Search Results (45)

Jabal Akhdar goats, native to Oman’s high-altitude Jabal Akhdar mountain range, are recognized for their high growth rate, remarkable twinning rate, and adaptability to harsh environmental conditions. This study assesses the genetic structure, inbreeding levels, effective population size (N_e), and linkage disequilibrium (LD) of Jabal Akhdar goats while identifying genomic regions under positive selection that may contribute to their environmental adaptation. The SNP genotypes from 72 Jabal Akhdar goats and two desert breeds from Egypt (153 Barki and 60 Saidi) revealed a clear genetic distinction between both groups. Within the Jabal Akhdar goats, genetic differentiation was also identified among the three sampled villages, indicating a village-specific genetic structure. The Jabal Akhdar breed exhibited a moderate level of inbreeding (F_ROH = 0.16), greater than that of the Barki and Saidi breeds. Additionally, Jabal Akhdar goats displayed greater LD and lower N_e levels compared to the Egyptian breeds. Analysis of runs of homozygosity (ROH) and extended haplotype homozygosity-based statistics (iHS and Rsb) identified 93 genomic regions exhibiting signatures of positive selection (80 from ROH, 5 from iHS, and 8 from Rsb). These regions harbor genes associated with traits essential for environmental adaptability, including hypoxia tolerance (SUCNR1, ANGPTL1, MITF, MTUS2), muscle development and function (MBNL1, ACTC1, CAPN5), fertility (GNRHR, CCNA1, SPAG1), UV radiation resistance (UVRAG, BRCA1), bone development (SOST, MEOX1), and lipid metabolism for energy utilization (DGAT2, G6PC, SUCLG2). The results of this study provide valuable insights for identifying causative variants and haplotypes underlying the Jabal Akhdar goat’s superior adaptability. These findings can guide breeders in designing conservation strategies and improving the productivity of this unique indigenous breed. Full article

Objectives: Evaluate the genetic diversity and productive traits of crossbred cattle in the Caribbean region of Colombia, through analyses derived from the assessment of the genome-wide single-nucleotide polymorphism (SNP). Methods: A total of 590 individuals and 66,098 SNPs were analyzed by principal components analysis (PCA) and detection of runs of homozygosity (ROH). The population was composed of 531 heifers marked as crossbreed and a group of 59 heifers marked as purebred Gyr. Additionally, allele frequencies were calculated for commercially important traits (CSN2, CSN3, LGB, DGAT1, GH1, CAPN1_316, CAPN1_350, CAPN1_4751, CAST_282, CAST_2870, and CAST_2959). Results: Global differences in PCA were 7.35%, and principal components explained 1.94% and 5.41% of the variation. Five ROH islands were identified in crossbred animals on chromosomes 2, 5, 7, 8, and 12. The majority of observed ROH classes were shorter than 2 Mb, 54% in crossbreed cattle and 47% in Gyr cattle. Individual inbreeding was 5.2% in crossbreed and 12% in Gyr cattle. Both groups had similar allelic and genotypic frequencies for most of the evaluated commercial traits. Only a wide variation was observed in the genes related to growth hormone (GH1) and Calpastatin (CAST_2870 and CAST_22959). Crossbreed heifers had desired allele frequencies for better milk production and quality in the genes CSN2, LGB, DGAT1, and GH1, as well as in the genes CAST_2870 and CAST_2959. Conclusions: Crossbreed cattle in the Colombian Caribbean region possess high genetic diversity and desirable allele frequencies to implement breeding and intense selection programs aimed at improving production yields. Full article

Background: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, with its incidence and recurrence rates steadily rising. To explore the relationship between CRC and longevity-associated genes (LAGs), and to offer new therapeutic avenues for CRC treatment, we developed a prognostic model based on these genes to predict the outcomes for CRC patients. Additionally, we conducted an immune correlation analysis. Methods: We conducted a comprehensive analysis of the effects of 81 LAGs in CRC by integrating multiple omics datasets. This analysis led to the identification of two distinct molecular subtypes and revealed that alterations in LAGs across various layers were linked to clinicopathological features, prognosis, and cell infiltration characteristics within the tumor microenvironment (TME). The training and validation cohorts for the models were derived from the TCGA-COAD, TCGA-READ, and GSE35279 datasets. Subsequently, we developed a risk score model, and the Kaplan–Meier method was employed to estimate overall survival (OS). Ultimately, we established a prognostic model based on five LAGs: BEDN3, EXOC3L2, CDKN2A, IL-13, and CAPN9. Furthermore, we assessed the correlations between the risk score and factors such as immune cell infiltration, microsatellite instability, and the stem cell index. Results: Our comprehensive bioinformatics analysis revealed a strong association between longevity genes and CRC. The risk score derived from the five newly identified LAGs was determined to be an independent prognostic factor for CRC. Patients categorized by this risk score demonstrated significant differences in immune status and microsatellite instability. Conclusions: Our comprehensive multi-omic analysis of LAGs highlighted their potential roles in the tumor immune microenvironment, clinicopathological features, and prognosis, offering new insights for the treatment of CRC. Full article

