Genome-wide Studies Research Articles

Merkel cell polyomavirus small tumor antigen contributes to immune evasion by interfering with type I interferon signaling.

Merkel cell polyomavirus (MCPyV) is the causative agent of the majority of Merkel cell carcinomas (MCC). The virus has limited coding capacity, with its early viral proteins, large T (LT) and small T (sT), being multifunctional and contributing to infection and transformation. A fundamental difference in early viral gene expression between infection and MCPyV-driven tumorigenesis is the expression of a truncated LT (LTtr) in the tumor. In contrast, sT is expressed in both conditions and contributes significantly to oncogenesis. Here, we identified novel functions of early viral proteins by performing genome-wide transcriptome and chromatin studies in primary human fibroblasts. Due to current limitations in infection and tumorigenesis models, we mimic these conditions by ectopically expressing sT, LT or LTtr, individually or in combination, at different time points. In addition to its known function in cell cycle and inflammation modulation, we reveal a fundamentally new function of sT. We show that sT regulates the type I interferon (IFN) response downstream of the type I interferon receptor (IFNAR) by interfering with the interferon-stimulated gene factor 3 (ISGF3)-induced interferon-stimulated gene (ISG) response. Expression of sT leads to a reduction in the expression of interferon regulatory factor 9 (IRF9) which is a central component of the ISGF3 complex. We further show that this function of sT is conserved in BKPyV. We provide a first mechanistic understanding of which early viral proteins trigger and control the type I IFN response, which may influence MCPyV infection, persistence and, during MCC progression, regulation of the tumor microenvironment.

A Systems Biology Analysis of Chronic Lymphocytic Leukemia

Whole-genome sequencing has revealed that TP53, NOTCH1, ATM, SF3B1, BIRC3, ABL, NXF1, BCR, and ZAP70 are often mutated in CLL, but not consistently across all CLL patients. This paper employs a statistical thermodynamics approach in combination with the systems biology of the CLL protein–protein interaction networks to identify the most significant participant proteins in the cancerous transformation. Betti number (a topology of complexity) estimates highlight a protein hierarchy, primarily in the Wnt pathway known for aberrant CLL activation. These individually identified proteins suggest a network-targeted strategy over single-target drug development. The findings advocate for a multi-target inhibition approach, limited to several key proteins to minimize side effects, thereby providing a foundation for designing therapies. This study emphasizes a shift towards a comprehensive, multi-scale analysis to enhance personalized treatment strategies for CLL, which could be experimentally validated using siRNA or small-molecule inhibitors. The result is not just the identification of these proteins but their rank-order, offering a potent signal amplification in the context of the 20,000 proteins produced by the human body, thus providing a strategic basis for therapeutic intervention in CLL, underscoring the necessity for a more holistic, cellular, chromosomal, and genome-wide study to develop tailored treatments for CLL patients.

The pathogenesis of gout: molecular insights from genetic, epigenomic and transcriptomic studies.

The pathogenesis of gout involves a series of steps beginning with hyperuricaemia, followed by the deposition ofmonosodium urate crystal in articular structures and culminating in an innate immune response, mediated by the NLRP3 inflammasome, to the deposited crystals. Large genome-wide association studies (GWAS) of serum urate levels initially identified the genetic variants with thestrongest effects, mapping mainlyto genes that encode urate transporters in the kidney and gut. Other GWAS highlighted the importance of uncommon genetic variants. More recently, genetic and epigenetic genome-wide studies have revealed new pathways in the inflammatory process of gout, including genetic associations with epigenomic modifiers. Epigenome-wide association studies are also implicating epigenomic remodelling in gout, which perhaps regulates the responsiveness of the innate immune system to monosodium urate crystals. Notably, genes implicated in gout GWAS do not include those encodingcomponents of the NLRP3 inflammasome itself, but instead include genes encoding moleculesinvolved in its regulation. Knowledge of the molecular mechanisms underlying gout has advanced through the translation of genetic associations into specific molecular mechanisms. Notable examples include ABCG2, HNF4A, PDZK1, MAF and IL37. Current genetic studies are dominated by participants of European ancestry; however, studies focusing on other population groups are discovering informative population-specific variants associated with gout.

