BMC Genomic Data

Lead is a toxic metal ubiquitous in our environment. While dramatic reductions in lead sources have paralleled equivalent decreases in lead-poisoning rates, chronic lead exposure remains a critical public health concern. Childhood lead exposure (at its lowest levels) is liked to changes in cognitive development but less is known about lead's effects on children's brain structure, especially as a result of in utero exposure. We measured prenatal and early-postnatal lead exposure in shed deciduous teeth of 448 9- and 10-year-old children (from 20 United States cities) and linked those lead levels to childhood brain structure, cognition/behavior, and neighborhood- and family-level socioeconomic characteristics. Here we show negative associations between tooth-lead levels and the thickness of the brain's cortex, particularly in regions linked to language processing. With increasing tooth-lead levels, children of lower-income (versus higher-income) families showed steeper declines in receptive vocabulary. Caregiver-reported behavioral problems exhibited similar associations. With in utero exposure linked to adverse neurodevelopmental outcomes (well before lead exposure and its risks are evaluated by healthcare professionals), prenatal screening of maternal lead levels/exposure, coupled with recommended strategies to reduce its placental transmission, may help reduce lead's effects on future generations.

Since the initial distribution of the SARS-CoV-19 vaccine, its widespread use has been hypothesized to act as a selective pressure that drives the COVID-19 virus to mutate. This study aims to investigate the correlation between global vaccination rates and the mutation rate of the SARS-CoV-2 Beta variant (B.1.351). From January to July 2021, nucleotide diversity increased in tandem with vaccination rates, demonstrating that the virus evolved more rapidly in response to selective pressure from mass vaccination. Statistical analysis revealed statistically significant positive correlations between both vaccination rates and vaccine doses administered with nucleotide diversity. Thus, our findings indicate a positive correlation between rising vaccination rates and nucleotide diversity, suggesting that increased vaccination coverage acted as a selective pressure that accelerated viral evolution of SARS CoV2.

Currently, the genetic architecture of Middle Eastern populations is underrepresented in global genomic databases. This gap increases the rate of Variants of Uncertain Significance (VUSs) and clinical misinterpretations of genomic data especially in Middle Eastern populations. Whole exome sequencing was conducted on 90 healthy individuals from Jordan and the data were analysed using Principal Component Analysis (PCA) and multi-computational filtering. PCA revealed a double ancestry (EUR-AFR) admixture rather than a triple admixture (EUR-AFR-AMR). More than 3,500 populations-specific variants (PSVs) were identified, of which 72% were singletons. Additionally, 19 variants were significantly enriched compared to the maximum allele frequencies in public global databases (Fisher's exact test with Benjamini-Hochberg false discovery rate correction, p-value < 0.05). Consequently, the results suggest the reclassification of variants of Uncertain Significance (VUS) which reside in the ECE2 gene to likely benign and the variants of Conflicting Classification of Pathogenicity in the genes IL1RN and THPO to benign based on the significant allele frequency (AF=0.0389, p-value < 0.05). Furthermore, a pathogenic ClinVar variant was identified in a healthy individual, warranting careful interpretation. The findings underscore the importance of identifying PSVs in order to minimize or even prevent clinical misdiagnosis and highlight the unique genetic signature in Jordan. The study serves as a foundational resource for precision medicine in the region.

INTRODUCTIONMounting evidence support exposome influences on brain function and health, complementing genome influences. Understanding the molecular imprint of exposome on brain metabolism and the biochemical communication between the body and brain can impact our fundamental understanding and treatment of neuropsychiatric diseases. METHODSLeveraging two complementary metabolomics platforms, we classified 1400 features in 514 brains from the ROSMAP collection. We evaluated the origin of these compounds using literature and databases. We correlated those metabolites with cognitive function using linear models. RESULTSWe identified over 230 non-endogenous compounds in the brain, including 103 drugs and metabolites, 120 dietary and microbial products and possibly 15 compounds from environmental exposures. Over 20 dietary and gut microbial compounds showed associations with cognition. DISCUSSIONComprehensive profiling of chemicals in the brain and the link to cognitive function provides foundational work to connect body and brain in the study of AD and related dementias.