Limb–girdle muscular dystrophy R1 (LGMDR1) is characterized by progressive proximal muscle weakness due to mutations in the CAPN3 gene. Little is known about CAPN3’s function in muscle, but its loss results in aberrant sarcomere formation. Human muscle structure was analyzed in this study, with observations including integrin β1D isoform (ITGβ1D) mislocalization, a lack of Talin-1 (TLN1) in the sarcolemma and the irregular expression of focal adhesion kinase (FAK) in LGMDR1 muscles, suggesting a lack of integrin activation with an altered sarcolemma, extracellular matrix (ECM) assembly and signaling pathway deregulation, which may cause frailty in LGMDR1 muscle fibers. Additionally, altered nuclear morphology, centrosome distribution and microtubule organization have been found in muscle cells derived from LGMDR1 patients. Full article

Background/Objectives: Rhabdomyolysis, a dangerous breakdown of skeletal muscle, has been reported as an adverse event in those prescribed a statin therapy for the treatment of hypercholesterolemia. Statin drugs are some of the most prescribed treatments for elevated cholesterol levels. The purpose of this comparative study was to determine the association between the statin drugs used and the risk of rhabdomyolysis using the FDA Adverse Event Reporting System (FAERS) and transcriptomic data. Methods: A disproportionality analysis was performed to compare the risk of rhabdomyolysis between the reference statin drug (simvastatin) and the treatment group, with patient age assessed as a possible confounder. In addition, association rule mining was utilized to both identify other adverse events that frequently presented with rhabdomyolysis and identify possible drug-drug interactions (DDIs). Finally, public transcriptomic data were explored to identify the possible genetic underpinnings highlighting these differences in rhabdomyolysis risk across statins. Results: Rhabdomyolysis is a commonly reported adverse event for patients treated with statins, particularly those prescribed simvastatin. Simvastatin was associated with a more than 2-fold increased likelihood of rhabdomyolysis compared to other statins. Men were twice as likely to report rhabdomyolysis than women regardless of statin treatment, with the highest risk observed for pravastatin (ROR = 2.30, p < 0.001) and atorvastatin (ROR = 2.03, p < 0.0001). Several possible DDIs were identified, including furosemide/Lasix, allopurinol clopidogrel/Plavix, and pantoprazole, which may elevate rhabdomyolysis risk through impaired muscle function and delayed statin metabolism. Finally, nine myopathic genes were identified as possible regulators of statin-induced rhabdomyolysis, including DYSF, DES, PLEC, CAPN3, SCN4A, TNNT1, SDHA, MYH7, and PYGM in primary human muscle cells. Conclusions: Simvastatin was associated with the highest risk of rhabdomyolysis. The risk of rhabdomyolysis was more pronounced in men than women. Several possible DDIs were identified including furosemide/Lasix, allopurinol clopidogrel/Plavix, and pantoprazole. Full article

Background and Objective: Unexplained infertility is a major challenge in reproductive medicine and requires advanced diagnostic approaches to identify the underlying factors accurately. This study aims to evaluate the utility of risk factor analysis and a gene panel in diagnosing unexplained infertility using the next-generation sequencing (NGS) technology. Our study aimed to characterize and identify risk and genetic factors associated with unexplained infertility. Materials and methods: A cohort of patients with unexplained infertility was comprehensively screened for risk factors and genetic variations using a targeted gene panel (10 couples with unexplained infertility (UI) and 36 fertile couples). 108 articles were selected (58 on female infertility and 50 on male infertility) presenting genes that may be associated with unexplained infertility. A gene panel for unexplained infertility was compiled based on the literature data. A customized virtual panel was created from the exome sequencing data. Results: In the female group, controls had a higher mean age, while in the male patients, both groups were similar in terms of age. Both gender groups had comparable BMI values. No significant associations (p > 0.05) between risk factors and unexplained infertility were found when evaluating anthropometric parameters and other sociodemographic characteristics. In two male patients (20%), a molecular defect was detected in NGS variants classified aspossible benign and probably benign In particular, missense variants were identified in the UGT2B7 and CATSPER2 genes, A molecular defect classified as probably damaging was found in five female patients (50%). In particular, missense variants were identified in the CAPN10, MLH3, HABP2, IRS1, GDF9, and SLC19A1 genes. Conclusions: The study emphasizes that unexplained infertility is often related to mechanisms beyond causative mutations and highlights the need for integrative genomic research involving broader gene panels and multi-faceted approaches, including transcriptomics and epigenetics, to uncover latent genetic predispositions. Full article

