Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy.

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype-phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10-3), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10-131). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype-phenotype screens in diverse populations.

Emerging roles of RNA-binding proteins in fatty liver disease.

A rampant and urgent global health issue of the 21st century is the emergence and progression of fatty liver disease (FLD), including alcoholic fatty liver disease and the more heterogenous metabolism-associated (or non-alcoholic) fatty liver disease (MAFLD/NAFLD) phenotypes. These conditions manifest as disease spectra, progressing from benign hepatic steatosis to symptomatic steatohepatitis, cirrhosis, and, ultimately, hepatocellular carcinoma. With numerous intricately regulated molecular pathways implicated in its pathophysiology, recent data have emphasized the critical roles of RNA-binding proteins (RBPs) in the onset and development of FLD. They regulate gene transcription and post-transcriptional processes, including pre-mRNA splicing, capping, and polyadenylation, as well as mature mRNA transport, stability, and translation. RBP dysfunction at every point along the mRNA life cycle has been associated with altered lipid metabolism and cellular stress response, resulting in hepatic inflammation and fibrosis. Here, we discuss the current understanding of the role of RBPs in the post-transcriptional processes associated with FLD and highlight the possible and emerging therapeutic strategies leveraging RBP function for FLD treatment. This article is categorized under: RNA in Disease and Development > RNA in Disease.

Mapping QTL controlling count traits with excess zeros and ones using a zero-and-one-inflated generalized Poisson regression model.

The research on the quantitative trait locus (QTL) mapping of count data has aroused the wide attention of researchers. There are frequent problems in applied research that limit the application of the conventional Poisson model in the analysis of count phenotypes, which include the overdispersion and excess zeros and ones. In this article, a novel model, that is, the zero-and-one-inflated generalized Poisson (ZOIGP) model, is proposed to deal with these problems. Based on the proposed model, a score test is performed for the inflation parameter, in which the ZOIGP model with a constant proportion of excess zeros and ones is compared with a standard generalized Poisson model. To illustrate the practicability of the ZOIGP model, we extend it to the QTL interval mapping application that underpins count phenotype with excess zeros and excess ones. The genetic effects are estimated utilizing the expectation-maximization algorithm embedded with the Newton-Raphson algorithm, and the genome-wide scan and likelihood ratio test is performed to map and test the potential QTLs. The statistical properties exhibited by the proposed method are investigated through simulation. Finally, a real data analysis example is used to illustrate the utility of the proposed method for QTL mapping.

Mendelian Causes of Autoimmunity: the Lupus Phenotype.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci. In the early 70s, complement deficiencies led to the description of familial forms of SLE caused by a single gene defect. High-throughput sequencing has recently identified an increasing number of monogenic defects associated with lupus, shaping the concept of monogenic lupus and enhancing our insights into immune tolerance mechanisms. Monogenic lupus (moSLE) should be suspected in patients with either early-onset lupus or syndromic lupus, in male, or in familial cases of lupus. This review discusses the genetic basis of monogenic SLE and proposes its classification based on disrupted pathways. These pathways include defects in the clearance of apoptotic cells or immune complexes, interferonopathies, JAK-STATopathies, TLRopathies, and T and B cell dysregulations.

Exploring the origin of a unique mutant allele in twin-tail goldfish using CRISPR/Cas9 mutants.

Artificial selection has been widely applied to genetically fix rare phenotypic features in ornamental domesticated animals. For many of these animals, the mutated loci and alleles underlying rare phenotypes are known. However, few studies have explored whether these rare genetic mutations might have been fixed due to competition among related mutated alleles or if the fixation occurred due to contingent stochastic events. Here, we performed genetic crossing with twin-tail ornamental goldfish and CRISPR/Cas9-mutated goldfish to investigate why only a single mutated allele-chdS with a E127X stop codon (also called chdAE127X)-gives rise to the twin-tail phenotype in the modern domesticated goldfish population. Two closely related chdS mutants were generated with CRISPR/Cas9 and compared with the E127X allele in F2 and F3 generations. Both of the CRISPR/Cas9-generated alleles were equivalent to the E127X allele in terms of penetrance/expressivity of the twin-tail phenotype and viability of carriers. These findings indicate that multiple truncating mutations could have produced viable twin-tail goldfish. Therefore, the absence of polymorphic alleles for the twin-tail phenotype in modern goldfish likely stems from stochastic elimination or a lack of competing alleles in the common ancestor. Our study is the first experimental comparison of a singular domestication-derived allele with CRISPR/Cas9-generated alleles to understand how genetic fixation of a unique genotype and phenotype may have occurred. Thus, our work may provide a conceptual framework for future investigations of rare evolutionary events in domesticated animals.