WD40 domains share a widespread {beta}-propeller fold, and often act as versatile scaffold proteins. Despite their central role in organizing dynamic cellular complexes, the molecular and structural mechanisms of many WD40 proteins remain poorly understood. Among them, DCAF7, an ubiquitously expressed and essential gene in human, also encodes a highly conserved WD40 protein in eukaryotic organisms. It is known to interact with multiple and functionnally diverse partners to coordinates cellular activity of several protein kinases as well as transcriptional regulators, thereby modulating key cellular processes such as cell growth, differentiation, and transcriptional regulation. However, the precise mode of action of DCAF7 is unknown and its important divergence in sequence from better characterize WD40 prevent information transfer by similarity. Structural interactomic can reveal how protein-protein interactions (PPIs) occur within an organism and are essential for understanding biological functions and developing new therapeutic strategies. Using SLiMAn2, AlphaFold2/3 and PSSMsearch, we identified a conserved -helical short linear motif (SLiM) in several well known DCAF7 partners that binds to the top surface of its {beta}-propeller. This motif was subsequently used to generate a regular expression, to identify potential new direct binders across the DCAF7 meta-interactome and the human proteome. Domain-domain interactions were also predicted for some other partners. Finally, modeling of oligomeric complexes with such new hits reveals the structural basis of DCAF7 scaffolding, with links to neurodevelopmental disorders such as autism.

The Na+/K+-ATPase (NKA) regulates ion balance in the kidney and influences cellular processes like proliferation and apoptosis through its signal transduction. The endogenous ligand 20-Hydroxyeicosatetraenoic acid (20-HETE) contributes to inflammation and fibrosis in chronic kidney disease (CKD) and inhibits NKA activity in renal tubules. However, the molecular mechanism of this interaction remains unclear. In this study, we used in-silico approach to investigate the potential interaction between 20-HETE and NKA. Various ligands, including known NKA ligands such as cardiotonic steroids (CTS), 20-HETE, and negative controls, were docked using rigid and Induced Fit Docking to predict the affinity of the ligands toward NKA. Binding free energy calculations with the Prime Molecular mechanics with generalized Born and surface area (Prime MM/GBSA) tools were used to confirm the involvement of key amino acids in ligand-receptor interactions. The docking analyses revealed that 20-HETE exhibited a binding affinity comparable to negative control, with some differences between rigid and induced fit docking. Binding free energy data highlighted key amino acids in the 20-HETE and NKA interaction. Interaction fingerprint and mutations such as Ala330Gly and Val329Ala significantly reduced binding free energy, while Thr804Ala showed a notable decrease, underscoring the potential importance of these amino acids in ligand stabilization. These findings provide computational evidence supporting potential direct interaction between 20-HETE and NKA and identify candidate residues for future experimental validation.

Purpose Patients carrying Germline Pathogenic Variants (GPVs) in multiple cancer susceptibility genes (CSGs) can be described within the context of Multi-locus Inherited Neoplasia Allele Syndrome (MINAS). The role of each GPV is typically interpreted based on clinical phenotypes. Here, we used tumor sequencing, particularly mutational signatures, to investigate the contribution of GPVs in MUTYH and PALB2 to colorectal polyposis and breast cancer in a single patient at a molecular level. Methods We analyzed tumor sequencing data, including mutational signatures and genomic scars, of a breast tumor and a colorectal polyp from a patient with biallelic GPVs in MUTYH and a heterozygous GPV in PALB2. Results The colorectal polyp showed a dominant contribution of MUTYH-associated Base Excision Repair deficiency (BERd) mutational signatures, with no evidence of Homologous Recombination Repair Deficiency (HRD). In contrast, the breast tumor showed both MUTYH-driven BERd and HRD-associated signatures, including SBS3, ID6 and an elevated HRD score, despite the absence of a detectable second hit in PALB2. These findings suggest a differential contribution from the CSGs, with MUTYH contributing to both lesions and PALB2 contributing specifically to the breast tumor. The observed pattern does not align with the additive or synergistic models described in MINAS. Conclusions Our study provides evidence that mutational signatures can elucidate the contribution of multiple CSGs to tumorigenesis within a single patient. These findings extend current interpretations of MINAS beyond additive or synergistic phenotypes, which may help to better understand tumor etiology, with potential clinical implications, including eligibility for targeted therapies.