Environmental heat stress represents a pervasive threat to warfighters, athletes, and occupational workers, impacting performance and increasing the risk of injury. Exertional heat illness (EHI) is a spectrum of clinical disorders of increasing severity. While frequently predictable, EHI can occur unexpectedly and may be followed by long-term comorbidities, including cardiovascular dysfunction and exercise intolerance. The objective of this study was to assess genetic factors contributing to EHI. Whole-exome sequencing was performed in a cohort of 53 cases diagnosed with EHI. Rare variants in prioritized gene sets were analyzed and classified per published guidelines. Clinically significant pathogenic and potentially pathogenic variants were identified in 30.2% of the study cohort. Variants were found in 14 genes, including the previously known RYR1 and ACADVL genes and 12 other genes (CAPN3, MYH7, PFKM, RYR2, TRPM4, and genes for mitochondrial disorders) reported here for the first time in EHI. Supporting structural and functional studies of the TRPM4 p.Arg905Trp variant show that it impairs the thermal sensitivity of the TRPM4 channel, revealing a potentially new molecular mechanism contributing to EHI susceptibility. Our study demonstrates associations between EHI and genes implicated in muscle disorders, cardiomyopathies, thermoregulation, and oxidative phosphorylation deficiencies. These results expand the genetic heterogeneity of EHI and shed light on its molecular pathogenesis. Full article

The production and release of cortisol during stress responses are key regulators of growth in teleosts. Understanding the molecular responses to cortisol is crucial for the sustainable farming of rainbow trout (Oncorhynchus mykiss) and other salmonid species. While several studies have explored the genomic and non-genomic impacts of cortisol on fish growth and skeletal muscle development, the long-term effects driven by epigenetic mechanisms, such as cortisol-induced DNA methylation, remain unexplored. In this study, we analyzed the transcriptome and genome-wide DNA methylation in the skeletal muscle of rainbow trout seven days after cortisol administration. We identified 550 differentially expressed genes (DEGs) by RNA-seq and 9059 differentially methylated genes (DMGs) via whole-genome bisulfite sequencing (WGBS) analysis. KEGG enrichment analysis showed that cortisol modulates the differential expression of genes associated with nucleotide metabolism, ECM-receptor interaction, and the regulation of actin cytoskeleton pathways. Similarly, cortisol induced the differential methylation of genes associated with focal adhesion, adrenergic signaling in cardiomyocytes, and Wnt signaling. Through integrative analyses, we determined that 126 genes showed a negative correlation between up-regulated expression and down-regulated methylation. KEGG enrichment analysis of these genes indicated participation in ECM-receptor interaction, regulation of actin cytoskeleton, and focal adhesion. Using RT-qPCR, we confirmed the differential expression of lamb3, itga6, limk2, itgb4, capn2, and thbs1. This study revealed for the first time the molecular responses of skeletal muscle to cortisol at the transcriptomic and whole-genome DNA methylation levels in rainbow trout. Full article