Individuals vary in their overt attention preference for positive images consistently across time and stimulus types.

What humans look at strongly determines what they see. We show that individual differences in the tendency to look at positive stimuli are stable across time and across contents, establishing gaze positivity preference as a perceptual trait that determines the amount of positively valence stimuli individuals select for visual processing. Furthermore, we show that patients with major depressive disorder exhibit consistently low positivity preference before treatment. In a subset of patients, we also assessed the positivity preference after two months of treatment in which positivity gaze preference increased to levels similar to healthy individuals. We discuss the possible practical diagnostic applications of these findings, as well as how this general gaze-related trait may influence other behavioral and psychological aspects.

StCoExpNet: a global co-expression network analysis facilitates identifying genes underlying agronomic traits in potatoes.

KEY MESSAGE: We constructed a gene expression atlas and co-expression network for potatoes and identified several novel genes associated with various agronomic traits. This resource will accelerate potato genetics and genomics research. Potato (Solanum tuberosum L.) is the world's most crucial non-cereal food crop and ranks third in food production after wheat and rice. Despite the availability of several potato transcriptome datasets at public databases like NCBI SRA, an effort has yet to be put into developing a global transcriptome atlas and a co-expression network for potatoes. The objectives of our study were to construct a global expression atlas for potatoes using publicly available transcriptome datasets, identify housekeeping and tissue-specific genes, construct a global co-expression network and identify co-expression clusters, investigate the transcriptional complexity of genes involved in various essential biological processes related to agronomic traits, and provide a web server (StCoExpNet) to easily access the newly constructed expression atlas and co-expression network to investigate the expression and co-expression of genes of interest. In this study, we used data from 2299 publicly available potato transcriptome samples obtained from 15 different tissues to construct a global transcriptome atlas. We found that roughly 87% of the annotated genes exhibited detectable expression in at least one sample. Among these, we identified 281 genes with consistent and stable expression levels, indicating their role as housekeeping genes. Conversely, 308 genes exhibited marked tissue-specific expression patterns. We exemplarily linked some co-expression clusters to important agronomic traits of potatoes, such as self-incompatibility, anthocyanin biosynthesis, tuberization, and defense responses against multiple pathogens. The dataset compiled here constitutes a new resource (StCoExpNet), which can be accessed at https://stcoexpnet.julius-kuehn.de . This transcriptome atlas and the co-expression network will accelerate potato genetics and genomics research.

Optimizing selection based on BLUPs or BLUEs in multiple sets of genotypes differing in their population parameters.

KEY MESSAGE: Selection response in truncation selection across multiple sets of candidates hinges on their post-selection proportions, which can deviate grossly from their initial proportions. For BLUPs, using a uniform threshold for all candidates maximizes the selection response, irrespective of differences in population parameters. Plant breeding programs typically involve multiple families from either the same or different populations, varying in means, genetic variances and prediction accuracy of BLUPs or BLUEs for true genetic values (TGVs) of candidates. We extend the classical breeder's equation for truncation selection from single to multiple sets of genotypes, indicating that the expected overall selection response ( Δ G Tot ) for TGVs depends on the selection response within individual sets and their post-selection proportions. For BLUEs, we show that maximizing Δ G Tot requires thresholds optimally tailored for each set, contingent on their population parameters. For BLUPs, we prove that Δ G Tot is maximized by applying a uniform threshold across all candidates from all sets. We provide explicit formulas for the origin of the selected candidates from different sets and show that their proportions before and after selection can differ substantially, especially for sets with inferior properties and low proportion. We discuss implications of these results for (a) optimum allocation of resources to training and prediction sets and (b) the need to counteract narrowing the genetic variation under genomic selection. For genomic selection of hybrids based on BLUPs of GCA of their parent lines, selecting distinct proportions in the two parent populations can be advantageous, if these differ substantially in the variance and/or prediction accuracy of GCA. Our study sheds light on the complex interplay of selection thresholds and population parameters for the selection response in plant breeding programs, offering insights into the effective resource management and prudent application of genomic selection for improved crop development.

Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.

Background: This study aimed to characterize the clinical phenotype and genetic variations in patients with Kallmann syndrome (KS). Methods: This study involved the collection and analysis of clinical data from an individual with sporadic KS. Following this, peripheral blood samples were obtained from the patient and his parents. Genomic deoxyribonucleic acid was extracted and subjected to whole-exome sequencing and genomic copy number variation (CNV) detection. Finally, Sanger sequencing was performed to validate the suspected pathogenic variants. Results: Whole-exome sequencing confirmed that the child carried both the IL17RD variant (c.2101G>A, p.Gly701Ser) inherited from the mother and the new CPEB4 variant (c.1414C>T, p.Arg472*). No pathogenic CNVs were identified in CNV testing. Conclusion: Bioinformatics analysis shows that the IL17RD protein undergoing Gly701Ser mutation and is speculated to be phosphorylated and modified, thereby disrupting fibroblast growth factor signaling. This study also suggested that the CPEB4 might play a crucial role in the key signaling process affecting olfactory bulb morphogenesis. Overall, the findings of this study broaden the gene expression profile of KS-related pathogenic genes. This offers a new avenue for exploring the pathogenic mechanism of KS and provides valuable insights for precise clinical diagnosis and treatment strategies for this condition.

TGIF2 is a potential biomarker for diagnosis and prognosis of glioma.

Background: TGFB-induced factor homeobox 2 (TGIF2), a member of the Three-Amino-acid-Loop-Extension (TALE) superfamily, has been implicated in various malignant tumors. However, its prognostic significance in glioma, impact on tumor immune infiltration, and underlying mechanisms in glioma development remain elusive. Methods: The expression of TGIF2 in various human normal tissues, normal brain tissues, and gliomas was investigated using HPA, TCGA, GTEx, and GEO databases. The study employed several approaches, including Kaplan-Meier analysis, ROC analysis, logistic regression, Cox regression, GO analysis, KEGG analysis, and GSEA, to explore the relationship between TGIF2 expression and clinicopathologic features, prognostic value, and potential biological functions in glioma patients. The impact of TGIF2 on tumor immune infiltration was assessed through Estimate, ssGSEA, and Spearman analysis. Genes coexpressed with TGIF2 were identified, and the protein-protein interaction (PPI) network of these coexpressed genes were constructed using the STRING database and Cytoscape software. Hub genes were identified using CytoHubba plugin, and their clinical predictive value was explored. Furthermore, in vitro experiments were performed by knocking down and knocking out TGIF2 using siRNA and CRISPR/Cas9 gene editing, and the role of TGIF2 in glioma cell invasion and migration was analyzed using transwell assay, scratch wound-healing assay, RT-qPCR, and Western blot. Results: TGIF2 mRNA was found to be upregulated in 21 cancers, including glioma. High expression of TGIF2 was associated with malignant phenotypes and poor prognosis in glioma patients, indicating its potential as an independent prognostic factor. Furthermore, elevated TGIF2 expression positively correlated with cell cycle regulation, DNA synthesis and repair, extracellular matrix (ECM) components, immune response, and several signaling pathways that promote tumor progression. TGIF2 showed correlations with Th2 cells, macrophages, and various immunoregulatory genes. The hub genes coexpressed with TGIF2 demonstrated significant predictive value. Additionally, in vitro experiments revealed that knockdown and knockout of TGIF2 inhibited glioma cell invasion, migration and suppressed the epithelial-mesenchymal transition (EMT) phenotype. Conclusion: TGIF2 emerges as a potential biomarker for glioma, possibly linked to tumor immune infiltration and EMT.

Increased Anti-Inflammatory Therapeutic Potential and Progenitor Marker Expression of Corneal Mesenchymal Stem Cells Cultured in an Optimized Propagation Medium.