Vitamin D signaling has recognized roles in female reproductive physiology, but its effects at the chromatin level in endometrial stromal cells are still unclear. Here, we investigated how the active form of vitamin D, 1,25-dihydroxyvitamin D3, or calcitriol, influences the accessible chromatin landscape of human endometrial stromal cells. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) was performed on T-HESCs treated with either a vehicle or 1,25(OH)2D3. Ligand treatment increased overall chromatin accessibility, shown by higher ATAC-seq signal intensity, while causing only minor changes in the total number of called peaks. Peak annotation revealed that accessible regions were spread across both promoter-proximal and distal genomic areas. Integrating this data with CUT&RUN and RNA sequencing showed that most vitamin D-responsive cistromic modifications and transcripts were linked to nearby open chromatin, though fewer were associated with regions that were significantly differentially accessible. These results suggest that 1,25(OH)2D3-dependent transcription mainly occurs within a permissive, pre-accessible chromatin environment. This study offers new evidence that active vitamin D influences the epigenomic landscape of human endometrial stromal cells, establishing the chromatin-based molecular response to a chemically-defined VDR ligand, 1,25(OH)2D3, relevant to stromal differentiation and preparation for decidualization. HighlightsO_LIFirst evidence suggesting the direct impact of active vitamin D, 1,25-dihydroxyvitamin D3, 1,25(OH)2D3, enhanced the signal intensity of chromatin accessibility in human endometrial stromal cells C_LIO_LIMost accessible chromatin regions were shared between vehicle and ligand-treated human endometrial stromal cells C_LIO_LI1,25(OH)2D3-responsive transcription occurs largely within pre-accessible chromatin in human endometrial stromal cells C_LIO_LIAssay for transposase-accessible chromatin sequencing (ATAC-seq) defines a chromatin-level pharmacologic response to a chemically defined VDR ligand in human endometrial stromal cells C_LI

Biological sequences are known to be not random. Thus, the comparison of in silico restriction fragment distributions of random and biological sequences may be an indicator of this non-randomness. Our analyses show that for most of the tested combinations of restriction enzyme and genome sequence the fragments per Megabase of the biological sequence deviate at least more then 10% from the corresponding random sequence. This deviation goes into both directions, i.e. clearly increased values are as common as clearly decreased values. Although there is no species- or restriction-enzyme-specific effect, a clear impact of the GC content both of the restriction site and of the genome sequence can be seen. In contrast to the random sequences, the genome sequences show distinct peaks in their fragment length distributions, hinting to repetitive elements such as transposons.

BackgroundThe diagnostic yield for 46,XY disorders of sex development (DSD) remains limited. Whole-genome sequencing (WGS) improves detection of both coding and non-coding variants that may be missed by routine testing. Cytochrome b5, encoded by CYB5A, is an essential co-factor for CYP17A1-mediated 17,20-lyase activity. We report on WGS on a Vietnamese family with 46,XY DSD with two siblings presenting with female external genitalia. MethodsClinical assessment and hormone profiling were conducted. WGS was conducted on peripheral blood DNA, in two affected siblings followed by variant annotation and ACMG-based classification. A minigene RNA splicing assay in HEK293 cells was used to evaluate the functional impact of the CYB5A intronic variant. ResultsThe patients hormone profile showed low testosterone and estradiol. WGS identified compound-heterozygous CYB5A variants: a paternally inherited missense variant (p.Val34Glu, likely pathogenic) and a maternally inherited deep intronic deletion (c.129+862_129+863del) for which SpliceAI predicted aberrant splicing. Minigene assays confirmed that the intronic deletion creates cryptic splice sites, resulting in pseudoexon inclusion and a premature stop codon, consistent with nonsense-mediated decay. The intronic variant meets ACMG criteria for pathogenicity. ConclusionThis family expands the spectrum of CYB5A-related DSD and demonstrates that compound-heterozygous variants, including deep intronic defects, can lead to a disruption in 17,20-lyase activity. These findings highlight the importance of WGS and functional assays for identifying clinically relevant non-coding variants in DSD.

Gene model for the ortholog of Lst8 (Lst8) in the May 2011 (WUGSC dyak_caf1/DyakCAF1) Genome Assembly (GenBank Accession: GCA_000005975.1) of Drosophila yakuba. This ortholog was characterized as part of a developing dataset to study the evolution of the Insulin/insulin-like growth factor signaling pathway (IIS) across the genus Drosophila using the Genomics Education Partnership gene annotation protocol for Course-based Undergraduate Research Experiences.