In this study, we measured the growth performance and intramuscular fat (IMF) content of the Longissimus dorsi (LD) of Fuqing goats (FQs) and Nubian goats (NBYs), which exhibit extreme phenotypic differences in terms of their production and meat quality traits. RNA-Seq analysis was performed, and transcriptome data were obtained from the LD tissue of 3-month fetuses (E3), 0-month lambs (0M), 3-month lambs (3M), and 12-month lambs (12M) to reveal the differences in the molecular mechanisms regulating the muscle development and IMF deposition between FQs and NBYs. The results showed that a higher body weight and average daily gain were observed in the NBYs at three developmental stages after birth, whereas a higher IMF content was registered in the FQs at 12M. Additionally, transcriptome profiles during the embryonic period and after birth were completely different for both FQs and NBYs. Moreover, DEGs (KIF23, CCDC69, CCNA2, MKI67, KIF11, RACGAP1, NUSAP1, SKP2, ZBTB18, NES, LOC102180034, CAPN6, TUBA1A, LOC102178700, and PEG10) significantly enriched in the cell cycle (ko04110) at E3 (FQs vs. NBYs), and DEGs (MRPS7, RPS8, RPL6, RPL4, RPS11, RPS10, RPL5, RPS6, RPL8, RPS13, RPS24, RPS15, RPL23) significantly enriched in ribosomes (ko03010) at 0M (FQs vs. NBYs) related to myogenic differentiation and fusion were identified. Meanwhile, the differences in glucose and lipid metabolism began at the E3 timepoint and continued to strengthen as growth proceeded in FQs vs. NBYs. DEGs (CD36, ADIROQR2, ACACA, ACACB, CPT1A, IGF1R, IRS2, LDH-A, PKM, HK2, PFKP, PCK1, GPI, FASN, FADS1, ELOVL6, HADHB, ACOK1, ACAA2, and ACSL4) at 3M (FQs vs. NBYs) and 12M (FQs vs. NBYs) significantly enriched in the AMPK signaling pathway (ko04152), insulin resistance (ko04931), the insulin signaling pathway (ko04910), fatty acid metabolism (ko01212), and glycolysis/gluconeogenesis (ko00010) related to IMF deposition were identified. Further, the results from this study provide the basis for future studies on the mechanisms regulating muscle development and IMF deposition in different breeds of goats, and the candidate genes identified could be used in the selection process. Full article

As societal progress elevates living standards, the focus on meat consumption has shifted from quantity to quality. In broiler production, optimizing meat quality has become paramount, prompting efforts to refine various meat attributes. Recent advancements in sequencing technologies have revealed the genome’s complexity, surpassing previous conceptions. Through experimentation, numerous genetic elements have been linked to crucial meat quality traits in broiler chickens. This review synthesizes the current understanding of genetic determinants associated with meat quality attributes in broilers. Researchers have unveiled the pivotal insights detailed herein by employing diverse genomic methodologies such as QTL-based investigations, candidate gene studies, single-nucleotide polymorphism screening, genome-wide association studies, and RNA sequencing. These studies have identified numerous genes involved in broiler meat quality traits, including meat lightness (COL1A2 and ACAA2), meat yellowness (BCMO1 and GDPD5), fiber diameter (myostatin and LncIRS1), meat pH (PRDX4), tenderness (CAPN1), and intramuscular fat content (miR-24-3p and ANXA6). Consequently, a comprehensive exploration of these genetic elements is imperative to devise novel molecular markers and potential targets, promising to revolutionize strategies for enhancing broiler meat quality. Full article

Non-alcoholic steatohepatitis (NASH, also known as MASH) is a severe form of non-alcoholic fatty liver disease (NAFLD, also known as MASLD). Emerging data indicate that the progression of the disease to MASH is higher in postmenopausal women and that genetic susceptibility increases the risk of MASH-related cirrhosis. This study aimed to investigate the association between genetic polymorphisms in MASH and sexual dimorphism. We applied whole-exome sequencing (WES) to identify gene variants in 8 age-adjusted matched pairs of livers from both male and female patients. Sequencing alignment, variant calling, and annotation were performed using standard methods. Polymerase chain reaction (PCR) coupled with Sanger sequencing and immunoblot analysis were used to validate specific gene variants. cBioPortal and Gene Set Enrichment Analysis (GSEA) were used for actionable target analysis. We identified 148,881 gene variants, representing 57,121 and 50,150 variants in the female and male cohorts, respectively, of which 251 were highly significant and MASH sex-specific (p < 0.0286). Polymorphisms in CAPN14, SLC37A3, BAZ1A, SRP54, MYH11, ABCC1, and RNFT1 were highly expressed in male liver samples. In female samples, Polymorphisms in RGSL1, SLC17A2, HFE, NLRC5, ACTN4, SBF1, and ALPK2 were identified. A heterozygous variant 1151G>T located on 18q21.32 for ALPK2 (rs3809983) was validated by Sanger sequencing and expressed only in female samples. Immunoblot analysis confirmed that the protein level of β-catenin in female samples was 2-fold higher than normal, whereas ALPK2 expression was 0.5-fold lower than normal. No changes in the protein levels of either ALPK2 or β-catenin were observed in male samples. Our study suggests that the perturbation of canonical Wnt/β-catenin signaling observed in postmenopausal women with MASH could be the result of polymorphisms in ALPK2. Full article