There is a huge unmet need for new treatment modalities for ocular surface inflammatory disorders (OSIDs) such as dry eye disease and meibomian gland dysfunction. Mesenchymal stem cell therapies may hold the answer due to their potent immunomodulatory properties, low immunogenicity, and ability to modulate both the innate and adaptive immune response. MSC-like cells that can be isolated from the corneal stroma (C-MSCs) offer a potential new treatment strategy; however, an optimized culture medium needs to be developed to produce the ideal phenotype for use in a cell therapy to treat OSIDs. The effects of in vitro expansion of human C-MSC in a medium of M199 containing fetal bovine serum (FBS) was compared to a stem cell medium (SCM) containing knockout serum replacement (KSR) with basic fibroblast growth factor (bFGF) and human leukemia inhibitory factor (LIF), investigating viability, protein, and gene expression. Isolating populations expressing CD34 or using siRNA knockdown of CD34 were investigated. Finally, the potential of C-MSC as a cell therapy was assessed using co-culture with an in vitro corneal epithelial cell injury model and the angiogenic effects of C-MSC conditioned medium were evaluated with blood and lymph endothelial cells. Both media supported proliferation of C-MSC, with SCM increasing expression of CD34, ABCG2, PAX6, NANOG, REX1, SOX2, and THY1, supported by increased associated protein expression. Isolating cell populations expressing CD34 protein made little difference to gene expression, however, knockdown of the CD34 gene led to decreased expression of progenitor genes. C-MSC increased viability of injured corneal epithelial cells whilst decreasing levels of cytotoxicity and interleukins-6 and -8. No pro-angiogenic effect of C-MSC was seen. Culture medium can significantly influence C-MSC phenotype and culture in SCM produced a cell phenotype more suitable for further consideration as an anti-inflammatory cell therapy. C-MSC show considerable potential for development as therapies for OSIDs, acting through anti-inflammatory action.

Multi-Omics Profiling Reveals Phenotypic and Functional Heterogeneity of Neutrophils in COVID-19.

Accumulating evidence has revealed unexpected phenotypic heterogeneity and diverse functions of neutrophils in several diseases. Coronavirus disease (COVID-19) can alter the leukocyte phenotype based on disease severity, including neutrophil activation in severe cases. However, the plasticity of neutrophil phenotypes and their relative impact on COVID-19 pathogenesis has not been well addressed. This study aimed to identify and validate the heterogeneity of neutrophils in COVID-19 and evaluate the functions of each subpopulation. We analyzed public single-cell RNA-seq, bulk RNA-seq, and proteome data from healthy donors and patients with COVID-19 to investigate neutrophil subpopulations and their response to disease pathogenesis. We identified eight neutrophil subtypes: pro-neutrophil, pre-neutrophil, immature neutrophil, and five mature neutrophil subpopulations. The subtypes exhibited distinct features, including diverse activation signatures and multiple enriched pathways. The pro-neutrophil subtype was associated with severe and fatal disease, while the pre-neutrophil subtype was particularly abundant in mild/moderate disease. One of the mature neutrophil subtypes showed consistently large fractions in patients with different disease severity. Bulk RNA-seq dataset analyses using a cellular deconvolution approach validated the relative abundances of neutrophil subtypes and the expansion of pro-neutrophils in severe COVID-19 patients. Cell-cell communication analysis revealed representative ligand-receptor interactions among the identified neutrophil subtypes. Further investigation into transcription factors and differential protein abundance revealed the regulatory network differences between healthy donors and patients with severe COVID-19. Overall, we demonstrated the complex interactions among heterogeneous neutrophil subtypes and other blood cell types during COVID-19 disease. Our work has great value in terms of both clinical and public health as it furthers our understanding of the phenotypic and functional heterogeneity of neutrophils and other cell populations in multiple diseases.

Pulsating Extremely Low-Frequency Electromagnetic Fields Influence Differentiation of Mouse Neural Stem Cells towards Astrocyte-like Phenotypes: In Vitro Pilot Study.

Even though electromagnetic fields have been reported to assist endogenous neurogenesis, little is known about the exact mechanisms of their action. In this pilot study, we investigated the effects of pulsating extremely low-frequency electromagnetic fields on neural stem cell differentiation towards specific phenotypes, such as neurons and astrocytes. Neural stem cells isolated from the telencephalic wall of B6(Cg)-Tyrc-2J/J mouse embryos (E14.5) were randomly divided into three experimental groups and three controls. Electromagnetic field application setup included a solenoid placed within an incubator. Each of the experimental groups was exposed to 50Hz ELF-EMFs of varied strengths for 1 h. The expression of each marker (NES, GFAP, ß-3 tubulin) was then assessed by immunocytochemistry. The application of high-strength ELF-EMF significantly increased and low-strength ELF-EMF decreased the expression of GFAP. A similar pattern was observed for ß-3 tubulin, with high-strength ELF-EMFs significantly increasing the immunoreactivity of ß-3 tubulin and medium- and low-strength ELF-EMFs decreasing it. Changes in NES expression were observed for medium-strength ELF-EMFs, with a demonstrated significant upregulation. This suggests that, even though ELF-EMFs appear to inhibit or promote the differentiation of neural stem cells into neurons or astrocytes, this effect highly depends on the strength and frequency of the fields as well as the duration of their application. While numerous studies have demonstrated the capacity of EMFs to guide the differentiation of NSCs into neuron-like cells or ß-3 tubulin+ neurons, this is the first study to suggest that ELF-EMFs may also steer NSC differentiation towards astrocyte-like phenotypes.

