprF P314L and L826F to be significantly associated with DAP resistance. These mutations were found to be homogenously distributed among clonal lineages suggesting convergent evolution. Additionally, rare and yet undescribed single nucleotide polymorphisms could be identified within mprF and putative candidate genes. Finally, we could show that each DAP resistant isolate exhibited at least one amino acid substitution within the open reading frame of mprF. Due to the presence of strong population stratification, no genetic variants could be associated with CPT resistance. However, the investigation of the staphylococcal cassette chromosome mec (SCCmec) revealed various mecA SNPs to be putatively linked with CPT resistance. Additionally, some CPT resistant isolates revealed no mecA mutations, supporting the hypothesis that further and still unknown resistance determinants are crucial for the development of CPT resistance in S. aureus.ConclusionWe hereby confirmed the potential of GWAS to identify genetic variants that are associated with antibiotic resistance traits in S. aureus. However, precautions need to be taken to prevent the detection of spurious associations. In addition, the implementation of different approaches is still essential to detect multiple forms of variations and mutations that occur with a low frequency.

scholarly journals A fast and agnostic method for bacterial genome-wide association studies: bridging the gap between kmers and genetic events

2018 ◽  
Author(s):  
Magali Jaillard ◽  
Leandro Lima ◽  
Maud Tournoud ◽  
Pierre Mahé ◽  
Alex van Belkum ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Genetic Variants ◽  
Association Studies ◽  
Bacterial Species ◽  
Bacterial Genome ◽  
Genome Wide Association ◽  
Compact Set ◽  
Genome Wide Association Studies ◽  
Alignment Free ◽  
Genome Wide

AbstractMotivationGenome-wide association study (GWAS) methods applied to bacterial genomes have shown promising results for genetic marker discovery or fine-assessment of marker effect. Recently, alignment-free methods based on kmer composition have proven their ability to explore the accessory genome. However, they lead to redundant descriptions and results which are hard to interpret.MethodsHere, we introduce DBGWAS, an extended kmer-based GWAS method producing interpretable genetic variants associated with pheno-types. Relying on compacted De Bruijn graphs (cDBG), our method gathers cDBG nodes identified by the association model into subgraphs defined from their neighbourhood in the initial cDBG. DBGWAS is fast, alignment-free and only requires a set of contigs and phenotypes. It produces annotated subgraphs representing local polymorphisms as well as mobile genetic elements (MGE) and offers a graphical framework to interpret GWAS results.ResultsWe validated our method using antibiotic resistance phenotypes for three bacterial species. DBGWAS recovered known resistance determinants such as mutations in core genes in Mycobacterium tuberculosis and genes acquired by horizontal transfer in Staphylococcus aureus and Pseudomonas aeruginosa – along with their MGE context. It also enabled us to formulate new hypotheses involving genetic variants not yet described in the antibiotic resistance literature.ConclusionOur novel method proved its efficiency to retrieve any type of phenotype-associated genetic variant without prior knowledge. All experiments were computed in less than two hours and produced a compact set of meaningful subgraphs, thereby outperforming other GWAS approaches and facilitating the interpretation of the results.AvailabilityOpen-source tool available at https://gitlab.com/leoisl/dbgwas

Genomic Analysis for the Detection of Bleeding and Thrombotic Disorders

2021 ◽  
Vol 47 (02) ◽  
pp. 174-182
Author(s):  
Keith Gomez
Keyword(s):  
Clinical Practice ◽  
High Throughput Sequencing ◽  
Clinical Medicine ◽  
Association Studies ◽  
New Technology ◽  
Clinical Manifestations ◽  
Genomic Analysis ◽  
Genomic Testing ◽  
Genome Wide Association Studies ◽  
Bleeding Disorders

AbstractThe development of high-throughput sequencing technologies has ushered in a new era of genomic testing in clinical medicine. This has greatly enhanced our diagnostic repertoire for hemostatic diseases particularly for milder or rarer bleeding disorders. New genetic causes for heritable platelet disorders have been discovered along with the recognition of clinical manifestations outside hemostasis, such as the association of leukemia with RUNX1 variation. Genome-wide association studies in heritable thrombophilia have demonstrated that some of the genetic variants that are commonly included in thrombophilia testing are of no clinical relevance, while uncovering new variants that should potentially be included. The implementation of new technology has necessitated far-reaching changes in clinical practice to deal with incidental findings, variants of uncertain significance, and genetic disease modifiers. Mild bleeding disorders that were previously considered to have a monogenic basis now appear to have an oligogenic etiology. To harness these advances in knowledge large databases have been developed to capture the new genomic information with phenotypic features on a population-wide scale. The use of this so-called “big data” requires new bioinformatics tools with the promise of delivering precision medicine in the foreseeable future. This review discusses the use of these technologies in clinical practice, the benefits of genomic testing, and some of the challenges associated with implementation.

Sign in / Sign up

Export Citation Format

Share Document