scholarly journals Strain variation in Clostridioides difficile toxin activity associated with genomic variation at both PaLoc and non-PaLoc loci

2021 ◽  
Author(s):  
Katie Saund ◽  
Ali Pirani ◽  
Borden Lacy ◽  
Philip C Hanna ◽  
Evan S Snitkin
Keyword(s):  
Evolutionary History ◽  
Genome Wide Association Study ◽  
Bacterial Genome ◽  
Genomic Variation ◽  
Clinical Severity ◽  
Clostridioides Difficile ◽  
Genome Wide ◽  
Net Method ◽  
Human Infections

Clinical disease from Clostridioides difficile infection can be mediated by two toxins and their neighboring regulatory genes encoded within the five-gene pathogenicity locus (PaLoc). We provide several lines of evidence that the toxin activity of C. difficile may be modulated by genomic variants outside of the PaLoc. We used a phylogenetic tree-based approach to demonstrate discordance between toxin activity and PaLoc evolutionary history, an elastic net method to show the insufficiency of PaLoc variants alone to model toxin activity, and a convergence-based bacterial genome-wide association study (GWAS) to identify correlations between non-PaLoc loci with changes in toxin activity. Combined, these data support a model of C. difficile disease wherein toxin activity may be strongly affected by many non-PaLoc loci. Additionally, we characterize multiple other in vitro phenotypes relevant to human infections including germination and sporulation. These phenotypes vary greatly in their clonality, variability, convergence, and concordance with genomic variation. Lastly, we highlight the intersection of loci identified by GWAS for different phenotypes and clinical severity. This strategy to identify the overlapping loci can facilitate the identification of genetic variation linking phenotypic variation to clinical outcomes.

scholarly journals Genomic variation across a clinical Cryptococcus population linked to disease outcome

2021 ◽  
Author(s):  
Poppy Channa Sakti Sephton-Clark ◽  
Jennifer Tenor ◽  
Dena Toffaletti ◽  
Nancy Meyers ◽  
Charles Giamberardino ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Sugar Transport ◽  
Genomic Variation ◽  
Clinical Isolates ◽  
Genome Wide ◽  
A Genome ◽  
Gwas Approach

Cryptococcus neoformans is the causative agent of cryptococcosis, a disease with poor patient outcomes, accounting for approximately 180,000 deaths each year. Patient outcomes may be impacted by the underlying genetics of the infecting isolate, however, our current understanding of how genetic diversity contributes to clinical outcomes is limited. Here, we leverage clinical, in vitro growth and genomic data for 284 C. neoformans isolates to identify clinically relevant pathogen variants within a population of clinical isolates from patients with HIV-associated cryptococcosis in Malawi. Through a genome-wide association study (GWAS) approach, we identify variants associated with fungal burden and growth rate. We also find both small and large-scale variation, including aneuploidy, associated with alternate growth phenotypes, which may impact the course of infection. Genes impacted by these variants are involved in transcriptional regulation, signal transduction, glycolysis, sugar transport, and glycosylation. When combined with clinical data, we show that growth within the CNS is reliant upon glycolysis in an animal model, and likely impacts patient mortality, as CNS burden modulates patient outcome. Additionally, we find genes with roles in sugar transport are under selection in the majority of these clinical isolates. Further, we demonstrate that two hypothetical proteins identified by GWAS impact virulence in animal models. Our approach illustrates links between genetic variation and clinically relevant phenotypes, shedding light on survival mechanisms within the CNS and pathways involved in this persistence.

scholarly journals The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

2020 ◽  
Vol 6 (43) ◽  
pp. eabb3063
Author(s):  
Wei Xu ◽  
Si-Da Han ◽  
Can Zhang ◽  
Jie-Qiong Li ◽  
Yan-Jiang Wang ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Genome Wide Association Study ◽  
In Vitro Study ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Pathophysiological Role ◽  
Independent Cohort

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

scholarly journals Panton-Valentine leucocidin is the key determinant of Staphylococcus aureus pyomyositis in a bacterial genome-wide association study

2018 ◽  
Author(s):  
Bernadette C Young ◽  
Sarah G Earle ◽  
Sona Soeng ◽  
Poda Sar ◽  
Varun Kumar ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Bacterial Genome ◽  
Strong Relationship ◽  
Genome Wide Association ◽  
Tropical Regions ◽  
Genome Wide ◽  
A Genome

AbstractPyomyositis is a severe bacterial infection of skeletal muscle, commonly affecting children in tropical regions and predominantly caused by Staphylococcus aureus. To understand the contribution of bacterial genomic factors to pyomyositis, we conducted a genome-wide association study of S. aureus cultured from 101 children with pyomyositis and 417 children with asymptomatic nasal carriage attending the Angkor Hospital for Children in Cambodia. We found a strong relationship between bacterial genetic variation and pyomyositis, with estimated heritability 63.8% (95% CI 49.2-78.4%). The presence of the Panton-Valentine leucocidin (PVL) locus increased the odds of pyomyositis 130-fold (p =10-17.9). The signal of association mapped both to the PVL-coding sequence and the sequence immediately upstream. Together these regions explained > 99.9% of heritability. Our results establish staphylococcal pyomyositis, like tetanus and diphtheria, as critically dependent on expression of a single toxin and demonstrate the potential for association studies to identify specific bacterial genes promoting severe human disease.