Biomolecular Condensates Decipher Molecular Codes of Cell Fate: From Biophysical Fundamentals to Therapeutic Practices.

Cell fate is precisely modulated by complex but well-tuned molecular signaling networks, whose spatial and temporal dysregulation commonly leads to hazardous diseases. Biomolecular condensates (BCs), as a newly emerging type of biophysical assemblies, decipher the molecular codes bridging molecular behaviors, signaling axes, and clinical prognosis. Particularly, physical traits of BCs play an important role; however, a panoramic view from this perspective toward clinical practices remains lacking. In this review, we describe the most typical five physical traits of BCs, and comprehensively summarize their roles in molecular signaling axes and corresponding major determinants. Moreover, establishing the recent observed contribution of condensate physics on clinical therapeutics, we illustrate next-generation medical strategies by targeting condensate physics. Finally, the challenges and opportunities for future medical development along with the rapid scientific and technological advances are highlighted.

A Gnotobiotic Mouse Model with Divergent Equol-Producing Phenotypes: Potential for Determining Microbial-Driven Health Impacts of Soy Isoflavone Daidzein.

The implications of soy consumption on human health have been a subject of debate, largely due to the mixed evidence regarding its benefits and potential risks. The variability in responses to soy has been partly attributed to differences in the metabolism of soy isoflavones, compounds with structural similarities to estrogen. Approximately one-third of humans possess gut bacteria capable of converting soy isoflavone daidzein into equol, a metabolite produced exclusively by gut microbiota with significant estrogenic potency. In contrast, lab-raised rodents are efficient equol producers, except for those raised germ-free. This discrepancy raises concerns about the applicability of traditional rodent models to humans. Herein, we designed a gnotobiotic mouse model to differentiate between equol producers and non-producers by introducing synthetic bacterial communities with and without the equol-producing capacity into female and male germ-free mice. These gnotobiotic mice display equol-producing phenotypes consistent with the capacity of the gut microbiota received. Our findings confirm the model's efficacy in mimicking human equol production capacity, offering a promising tool for future studies to explore the relationship between endogenous equol production and health outcomes like cardiometabolic health and fertility. This approach aims to refine dietary guidelines by considering individual microbiome differences.

Genotype and phenotype in patients with ACAN gene variants: Three cases and literature review.

OBJECTIVE: To characterize the phenotype spectrum, diagnosis, and response to growth-promoting therapy in patients with ACAN variants causing familial short stature. METHODS: Three families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed. RESULTS: Three novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early-onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD, p < 0.001). CONCLUSION: Our study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype-phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants.

Bringing traits back into the equation: A roadmap to understand species redistribution.

Ecological and evolutionary theories have proposed that species traits should be important in mediating species responses to contemporary climate change; yet, empirical evidence has so far provided mixed evidence for the role of behavioral, life history, or ecological characteristics in facilitating or hindering species range shifts. As such, the utility of trait-based approaches to predict species redistribution under climate change has been called into question. We develop the perspective, supported by evidence, that trait variation, if used carefully can have high potential utility, but that past analyses have in many cases failed to identify an explanatory value for traits by not fully embracing the complexity of species range shifts. First, we discuss the relevant theory linking species traits to range shift processes at the leading (expansion) and trailing (contraction) edges of species distributions and highlight the need to clarify the mechanistic basis of trait-based approaches. Second, we provide a brief overview of range shift-trait studies and identify new opportunities for trait integration that consider range-specific processes and intraspecific variability. Third, we explore the circumstances under which environmental and biotic context dependencies are likely to affect our ability to identify the contribution of species traits to range shift processes. Finally, we propose that revealing the role of traits in shaping species redistribution may likely require accounting for methodological variation arising from the range shift estimation process as well as addressing existing functional, geographical, and phylogenetic biases. We provide a series of considerations for more effectively integrating traits as well as extrinsic and methodological factors into species redistribution research. Together, these analytical approaches promise stronger mechanistic and predictive understanding that can help society mitigate and adapt to the effects of climate change on biodiversity.