The high efficiency of genome editing presents a challenge when modifying genes associated with viability, welfare, or fertility issues, as implementation of the technology frequently results in mosaic animals with bi-allelic mutations. Combining deactivated Cas9 (dCas9) with Cas9 has been proposed as a strategy to protect one of the two target alleles from editing. We piloted this strategy with 11 genes that are reported as homozygous lethal or associated with welfare issues. We showed that the viability of founders was significantly increased when using 80:20 or 90:10 dCas9:Cas9 ratios, whereas the 70:30 ratio did not yield an equivalent protective effect. The associated overall production rate of mutated founder per manipulated embryo was significantly higher for the 80:20 ratio. Concomitantly, an increased proportion of dCas9 was associated with a significant increase in retention of unedited target alleles but, importantly, did not hinder germline transmission. In addition, editing genes in a paralog cluster with a combination of dCas9 and Cas9 reduced unwanted off-target editing, illustrating a further potential applicability of this approach. This study defines the optimal ratio between dCas9 and Cas9 for strategies aimed at achieving mono-allelic mutations within mosaic founders and proposes a means to reduce the incidence of off-target effects in experiments with limited gRNA options.

NKCC2, localized to the apical membrane of thick ascending limb epithelial cells, is essential for renal salt handling and systemic electrolyte homeostasis. NKCC2 undergoes extensive ubiquitylation, with the E3 protein ligase Nedd4-2 implicated as a key regulator. However, progress has been limited by challenges expressing NKCC2 in mammalian cell lines, hindering mechanistic studies of NKCC2 ubiquitylation. Therefore, the aims of this study were to develop a mammalian cell model enabling mechanistic investigations of NKCC2 ubiquitylation, including the role of Nedd4-2 and the functional consequences of site-specific modification. A tetracycline-inducible MDCKI cell line was generated expressing human NKCC2 and used to assess Nedd4-2-dependent and site-specific ubiquitylation of NKCC2 using biochemical, imaging, and functional assays. The MDCKI cell line demonstrated stable, inducible expression of full-length human NKCC2. In this cell line, mutating the ubiquitylation site at K871 increased membrane abundance and uptake activity, without altering internalization rates. Nedd4-2 co-immunoprecipitated with NKCC2, and Nedd4-2 deletion increased total, but not membrane NKCC2 abundance. In summary, ubiquitylation on NKCC2 at K871 plays a key role in controlling NKCC2 membrane localization and thus function. Although Nedd4-2 can modulate NKCC2 abundance, it is not involved in NKCC2 trafficking. We conclude that the generated cell line provides a robust model for mechanistic studies of NKCC2 and will aid studies examining posttranslational regulation of NKCC2.

Nucleobindin 1 (NUCB1) is a multifunctional conserved protein located in Golgi luminal, nucleus, extracellular and cytosolic pools. NUCB1 is multidomain protein comprised of a signal peptide, a DNA-binding domain, a leucine zipper and Ca2+ -binding domain. The multiple domains and localization of NUCB1 potentiates its interactions with various partners, such as DNA, Gi3 protein, cyclooxygenase 2, LRP10 and RNA suggests its importance in the regulation of many cellular events. We revealed that NUCB1 contains three RNA-binding regions and able to interact with two RNA fragments. It was suggested possible variants of the participation of NUCB1 in the interaction of the two partially complementary RNAs. The RNA-binding properties of the NUCB1 were also confirmed in vivo experiments.

Mutations in MAP3K7 are responsible for two distinct syndromes Cardiospondylocarpofacial (CSCF) and Frontometaphyseal dysplasia 2 (FMD2). Both are characterized by skeletal malformations, facial dysmorphisms, hearing loss, and mild intellectual disability. While cardiac defects are predominant in CSCF, keloid scar is a distinct feature in FMD2. Problem with gonadal development and disorders of sexual development (DSD) have not been previously chracterized. Here we report three syndromic cases of 46,XY DSD with CSCF or FMD2, each carrying a novel heterozygous missense variants in MAP3K7 (NM_145331.3:c.250G>A; p.V84M, NM_145331.3:c.195A>G; p.I65M, and NM_145331.3: c.574A>G; p.S192G). The DSD phenotypes include cryptorchidism, micropenis, small testis, and hypospadias. In silico tools predict all three variants are deleterious. All three MAP3K7 variants occur in the kinase domain at highly conservative positions among mammals. MAP3K7 is highly expressed in human fetal Sertoli cells. MAP3K7 knock-out in HEK293T cells led to downregulation of GATA4 and FOG2 expression by RNA-Seq. Like MAP3K1, MAP3K7 phosphorylated p38 while all three MAP3K7 variants did not alter phosphorylated p38 compared to wildtype in HEK293TMAP3K7-/- cells. Two MAP3K7 missense mutants (p.V84M and p.I65M) ectopically activate ovarian beta catenin/ Wnt signalling in TOPFLASH assays. Our data suggest that MAP3K7 contributes to male sex differentiation by increasing expression of pro-testis genes GATA4 and FOG2 in HEK293TMAP3K7-/- cells and antagonizing pro-ovarian beta-catenin signalling, and that one or more of these activities were likely affected in 3 cases of 46,XY DSD with CSCF/FMD2 during sex development.