Genome-wide investigation of the OR gene family in Helicoverpa armigera and functional analysis of OR48 and OR75 in metamorphosis development

The cotton bollworm, Helicoverpa armigera, is a significant global agricultural pest, particularly detrimental during its larval feeding period. Insects' odorant receptors (ORs) are crucial for their crop-feeding activities, yet a comprehensive analysis of H. armigera ORs has been lacking, and the influence of hormones on ORs remain understudied. Herein, we conducted a genome-wide study and identified 81 ORs, categorized into 15 distinct groups. Analyses of protein motifs and gene structures revealed both conservation within groups and divergence among them. Comparative gene duplication analysis between H. armigera and Bombyx mori highlighted different duplication patterns. We further investigated subcellular localization and protein interactions within the odorant receptor family, providing valuable insights for future functional and interaction studies of ORs. Specifically, we identified that OR48 and OR75 were abundantly expressed during molting/metamorphosis and feeding stages, respectively. We demonstrated that 20E induced the upregulation of OR48 via EcR, while insulin upregulated OR75 expression through InR. Moreover, 20E induced the translocation of OR48 to the cell membrane, mediating its effects. Functional studies involving the knockdown of OR48 and OR75 revealed their roles in metamorphosis development, with OR48 knockdown resulting in delayed pupation and OR75 knockdown leading to premature pupation. OR48 can promote autophagy and apoptosis in fat body, while OR75 can significantly inhibit apoptosis and autophagy. These findings significantly contribute to our understanding of OR function in H. armigera and shed light on potential avenues for pest control strategies.

KDM6A regulates immune response genes in multiple myeloma

AbstractThe histone H3 at lysine 27 (H3K27) demethylase lysine demethylase 6A (KDM6A) is a tumor suppressor in multiple cancers, including multiple myeloma (MM). We created isogenic MM cells disrupted for KDM6A and tagged the endogenous protein to facilitate genome-wide studies. KDM6A binds genes associated with immune recognition and cytokine signaling. Most importantly, KDM6A binds and activates NLRC5 and CIITA, which encode regulators of major histocompatibility complex genes. Patient data indicate that NLRC5 and CIITA are downregulated in MM with low KDM6A expression. Chromatin analysis shows that KDM6A binds poised and active enhancers and KDM6A loss led to decreased H3K27ac at enhancers, increased H3K27me3 levels in body of genes bound by KDM6A, and decreased gene expression. Reestablishing histone acetylation with an HDAC3 inhibitor leads to upregulation of major histocompatibility complex expression, offering a strategy to restore immunogenicity of KDM6A-deficient tumors. Loss of Kdm6a in Kirsten rat sarcoma virus (K-RAS)-transformed murine fibroblasts led to increased growth in vivo associated with decreased T-cell infiltration.

Causal associations among gut microbiota, 1400 plasma metabolites, and asthma: a two-sample Mendelian randomization study.

Emerging evidence indicates a correlation between imbalances in intestinal microbiota and changes in plasma metabolites in the progression of asthma. However, the causal link between these factors remains unclear. A two-sample Mendelian randomization (MR) study was employed to evaluate the potential causal connection between gut microbiota, plasma metabolites, and asthma susceptibility. Gut microbiota data from expansive genome-wide genotype studies and 16S fecal microbiome datasets were examined by the MiBioGen Alliance. Asthma data were procured from the FinnGen biobank analysis, while comprehensive Genome-Wide Association Studies (GWAS) summary statistics for plasma metabolites were derived from the NHGRI-EBI GWAS Catalog. Fluctuations in intestinal flora and plasma metabolites in asthma patients were evaluated using the weighted mode method. Additionally, pleiotropic and heterogeneity analyses were performed to ascertain the reliability of the findings. Upon examining the gut microbiota through MR with the IVW method, alongside tests for heterogeneity and pleiotropy, findings reveal a negative association between the abundance of the Christensenellaceae R.7 group and asthma risk. In contrast, the Bifidobacterium and Prevotella 7 genera exhibit a positive association with asthma risk, indicating they may be potential risk factors (p < 0.05). Furthermore, MR analysis of 1,400 metabolites employing Weighted median, IVW, and Weighted mode methods resulted in p-values below 0.05. Subsequent tests for pleiotropy and heterogeneity showed that the levels of 3,5-dichloro-2,6-dihydroxybenzoic acid have a negative correlation with asthma, whereas the phenylalanine to phosphate ratio has a positive correlation, suggesting their potential as risk factors for asthma (p < 0.05). The current Mendelian randomization study provides evidence supporting a potential causal link between specific gut microbiota taxa, plasma metabolites, and asthma. These findings offer novel perspectives for future research and the development of treatment and prevention strategies for asthma.

Genome-wide study of UDP-glycosyltransferases gene family in Cannabis sativa.