Genetic insights into superior grain number traits: a QTL analysis of wheat-Agropyron cristatum derivative pubing3228.

BACKGROUND: Agropyron cristatum (L.) is a valuable genetic resource for expanding the genetic diversity of common wheat. Pubing3228, a novel wheat-A. cristatum hybrid germplasm, exhibits several desirable agricultural traits, including high grain number per spike (GNS). Understanding the genetic architecture of GNS in Pubing3228 is crucial for enhancing wheat yield. This study aims to analyze the specific genetic regions and alleles associated with high GNS in Pubing3228. METHODS: The study employed a recombination inbred line (RIL) population derived from a cross between Pubing3228 and Jing4839 to investigate the genetic regions and alleles linked to high GNS. Quantitative Trait Loci (QTL) analysis and candidate gene investigation were utilized to explore these traits. RESULTS: A total of 40 QTLs associated with GNS were identified across 16 chromosomes, accounting for 4.25-17.17% of the total phenotypic variation. Five QTLs (QGns.wa-1D, QGns.wa-5 A, QGns.wa-7Da.1, QGns.wa-7Da.2 and QGns.wa-7Da.3) accounter for over 10% of the phenotypic variation in at least two environments. Furthermore, 94.67% of the GNS QTL with positive effects originated from Pubing3228. Candidate gene analysis of stable QTLs identified 11 candidate genes for GNS, including a senescence-associated protein gene (TraesCS7D01G148000) linked to the most significant SNP (AX-108,748,734) on chromosome 7D, potentially involved in reallocating nutrients from senescing tissues to developing seeds. CONCLUSION: This study provides new insights into the genetic mechanisms underlying high GNS in Pubing3228, offering valuable resources for marker-assisted selection in wheat breeding to enhance yield.

A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study.

Inherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (< 1%) epidemiological contributions. The exception is GJB2, the gene encoding connexin-26 and underlying DFNB1, which is the most frequent type of autosomal recessive non-syndromic hearing impairment (ARNSHI) in most populations (up to 40% of ARNSHI cases). DFNB1 is caused by different types of pathogenic variants in GJB2, but also by large deletions that keep the gene intact but remove an upstream regulatory element that is essential for its expression. Such large deletions, found in most populations, behave as complete loss-of-function variants, usually associated with a profound hearing impairment. By using CRISPR-Cas9 genetic edition, we have generated a murine model (Dfnb1em274) that reproduces the most frequent of those deletions, del(GJB6-D13S1830). Dfnb1em274 homozygous mice are viable, bypassing the embryonic lethality of the Gjb2 knockout, and present a phenotype of profound hearing loss (> 90 dB SPL) that correlates with specific structural abnormalities in the cochlea. We show that Gjb2 expression is nearly abolished and its protein product, Cx26, is nearly absent all throughout the cochlea, unlike previous conditional knockouts in which Gjb2 ablation was not obtained in all cell types. The Dfnb1em274 model recapitulates the clinical presentation of patients harbouring the del(GJB6-D13S1830) variant and thus it is a valuable tool to study the pathological mechanisms of DFNB1 and to assay therapies for this most frequent type of human ARNSHI.

Scoary2: rapid association of phenotypic multi-omics data with microbial pan-genomes.

Unraveling bacterial gene function drives progress in various areas, such as food production, pharmacology, and ecology. While omics technologies capture high-dimensional phenotypic data, linking them to genomic data is challenging, leaving 40-60% of bacterial genes undescribed. To address this bottleneck, we introduce Scoary2, an ultra-fast microbial genome-wide association studies (mGWAS) software. With its data exploration app and improved performance, Scoary2 is the first tool to enable the study of large phenotypic datasets using mGWAS. As proof of concept, we explore the metabolome of yogurts, each produced with a different Propionibacterium reichii strain and discover two genes affecting carnitine metabolism.