scholarly journals A Genome-wide Association Study to Identify Candidate Genes for Metabolic Disorders in Offspring by in Vitro Fertilization

2022 ◽  
Author(s):  
Lihong Liu ◽  
Siyao HA ◽  
MingQing Li ◽  
Zhiling Li
Keyword(s):  
Lipid Metabolism ◽  
Health Risks ◽  
Genome Wide Association Study ◽  
Vitro Fertilization ◽  
Genome Wide ◽  
A Genome ◽  
Offspring Health

Abstract BackgroundIn vitro fertilization (IVF) processes increase offspring's short-term and long-term health risks, but their mechanisms remain unclear. MethodsWe conducted a bibliometric analysis to determine the landscape of IVF offspring health. Subsequently, a bioinformatics method was utilized to identify the co-genes properties and biological function mechanisms of IVF and type 2 diabetes mellitus (T2DM). Finally, we predicted compounds against key targets and performed multiple validations of the mechanisms underlying IVF offspring health risks. ResultsWe identified 15 genes associated with T2DM, and their biological functions are primarily associated with lipid metabolism. We also identified the properties of co-genes, modified characteristics, identified 3 SNPs sites, and determined the three core genes, APOA1, APOB, and APOE, which were mainly correlated with metabolic and cardiovascular diseases. In addition, we predicted drugs that may improve metabolic abnormalities in IVF offspring. ConclusionsThe impact of aberrant lipid metabolism in offspring after IVF therapy warrants additional investigation, particularly in terms of long-term health consequences and possible mechanisms.

scholarly journals Multiple-Replicon Resistance Plasmids of Klebsiella Mediate Extensive Dissemination of Antimicrobial Genes

2021 ◽  
Vol 12 ◽  
Author(s):  
Xue Wang ◽  
Jianan Zhao ◽  
Fang Ji ◽  
Han Chang ◽  
Jiao Qin ◽  
...  
Keyword(s):  
Resistance Genes ◽  
Bacterial Resistance ◽  
Genome Wide Association Study ◽  
Bacterial Genome ◽  
Antibiotic Resistance Genes ◽  
Genomic Analysis ◽  
Dilution Method ◽  
Genome Wide ◽  
Extensive Drug Resistance ◽  
Resistance Plasmids

Multiple-replicon resistance plasmids have become important carriers of resistance genes in Gram-negative bacteria, and the evolution of multiple-replicon plasmids is still not clear. Here, 56 isolates of Klebsiella isolated from different wild animals and environments between 2018 and 2020 were identified by phenotyping via the micro-broth dilution method and were sequenced and analyzed for bacterial genome-wide association study. Our results revealed that the isolates from non-human sources showed more extensive drug resistance and especially strong resistance to ampicillin (up to 80.36%). The isolates from Malayan pangolin were particularly highly resistant to cephalosporins, chloramphenicol, levofloxacin, and sulfamethoxazole. Genomic analysis showed that the resistance plasmids in these isolates carried many antibiotic resistance genes. Further analysis of 69 plasmids demonstrated that 28 plasmids were multiple-replicon plasmids, mainly carrying beta-lactamase genes such as blaCTX–M–15, blaCTX–M–14, blaCTX–M–55, blaOXA–1, and blaTEM–1. The analysis of plasmids carried by different isolates showed that Klebsiella pneumoniae might be an important multiple-replicon plasmid host. Plasmid skeleton and structure analyses showed that a multiple-replicon plasmid was formed by the fusion of two or more single plasmids, conferring strong adaptability to the antibiotic environment and continuously increasing the ability of drug-resistant isolates to spread around the world. In conclusion, multiple-replicon plasmids are better able to carry resistance genes than non-multiple-replicon plasmids, which may be an important mechanism underlying bacterial responses to environments with high-antibiotic pressure. This phenomenon will be highly significant for exploring bacterial resistance gene transmission and diffusion mechanisms in the future.

scholarly journals Genome-wide association mapping for agronomic and quality traits in foxtail millet

2019 ◽  
Author(s):  
Yanhong Lou ◽  
Yun Chen ◽  
Zhihao Liu ◽  
Mingjie Sun ◽  
Fei Han ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Foxtail Millet ◽  
Significant Snps ◽  
Genomic Variation ◽  
Genome Wide Association ◽  
Quality Traits ◽  
Nucleotide Polymorphisms ◽  
High Quality ◽  
Genome Wide ◽  
A Genome

Abstract Background: Foxtail millet [Setaria italica (L.) P. Beauv.] is a particularly important cereal and fodder crop in arid and semi-arid regions. The genomic variation and alleles underpinning agronomic and quality traits are important for foxtail millet improvement. To better understand the diversity of foxtail millet and facilitate the genetic dissection of its agronomic and quality traits, we used high-quality single nucleotide polymorphisms (SNPs) to perform a genome-wide association study (GWAS). Results: Using genotyping-by-sequencing, 107 foxtail millet accessions were sequenced, and further analysis revealed 72,181 high-quality SNPs, of which 53 were significantly associated with 15 agronomic and quality traits. These SNPs were distributed across the nine chromosomes of foxtail millet; 44 were located in intergenic regions, whereas one and eight SNPs were located in exon and intron regions, respectively. The GWAS revealed that 28 SNPs were associated with a single trait. Conclusions: For some of the significant SNPs, favourable genotypes showed pyramiding effects for several traits. The 53 loci identified in this study will therefore be useful for breeding programs aimed at foxtail millet improvement.

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