The online version contains supplementary material available at 10.1007/s13205-024-04025-3.

MIAMI-AD (Methylation in Aging and Methylation in AD): an integrative knowledgebase that facilitates explorations of DNA methylation across sex, aging, and Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur specifically in each sex. We created MIAMI-AD, a comprehensive knowledgebase containing manually curated summary statistics from 98 published tables in 38 studies, all of which included at least 100 participants. MIAMI-AD enables easy browsing, querying, and downloading DNAm associations at multiple levels-at individual CpG, gene, genomic regions, or genome-wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI-AD facilitates our understanding of age-associated CpGs in AD and the sex-specific roles of DNAm in AD. This open-access resource is freely available to the research community, and all the underlying data can be downloaded. MIAMI-AD facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD. Database URL: https://miami-ad.org/.

Chromosome X-Wide Common Variant Association Study (XWAS) in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD. The "female protective effect" in ASD suggests that females may require a higher genetic burden to manifest similar symptoms as males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leave them underrepresented in genome-wide studies. Here, we conducted an X chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Cohort SSC, and Simons Foundation Powering Autism Research SPARK, alongside 8,981 population controls (43% males). We analyzed 418,652 X-chromosome variants, identifying 59 associated with ASD (p-values 7.9×10-6 to 1.51×10-5), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on chrXp22.2 (lead SNP=rs12687599, p=3.57×10-7) harboring ASB9/ASB11, and another encompassing DDX53/PTCHD1-AS long non-coding RNA (lead SNP=rs5926125, p=9.47×10-6). When mapping genes within 10kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, SH3KBP1). FGF13 emerged as a novel X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant new insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation.

Causal relationship between type 2 diabetes and glioblastoma: bidirectional Mendelian randomization analysis

As the prevalence of Type 2 Diabetes Mellitus (T2DM) and Glioblastoma (GBM) rises globally, the relationship between T2DM and GBM remains controversial. This study aims to investigate whether genetically predicted T2DM is causally associated with GBM. We performed bidirectional Mendelian randomization (MR) analysis using data from genome-wide studies on T2DM (N = 62,892) and GBM (N = 218,792) in European populations. The results of the inverse-variance weighted (IVW) approach served as the primary outcomes. We applied Cochran’s Q test and MR-Egger regression for heterogeneity assessment. Leave-one-out analysis was used to evaluate whether any single SNP significantly influenced the observed effect. Our findings reveal a significant causal association between T2DM and an increased risk of GBM (OR [95% CI] 1.70 [1.09, 2.65], P = 0.019). Conversely, the reverse association between T2DM and GBM was insignificant (OR [95% CI] 1.00 [0.99, 1.01], P = 0.408) (P > 0.40). Furthermore, the results from Cochran’s Q-test and funnel plots in the MR-Egger method indicated no evidence of pleiotropy between the SNPs and GBM. Additionally, we mapped causal SNPs to genes and identified 10 genes, including MACF1, C1orf185, PTGFRN, NOTCH2, ABCB10, GCKR, THADA, RBMS1, SPHKAP, and PPARG, located on chromosomes 1, 2, and 3. These genes are involved in key biological processes such as the BMP signaling pathway and various metabolic pathways relevant to both conditions. This study provides robust evidence of a significant causal relationship between T2DM and an increased risk of GBM. The identified SNP-mapped genes highlight potential biological mechanisms underlying this association.

Childhood-onset type 1 diabetes and subsequent adult psychiatric disorders: a nationwide cohort and genome-wide Mendelian randomization study

Childhood-onset type 1 diabetes (T1D) is associated with substantial psychiatric morbidity in later life, but it remains unknown whether these associations are due to common underlying biological mechanisms or the impacts of living with the condition and its treatment. Here, using Czech national register data, we identified children with T1D aged ≤14 years between 1994 and 2007 and estimated the risk of psychiatric disorders up to 24 years later. We found that children diagnosed with T1D had an elevated risk of developing substance use, mood, anxiety and personality disorders, and behavioral syndromes. Conversely, we found that children with T1D had a lower risk of developing psychotic disorders. In Mendelian randomization analysis, we found an association with schizophrenia, which, however, did not persist following multiple testing adjustment. The combined observational and Mendelian randomization evidence suggests that T1D diagnosis in childhood predisposes to far-reaching, extensive psychiatric morbidity, which is unlikely to be explicable by common underlying biological mechanisms. The findings of this study highlight that monitoring and addressing the mental health needs of children with T1D is imperative, whereas glucose dysregulation and/or inflammation implicated in schizophrenia pathogenesis warrants future research.