BackgroundHypertension is a highly heritable cardiovascular disorder and a major determinant of cardiometabolic disease, including diabetes. However, the regulatory genes and tissue-specific mechanisms underlying blood pressure variations remain incompletely understood. MethodsLeveraging a well-characterized prospective population-based cohort comprised of 27,308 participants from the Singapore Chinese Health Study (SCHS), we evaluated genome-wide genetic associations for five blood pressure traits: hypertension status, systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP) and pulse pressure (PP). Additionally, we conducted a transcriptome-wide association study (TWAS), integrating gene expression data from 49 tissues, followed by colocalization and fine-mapping to prioritize regulatory genes. Association of identified variants with incident diabetes was additionally evaluated in the longitudinal data. ResultsWe validated 10 blood pressure loci (P between 1.64 x 10-20 - 4.10 x 10-8) and identified an East-Asian specific splice donor variant at the COL21A1 gene associated with PP (rs149344559, P = 6.78 x 10-10). Integrative analyses prioritized FGF5 in kidney cortex and ENPEP in pituitary tissue as candidate regulatory genes. The blood pressure-lowering allele at ENPEP (T allele, rs1879056) was associated with reduced risk of incident diabetes. Mediation analysis demonstrated that approximately 21% of the genetic association with diabetes was mediated through MAP (Pindirect-effect = 2 x 10-16). ConclusionThis study refines genetic predispositions for blood pressure among East-Asians. We further delineate tissue-specific regulatory pathways underlying blood pressure variations and identify ENPEP-mediated dysfunctions linking blood pressure genetics to diabetes risk, underscoring integrated disease mechanisms.

In wheat, weak seed dormancy (SD) is related to an increased tendency for pre-harvest sprouting (PHS), which reduces yield and quality. However, the molecular mechanism underlying SD remains elusive. Here, we identified a wheat R2R3-MYB transcription factor (TaMYB83-7B) related to SD. Expression analysis showed that TaMYB83-7B was highly expressed in wheat seeds, and was more highly expressed in strong-dormancy varieties than in weak-dormancy varieties. Sequence and association analysis indicated that T/C mutations at -907 bp and -1133 bp in the TaMYB83-7B promoter were significantly associated with wheat SD, with C at both sites related to strong dormancy. Dual-luciferase reporter assays demonstrated that the transcriptional activity of the TaMYB83-7B promoter was significantly higher in strong-dormancy varieties than in weak-dormancy varieties. Further analyses indicated that TaMYB83-7B functions as a transcriptional inhibitor. Germination experiments revealed that overexpression of TaMYB83-7B significantly enhanced SD, while its loss-of-function reduced SD. Finally, TaMYB83-7B was found to regulate SD by influencing the balance between abscisic acid (ABA) and gibberellin (GA) in wheat seeds. Overall, the results of this study enhance our understanding of the complex regulatory mechanism underlying SD, and provide gene targets and molecular markers for the genetic improvement of PHS resistance in wheat.

BackgroundSickle cell disease (SCD) is the most common recessive genetic disorder, caused by pathogenic variants of the HBB gene. SCD is associated with a range of clinical manifestations, including vaso-occlusive crises, infections, and severe anaemia, which contribute to increased morbidity and mortality. The frequency of pathogenic alleles is high in Sub-Saharan African countries, with heterozygous carriers reaching up to 25% of the population. Several methods can be employed for molecular diagnostics, with HBB gene sequencing being the most precise. However, access to DNA analyses and sequencing in Low- and Middle-Income Countries (LMICs), where SCD prevalence is high, is limited. Understanding genetic profiles is crucial at both individual and population levels, as it can guide public health strategies and facilitate accurate genetic counselling. AimThis feasibility study aimed to demonstrate that a portable medical genetic laboratory (in suitcases) can be used to genotype individuals for the HBB A, S, and C alleles and their combinations within a few hours outside of a laboratory setting. Methods and resultsWe established a portable medical genetics laboratory capable of DNA extraction and isothermal DNA amplification using a commercially available kit for the A, S, and C alleles of the HBB gene. During one single study day, this portable lab was set up in a room where the Swiss Association of Patients with SCD was holding its annual meeting. We analysed the samples of 27 participants who were aware of their A, S, or C status. We collected buccal swabs and dried blood samples for genotyping. Genotype results for all participants were obtained within five hours after sample collection. In four cases, we observed discrepancies between the buccal swab and blood genotypes; three were resolved upon repeat testing, and one reflected donor chimerism following hematopoietic stem-cell transplantation. ConclusionsThis study demonstrates the feasibility and efficiency of using a portable medical genetics laboratory for rapid genotyping of HBB SCD alleles in community settings.This approach can improve access to molecular diagnostics in resource-limited environments. Such tools have the potential to significantly enhance local capabilities for genetic screening, counselling, and public health planning in regions heavily affected by SCD.

