Bacterial pathogens adapt their metabolism to the plant environment to successfully colonize their hosts. In our efforts to uncover the metabolic pathways that contribute to the colonization of ...Arabidopsis thaliana leaves by Pseudomonas syringae pv tomato DC3000 (Pst DC3000), we created iPst19, an ensemble of 100 genome-scale network reconstructions of Pst DC3000 metabolism. We developed a novel approach for gene essentiality screens, leveraging the predictive power of iPst19 to identify core and ancillary condition-specific essential genes. Constraining the metabolic flux of iPst19 with Pst DC3000 gene expression data obtained from naïve-infected or pre-immunized-infected plants, revealed changes in bacterial metabolism imposed by plant immunity. Machine learning analysis revealed that among other amino acids, branched-chain amino acids (BCAAs) metabolism significantly contributed to the overall metabolic status of each gene-expression-contextualized iPst19 simulation. These predictions were tested and confirmed experimentally. Pst DC3000 growth and gene expression analysis showed that BCAAs suppress virulence gene expression in vitro without affecting bacterial growth. In planta, however, an excess of BCAAs suppress the expression of virulence genes at the early stages of infection and significantly impair the colonization of Arabidopsis leaves. Our findings suggesting that BCAAs catabolism is necessary to express virulence and colonize the host. Overall, this study provides valuable insights into how plant immunity impacts Pst DC3000 metabolism, and how bacterial metabolism impacts the expression of virulence.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The hominid SINE-VNTR-
(SVA) retrotransposons represent a repertoire of genomic variation which could have significant effects on genome function. A human-specific SVA in the promoter region of the ...gene leucine-rich repeats and immunoglobulin-like domains 2 (
), which we termed SVA_LRIG2, is a common retrotransposon insertion polymorphism (RIP), defined as an element which is polymorphic for its presence or absence in the genome. We hypothesised that this RIP might be associated with differential levels of expression of LRIG2. The RIP genotype of SVA_LRIG2 was determined in a subset of frontal cortex DNA samples from the North American Brain Expression Consortium (NABEC) cohort and was imputed for a larger set of that cohort. Utilising available frontal cortex total RNA-seq and CpG methylation data for this cohort, we observed that increased allele dosage of SVA_LRIG2 was non-significantly associated with a decrease in transcription from the region and significantly associated with increased methylation of the CpG probe nearest to SVA_LRIG2, i.e., SVA_LRIG2 is a significant methylation quantitative trait loci (mQTL) at the
locus. These data are consistent with SVA_LRIG2 being a transcriptional regulator, which in part may involve epigenetic modulation.
Abstract Parkinson’s disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains ...unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants. More complex forms of variation, such as structural variants and tandem repeats, are already associated with several synucleinopathies. However, because more sophisticated sequencing methods are usually required to detect these regions, little is understood regarding their contribution to PD. One example is a polymorphic CT-rich region in intron 4 of the SNCA gene. This haplotype has been suggested to be associated with risk of Lewy Body (LB) pathology in Alzheimer’s Disease and SNCA gene expression, but is yet to be investigated in PD. Here, we attempt to resolve this CT-rich haplotype and investigate its role in PD. We performed targeted PacBio HiFi sequencing of the region in 1375 PD cases and 959 controls. We replicate the previously reported associations and a novel association between two PD risk SNVs (rs356182 and rs5019538) and haplotype 4, the largest haplotype. Through quantitative trait locus analyzes we identify a significant haplotype 4 association with alternative CAGE transcriptional start site usage, not leading to significant differential SNCA gene expression in post-mortem frontal cortex brain tissue. Therefore, disease association in this locus might not be biologically driven by this CT-rich repeat region. Our data demonstrates the complexity of this SNCA region and highlights that further follow up functional studies are warranted.
Neurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation in the brain. In Parkinson's Disease (PD), iron ...accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death. The aim of this study was to explore the genetic and genomic connection between NBIA and PD. We screened for known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons' Disease Program and the UKBiobank. We examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. In addition, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1886 PD cases and 1285 controls. Out of 29 previously reported NBIA screened coding variants, four were associated with PD risk at a nominal p value < 0.05. No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested that DCAF17 is differentially expressed in blood from PD cases and controls. Due to low mutation occurrence in the datasets and lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, with one in nine people over the age of 65 living with the disease in 2023. In this study, we used a phenome wide ...association study (PheWAS) approach to identify cross-phenotype between previously identified genetic associations for AD and electronic health record (EHR) diagnoses from the UK Biobank (UKBB) (n=361,194 of European ancestry) and the eMERGE Network (n=105,108 of diverse ancestry). Based on 497 previously identified AD-associated variants from the Alzheimer's Disease Variant Portal (ADVP), we found significant associations primarily in immune and cardiac related diseases in our PheWAS. Replicating variants have widespread impacts on immune genes in diverse tissue types. This study demonstrates the potential of using the PheWAS strategy to improve our understanding of AD progression as well as identify potential drug repurposing opportunities for new treatment and disease prevention strategies.
Parkinson’s disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. An association has been described 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 unaffected 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.
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic ...architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
Genetic risk factors are occasionally shared between different neurodegenerative diseases. Previous studies have linked ANG, a gene encoding angiogenin, to both Parkinson's disease (PD) and ...amyotrophic lateral sclerosis (ALS). Functional studies suggest ANG plays a neuroprotective role in both PD and amyotrophic lateral sclerosis by reducing cell death. We further explored the genetic association between ANG and PD by analyzing genotype data from the International Parkinson's Disease Genomics Consortium (14,671 cases and 17,667 controls) and whole genome sequencing data from the Accelerating Medicines Partnership - Parkinson's disease initiative (AMP-PD, https://amp-pd.org/) (1,647 cases and 1,050 controls). Our analysis did not replicate the findings of previous studies and identified no significant association between ANG variants and PD risk.
Microbial community composition in selected karst groundwater sites in the Yucatan Peninsula, Mexico, was assessed to determine the environmental variables influencing groundwater microbial ...diversity. The karst aquifer system is a groundwater-dependent ecosystem and is the world’s second largest underwater karst cave system. The area’s geology allows precipitation to infiltrate into the groundwater system and prevents accumulation of surface water; as such, groundwater is the only source of fresh water on the peninsula. The sampling locations consisted of three karst sinkholes that extend through the freshwater zone into the saline water, and an abandoned drinking water well of an ocean-side resort, during the dry and rainy seasons. The analysis showed that highly diverse microbial communities are present in the Yucatan groundwater, sustained by permanently warm temperatures and high nutrient input from human activity. Proximity to densely populated areas, such as tourist resorts, is the most important factor influencing both the diversity and presence of fecal bacteria and the antibiotic resistance profile.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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