Shared genetic correlations between kidney diseases and sepsis.

Clinical studies have indicated a comorbidity between sepsis and kidney diseases. Individuals with specific mutations that predispose them to kidney conditions are also at an elevated risk for developing sepsis, and vice versa. This suggests a potential shared genetic etiology that has not been fully elucidated. Summary statistics data on exposure and outcomes were obtained from genome-wide association meta-analysis studies. We utilized these data to assess genetic correlations, employing a pleiotropy analysis method under the composite null hypothesis to identify pleiotropic loci. After mapping the loci to their corresponding genes, we conducted pathway analysis using Generalized Gene-Set Analysis of GWAS Data (MAGMA). Additionally, we utilized MAGMA gene-test and eQTL information (whole blood tissue) for further determination of gene involvement. Further investigation involved stratified LD score regression, using diverse immune cell data, to study the enrichment of SNP heritability in kidney-related diseases and sepsis. Furthermore, we employed Mendelian Randomization (MR) analysis to investigate the causality between kidney diseases and sepsis. In our genetic correlation analysis, we identified significant correlations among BUN, creatinine, UACR, serum urate, kidney stones, and sepsis. The PLACO analysis method identified 24 pleiotropic loci, pinpointing a total of 28 nearby genes. MAGMA gene-set enrichment analysis revealed a total of 50 pathways, and tissue-specific analysis indicated significant enrichment of five pairs of pleiotropic results in kidney tissue. MAGMA gene test and eQTL information (whole blood tissue) identified 33 and 76 pleiotropic genes, respectively. Notably, genes PPP2R3A for BUN, VAMP8 for UACR, DOCK7 for creatinine, and HIBADH for kidney stones were identified as shared risk genes by all three methods. In a series of immune cell-type-specific enrichment analyses of pleiotropy, we identified a total of 37 immune cells. However, MR analysis did not reveal any causal relationships among them. This study lays the groundwork for shared etiological factors between kidney and sepsis. The confirmed pleiotropic loci, shared pathogenic genes, and enriched pathways and immune cells have enhanced our understanding of the multifaceted relationships among these diseases. This provides insights for early disease intervention and effective treatment, paving the way for further research in this field.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

Prioritizing drug targets in systemic lupus erythematosus from a genetic perspective: a druggable genome-wide Mendelian randomization study

ObjectivesSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with an unsatisfactory state of treatment. We aim to explore novel targets for SLE from a genetic standpoint. MethodsCis-expression quantitative trait loci (eQTLs) for whole blood from 31,684 samples provided by the eQTLGen Consortium as well as two large SLE cohorts were utilized for screening and validating genes causally associated with SLE. Colocalization analysis was employed to further investigate whether changes in the expression of risk genes, as indicated by GWAS signals, influence the occurrence and development of SLE. Targets identified for drug development were evaluated for potential side effects using a phenome-wide association study (PheWAS). Based on the multiple databases, we explored the interactions between drugs and genes for drug prediction and the assessment of current medications.ResultsThe analysis comprised 5427 druggable genes in total. The two-sample Mendelian randomization (MR) in the discovery phase identified 20 genes causally associated with SLE and validated 8 genes in the replication phase. Colocalization analysis ultimately identified five genes (BLK, HIST1H3H, HSPA1A, IL12A, NEU1) with PPH4 > 0.8. PheWAS further indicated that drugs acting on BLK and IL12A are less likely to have potential side effects, while HSPA1A and NEU1 were associated with other traits. Four genes (BLK, HSPA1A, IL12A, NEU1) have been targeted for drug development in autoimmune diseases and other conditions.Conclusions.This study identified five genes as therapeutic targets for SLE. Repurposing and developing drugs targeting these genes is anticipated to improve the existing treatment state for SLE.Key Points• We identified five gene targets of priority for the treatment of SLE, with BLK and IL12A indicating fewer side effects.• Among the existing drugs that target these candidate genes, Ustekinumab, Ebdarokimab, and Briakinumab (targeting the IL12 gene) and CD24FC (targeting HSPA1A) may potentially be repurposed for the treatment of SLE.