BackgroundPolycystic kidney disease (PKD) is the leading genetic cause of renal failure, resulting in the accumulation of fluid filled cysts and gross enlargement of the kidney. Mutations in PKD1 or PKD2, which encode ciliary polycystin proteins, are the most common cause of PKD. These proteins function in a cilia-dependent cyst activation (CDCA) pathway-one that requires cilia for its pro-cystic function-yet the molecular driver(s) of this pathway are unknown. ARL13B is a regulatory GTPase enriched in cilia and links to renal cystogenesis. ARL13B possesses guanine nucleotide exchange factor (GEF) activity for ARL3, another ARL with links to cilia. MethodsWe used two distinct Arl13b mouse alleles to investigate whether ARL13B is a component of the CDCA pathway: Arl13bV358Aencodes for enzymatically normal ARL13B that is undetectable in cilia, and Arl13bR79Qencodes for cilia-localized ARL13B lacking a residue critical for its ARL3 GEF activity. We used these alleles in a Pkd1-deficient adult mouse model and investigated renal morphology (H&E and cystic index analysis), physiology (blood urea nitrogen measurements), renal fibrosis (picrosirius staining and -smooth muscle actin levels), renal injury (SOX9 immunofluorescent staining and quantification), and Wnt signaling ({beta}-catenin and cyclin D1 protein levels). ResultsWe found that loss of ciliary ARL13B or mutation of a single residue critical for its ARL3 GEF activity suppressed Pkd1-dependent cysts. We observed reductions in kidney size, cystic index, and blood urea nitrogen. We also observed suppression of renal fibrosis, renal injury, and {beta}-catenin and cyclin D1 protein levels. ConclusionsOur results identified a subcellular location and mechanism driving Pkd1-dependent renal cystogenesis. We demonstrated that expression of a critical residue for ARL13Bs GEF activity specifically in cilia is a key mechanism of the CDCA pathway driving renal cystogenesis. Key PointsO_LILoss of ciliary ARL13B suppressed renal cystogenesis in an adult mouse model of polycystic kidney disease (PKD) without ablating cilia C_LIO_LILoss of ciliary ARL13B or mutation of the residue critical for its GEF activity did not affect renal morphology or physiology in a PKD mouse model C_LIO_LIMutation of a residue critical for ARL13B activation of ARL3 suppressed cystic phenotypes in Pkd1-dependent cysts C_LI

Bladder outlet obstruction leads to pathological remodeling and emergence of lower urinary tract symptoms. Although relief of obstruction is associated with symptomatic improvement, it is not universally successful, reflecting persistent alterations in the bladder. Reliable surrogate biomarkers of obstruction are lacking, particularly early in the disease course before irreversible damage to the bladder may have occurred. In this study, re-analysis of publicly available transcriptomic datasets from diverse rodent models of obstruction identified tissue transcripts including Cthrc1, Grem1, Ltbp2 and Msn that were induced in response to injury. Candidate markers were validated experimentally in an independent model of neurogenic obstruction demonstrating time-dependent changes. Candidate markers were also attenuated with either surgical removal of obstruction or treatment with anticholinergic medication or inosine. Integrated analysis of tissue transcriptomics data and tissue and urine proteomics data from a model of neurogenic obstruction revealed significant concordance between markers observed in tissue and urine. Urinary proteomics analysis identified a statistically significant increase in MSN in patients with neurogenic bladder compared to unaffected controls. These findings identify tissue and urine biomarkers of both non-neurogenic and neurogenic obstruction that may reflect early changes in obstructive uropathy that could be monitored in a non-invasive manner.