Temperament can be defined as the emotional variability among animals of the same species in response to the same stimulus, grouping animals by their reactivity as nervous, intermediate, or calm. Our goal was to identify genomic regions with the temperament phenotype measured by the Isolation Box Test (IBT) by single-step genome-wide association studies (ssGWAS). The database consisted of 4317 animals with temperament records, and 1697 genotyped animals with 38,268 effective Single Nucleotide Polymorphism (SNP) after quality control. We identified three genomic regions that explained the greatest percentage of the genetic variance, resulting in 25 SNP associated with candidate genes on chromosomes 6, 10, and 21. A total of nine candidate genes are reported for the temperament trait, which is: PYGM, SYVN1, CAPN1, FADS1, SYT7, GRID2, GPRIN3, EEF1A1 and FRY, linked to the energetic activity of the organism, synaptic transmission, meat tenderness, and calcium associated activities. This is the first study to identify these genetic variants associated with temperament in sheep, which could be used as molecular markers in future behavioral research. Full article

The molecular explanation about why some pancreatic cancer (PaCa) patients die early and others die later is poorly understood. This study aimed to discover potential novel markers and drug targets that could be useful to stratify and extend expected survival in prospective early-death patients. We deployed a deep learning algorithm and analyzed the gene copy number, gene expression, and protein expression data of death versus alive PaCa patients from the GDC cohort. The genes with higher relative amplification (copy number $>4$ times in the dead compared with the alive group) were EWSR1, FLT3, GPC3, HIF1A, HLF, and MEN1. The most highly up-regulated genes (>8.5-fold change) in the death group were RPL30, RPL37, RPS28P7, RPS11, Metazoa_SRP, CAPNS1, FN1, H3−3B, LCN2, and OAZ1. None of their corresponding proteins were up or down-regulated in the death group. The mRNA of the RPS28P7 pseudogene could act as ceRNA sponging the miRNA that was originally directed to the parental gene RPS28. We propose RPS28P7 mRNA as the most druggable target that can be modulated with small molecules or the RNA technology approach. These markers could be added as criteria to patient stratification in future PaCa drug trials, but further validation in the target populations is encouraged. Full article

Previously, we reported the modest but durable anticancer activity of regorafenib/nivolumab in mismatch repair-proficient (pMMR) refractory colorectal cancer in our I/Ib study. Our finding suggests the necessity of biomarkers for better selection of patients. Baseline clinical and pathological characteristics, blood and tumor samples from the patients in the trial were collected and evaluated to discover potential biomarkers. The obtained samples were assessed for immunohistochemistry, ELISA and RNA sequencing. Their correlations with clinical outcome were analyzed. A high albumin level was significantly associated with improved progression-free survival (PFS), overall survival (OS) and disease control. Non-liver metastatic disease showed prolonged PFS and OS. Low regulatory T-cell (Treg) infiltration correlated with prolonged PFS. Low MIP-1β was associated with durable response and improved OS significantly. Upregulation of 23 genes, including CAPN9, NAPSA and ROS1, was observed in the durable disease control group, and upregulation of 10 genes, including MRPS18A, MAIP1 and CMTR2, was associated with a statistically significant improvement of PFS. This study suggests that pretreatment albumin, MIP-1β, non-liver metastatic disease and Treg infiltration may be potential predictive biomarkers of regorafenib/nivolumab in pMMR colorectal cancer. Further studies are needed to confirm these findings. Full article

The single-nucleotide polymorphism (SNP) form of genes is a valuable source of information regarding their suitability for use as specific markers of desirable traits in beef cattle breeding. For several decades, breeding work focused on improving production efficiency through optimizing the feed conversion ratio and improving daily gains and meat quality. Many research teams previously undertook research work on single-nucleotide polymorphism in myostatin (MSTN), thyroglobulin (TG), calpain (CAPN), and calpastatin (CAST) proteins. The literature review focuses on the most frequently addressed issues concerning these genes in beef cattle production and points to a number of relevant studies on the genes’ polymorphic forms. The four genes presented are worth considering during breeding work as a set of genes that can positively influence productivity and production quality. Full article