Characterising the genetic architecture of changes in adiposity during adulthood using electronic health records

Obesity is a heritable disease, characterised by excess adiposity that is measured by body mass index (BMI). While over 1,000 genetic loci are associated with BMI, less is known about the genetic contribution to adiposity trajectories over adulthood. We derive adiposity-change phenotypes from 24.5 million primary-care health records in over 740,000 individuals in the UK Biobank, Million Veteran Program USA, and Estonian Biobank, to discover and validate the genetic architecture of adiposity trajectories. Using multiple BMI measurements over time increases power to identify genetic factors affecting baseline BMI by 14%. In the largest reported genome-wide study of adiposity-change in adulthood, we identify novel associations with BMI-change at six independent loci, including rs429358 (APOE missense variant). The SNP-based heritability of BMI-change (1.98%) is 9-fold lower than that of BMI. The modest genetic correlation between BMI-change and BMI (45.2%) indicates that genetic studies of longitudinal trajectories could uncover novel biology of quantitative traits in adulthood.

Genomic co-localization of variation affecting agronomic and human gut microbiome traits in a meta-analysis of diverse sorghum.

Substantial functional metabolic diversity exists within species of cultivated grain crops that directly or indirectly provide more than half of all calories consumed by humans around the globe. While such diversity is the molecular currency used for improving agronomic traits, diversity is poorly characterized for its effects on human nutrition and utilization by gut microbes. Moreover, we know little about agronomic traits' potential tradeoffs and pleiotropic effects on human nutritional traits. Here, we applied a quantitative genetics approach using a meta-analysis and parallel genome-wide association studies of Sorghum bicolor traits describing changes in the composition and function of human gut microbe communities, and any of 200 sorghum seed and agronomic traits across a diverse sorghum population to identify associated genetic variants. A total of 15 multiple-effect loci (MEL) were initially found where different alleles in the sorghum genome produced changes in seed that affected the abundance of multiple bacterial taxa across 2 human microbiomes in automated in vitro fermentations. Next, parallel genome-wide studies conducted for seed, biochemical, and agronomic traits in the same population identified significant associations within the boundaries of 13/15 MEL for microbiome traits. In several instances, the colocalization of variation affecting gut microbiome and agronomic traits provided hypotheses for causal mechanisms through which variation could affect both agronomic traits and human gut microbes. This work demonstrates that genetic factors affecting agronomic traits in sorghum seed can also drive significant effects on human gut microbes, particularly bacterial taxa considered beneficial. Understanding these pleiotropic relationships will inform future strategies for crop improvement toward yield, sustainability, and human health.

Androgen receptor-mediated pharmacogenomic expression quantitative trait loci: implications for breast cancer response to AR-targeting therapy

BackgroundEndocrine therapy is the most important treatment modality of breast cancer patients whose tumors express the estrogen receptor α (ERα). The androgen receptor (AR) is also expressed in the vast majority (80–90%) of ERα-positive tumors. AR-targeting drugs are not used in clinical practice, but have been evaluated in multiple trials and preclinical studies.MethodsWe performed a genome-wide study to identify hormone/drug-induced single nucleotide polymorphism (SNP) genotype - dependent gene-expression, known as PGx-eQTL, mediated by either an AR agonist (dihydrotestosterone) or a partial antagonist (enzalutamide), utilizing a previously well characterized lymphoblastic cell line panel. The association of the identified SNPs-gene pairs with breast cancer phenotypes were then examined using three genome-wide association (GWAS) studies that we have published and other studies from the GWAS catalog.ResultsWe identified 13 DHT-mediated PGx-eQTL loci and 23 Enz-mediated PGx-eQTL loci that were associated with breast cancer outcomes post ER antagonist or aromatase inhibitors (AI) treatment, or with pharmacodynamic (PD) effects of AIs. An additional 30 loci were found to be associated with cancer risk and sex-hormone binding globulin levels. The top loci involved the genes IDH2 and TMEM9, the expression of which were suppressed by DHT in a PGx-eQTL SNP genotype-dependent manner. Both of these genes were overexpressed in breast cancer and were associated with a poorer prognosis. Therefore, suppression of these genes by AR agonists may benefit patients with minor allele genotypes for these SNPs.ConclusionsWe identified AR-related PGx-eQTL SNP-gene pairs that were associated with risks, outcomes and PD effects of endocrine therapy that may provide potential biomarkers for individualized treatment of breast cancer.

Clusters of mammalian conserved RNA structures in UTRs associate with RBP binding sites.

RNA secondary structures play essential roles in the formation of the tertiary structure and function of a transcript. Recent genome-wide studies highlight significant potential for RNA structures in the mammalian genome. However, a major challenge is assigning functional roles to these structured RNAs. In this study, we conduct a guilt-by-association analysis of clusters of computationally predicted conserved RNA structure (CRSs) in human untranslated regions (UTRs) to associate them with gene functions. We filtered a broad pool of ∼500 000 human CRSs for UTR overlap, resulting in 4734 and 24 754 CRSs from the 5' and 3' UTR of protein-coding genes, respectively. We separately clustered these CRSs for both sets using RNAscClust, obtaining 793 and 2403 clusters, each containing an average of five CRSs per cluster. We identified overrepresented binding sites for 60 and 43 RNA-binding proteins co-localizing with the clustered CRSs. Furthermore, 104 and 441 clusters from the 5' and 3' UTRs, respectively, showed enrichment for various Gene Ontologies, including biological processes such as 'signal transduction', 'nervous system development', molecular functions like 'transferase activity'and the cellular components such as 'synapse' among others. Our study shows that significant functional insights can be gained by clustering RNA structures based on their structural characteristics.

Diversity, abundance, and domain architecture of plant NLR proteins in Fabaceae

The resistance (R) gene family in plants is a vital component of the plant defense system, enabling host resistance against pathogens through interactions with pathogen effector proteins. These R genes often encode nucleotide-binding (NB-ARC or N) and leucine-rich-repeat (LRR or L) domains, collectively forming the NLR protein family. The NLR proteins have been widely explored in crops from Poaceae and Brassicaceae, but limited studies are available for crops in other families, including Fabaceae. To address this gap, we conducted a comprehensive genome-wide analysis of putative NLR proteins in nine Fabaceae crops, including Glycine max, Lupinus angustifolius, Medicago truncatula, Pisum sativum, Phaseolus vulgaris, Trifolium pratense, Vigna angularis, Vigna radiata, and Vigna unguiculata. Our study revealed a substantial variation in the number of NLR proteins, independent of genome size. Notably, the NB-ARC domain exhibited a preferential co-occurrence with a specific LRR domain (IPR001611) in Fabaceae. Furthermore, through protein signature analysis, we identified both species-specific and shared domains across the nine crops. By classifying the identified proteins into seven distinct classes (N, L, CN, TN, NL, CNL, and TNL), we observed species-specific clustering within the CN, TN, and CNL classes, reflecting the diversification of species within Fabaceae. This genome-wide study enhances our understanding of the NLR protein repertoire and comprehensive protein signatures in nine Fabaceae species and provides valuable insights into plant defense mechanisms.

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

Lung adenocarcinoma (LUAD) among never-smokers is a public health burden especially prevalent in East Asian (EAS) women. Polygenic risk scores (PRSs), which quanefy geneec suscepebility, are promising for straefying risk, yet have mainly been developed in European (EUR) populaeons. We developed and validated single-and mule-ancestry PRSs for LUAD in EAS never-smokers, using the largest available genome-wide associaeon study (GWAS) dataset. We used GWAS summary staesecs from both EAS (8,002 cases; 20,782 controls) and EUR (2,058 cases; 5,575 controls) populaeons, as well as independent EAS individual level data. We evaluated several PRSs approaches: a single-ancestry PRS using 25 variants that reached genome-wide significance (PRS-25), a genome-wide Bayesian based approach (LDpred2), and a mule-ancestry approach that models geneec correlaeons across ancestries (CT-SLEB). PRS performance was evaluated based on the associaeon with LUAD and AUC values. We then esemated the lifeeme absolute risk of LUAD (age 30-80) and projected the AUC at different sample sizes using EAS-derived effect-size distribueon and heritability esemates. The CT-SLEB PRS showed a strong associaeon with LUAD risk (odds raeo=1.71, 95% confidence interval (CI): 1.61, 1.82) with an AUC of 0.640 (95% CI: 0.629, 0.653). Individuals in the 95 th percenele of the PRS had an esemated 6.69% lifeeme absolute risk of LUAD. Comparison of LUAD risk between individuals in the highest and lowest 20% PRS quaneles revealed a 3.92-fold increase. Projeceon analyses indicated that achieving an AUC of 0.70, which approaches the maximized prediceon poteneal of the PRS given the esemated geneec variance, would require a future study encompassing 55,000 EAS LUAD cases with a 1:10 case-control raeo. Our study underscores the poteneal of mule-ancestry PRS approaches to enhance LUAD risk straeficaeon in never-smokers, parecularly in EAS populaeons, and highlights the necessary scale of future research to uncover the geneec underpinnings of LUAD.