Genes, Volume 15, Issue 5 (May 2024) – 59 articles

Leaf rust caused by the pathogen Puccinia triticina (Pt) is a destructive fungal disease of wheat that occurs in almost all wheat-growing areas across the globe. Genetic resistance has proven to be the best solution to mitigate the disease. Wheat breeders are continuously seeking new diversified and durable sources of resistance to use in developing new varieties. We developed recombinant inbred line (RIL) populations from two leaf rust-resistant genotypes (Kenya Kudu and AUS12568) introduced from Kenya to identify and characterize resistance to Pt and to develop markers linked closely to the resistance that was found. Our studies detected four QTL conferring adult plant resistance (APR) to leaf rust. Two of these loci are associated with known genes, Lr46 and Lr68, residing on chromosomes 1B and 7B, respectively. The remaining two, QLrKK_2B and QLrAus12568_5A, contributed by Kenya Kudu and AUS12568 respectively, are putatively new loci for Pt resistance. Both QLrKK_2B and QLrAus12568_5A were found to interact additively with Lr46 in significantly reducing the disease severity at adult plant growth stages in the field. We further developed a suite of six closely linked markers within the QLrAus12568_5A locus and four within the QLrKK_2B region. Among these, markers sunKASP_522 and sunKASP_524, flanking QLrAus12568_5A, and sunKASP_536, distal to QLrKK_2B, were identified as the most closely linked and reliable for marker-assisted selection. The markers were validated on a selection of 64 Australian wheat varieties and found to be polymorphic and robust, allowing for clear allelic discrimination. The identified new loci and linked molecular markers will enable rapid adoption by breeders in developing wheat varieties carrying diversified and durable resistance to leaf rust. Full article

High-dimensional biomedical datasets have become easier to collect in the last two decades with the advent of multi-omic and single-cell experiments. These can generate over 1000 measurements per sample or per cell. More recently, focus has been drawn toward the need for longitudinal datasets, with the appreciation that important dynamic changes occur along transitions between health and disease. Analysis of longitudinal omics data comes with many challenges, including type I error inflation and corresponding loss in power when thousands of hypothesis tests are needed. Multivariate analysis can yield approaches with higher statistical power; however, multivariate methods for longitudinal data are currently limited. We propose a multivariate distance-based drift-diffusion framework (MD3F) to tackle the need for a multivariate approach to longitudinal, high-throughput datasets. We show that MD3F can result in surprisingly simple yet valid and powerful hypothesis testing and estimation approaches using generalized linear models. Through simulation and application studies, we show that MD3F is robust and can offer a broadly applicable method for assessing multivariate dynamics in omics data. Full article

In many countries, some form of genetic screening is offered to all or part of the population, either in the form of well-organized screening programs or in a less formalized way. Screening can be offered at different phases of life, such as preconception, prenatal, neonatal and later in life. Screening should only be offered if the advantages outweigh the disadvantages. Technical innovations in testing and treatment are driving changes in the field of prenatal and neonatal screening, where many jurisdictions have organized population-based screening programs. As a result, a greater number and wider range of conditions are being added to the programs, which can benefit couples’ reproductive autonomy (preconception and prenatal screening) and improve early diagnosis to prevent irreversible health damage in children (neonatal screening) and in adults (cancer and cascade screening). While many developments in screening are technology-driven, citizens may also express a demand for innovation in screening, as was the case with non-invasive prenatal testing. Relatively new emerging issues for genetic screening, especially if testing is performed using DNA sequencing, relate to organization, data storage and interpretation, benefit–harm ratio and distributive justice, information provision and follow-up, all connected to acceptability in current healthcare systems. Full article

Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person’s intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD. Full article

T-2 toxin (T-2), an A-type mono mycotoxin produced by various Fusarium species, disrupts DNA/RNA and protein synthesis upon entering the body, resulting in pathological conditions in various tissues/organs and posing a significant threat to human and animal health. However, the mechanisms underlying its toxicity remain unclear. With the goal of learning how T-2 affects reproduction in animals, we utilized primary porcine ovarian granulosa cells (pGCs) as a carrier in vitro and constructed concentration models for analyzing cell morphology and RNA-sequencing (RNA-seq). Our findings showed that T-2 could influence pGCs morphology, induce cell cycle arrest, and promote apoptosis in a dose-dependent manner. The results of RNA-seq analyses indicated that a total of 8216 genes exhibited significant differential expression (DEG) following T-2 treatment, of which 4812 were observed to be down-regulated and 3404 were up-regulated. The DEGs following T-2 toxin treatment of pGCs had a notable impact on many metabolic pathways such as PI3K-Akt, Ras, MAPK, and apoptosis, which in turn altered important physiological processes. Gene set enrichment analysis (GSEA) indicated that the differences in the harmful effects of T-2 might be caused by the varying control of cellular processes and the pathway responsible for steroid metabolism. These results present further insights regarding the mechanism of T-2 action on sow reproductive toxicity, enhance our understanding of T-2 reproductive toxicological effects, and lay a theoretical foundation for the judicious prevention of T-2-induced reproductive toxicity. Full article

Zinc finger-homeodomain transcription factors (ZF-HDs) are pivotal in regulating plant growth, development, and diverse stress responses. In this study, we found 8 ZF-HD genes in barley genome. Theses eight HvZF-HD genes were located on five chromosomes, and classified into ZHD and MIF subfamily. The collinearity, gene structure, conserved motif, and cis-elements of HvZF-HD genes were also analyzed. Real-time PCR results suggested that the expression of HvZF-HD4, HvZF-HD6, HvZF-HD7 and HvZF-HD8 were up-regulated after hormones (ABA, GA3 and MeJA) or PEG treatments, especially HvZF-HD6 was significantly induced. These results provide useful information of ZF-HD genes to future study aimed at barley breeding. Full article

P53 overexpression plays a critical role in cancer pathogenesis by disrupting the intricate regulation of cellular proliferation. Despite its firmly established function as a tumor suppressor, elevated p53 levels can paradoxically contribute to tumorigenesis, influenced by factors such as exposure to carcinogens, genetic mutations, and viral infections. This phenomenon is observed across a spectrum of cancer types, including bladder (BLCA), ovarian (OV), cervical (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC). This broad spectrum of cancers is often associated with increased aggressiveness and recurrence risk. Effective therapeutic strategies targeting tumors with p53 overexpression require a comprehensive approach, integrating targeted interventions aimed at the p53 gene with conventional modalities such as chemotherapy, radiation therapy, and targeted drugs. In this extensive study, we present a detailed analysis shedding light on the multifaceted role of TP53 across various cancers, with a specific emphasis on its impact on disease-free survival (DFS). Leveraging data from the TCGA database and the GTEx dataset, along with GEPIA, UALCAN, and STRING, we identify TP53 overexpression as a significant prognostic indicator, notably pronounced in prostate adenocarcinoma (PRAD). Supported by compelling statistical significance (p < 0.05), our analysis reveals the distinct influence of TP53 overexpression on DFS outcomes in PRAD. Additionally, graphical representations of overall survival (OS) underscore the notable disparity in OS duration between tumors exhibiting elevated TP53 expression (depicted by the red line) and those with lower TP53 levels (indicated by the blue line). The hazard ratio (HR) further emphasizes the profound impact of TP53 on overall survival. Moreover, our investigation delves into the intricate TP53 protein network, unveiling genes exhibiting robust positive correlations with TP53 expression across 13 out of 27 cancers. Remarkably, negative correlations emerge with pivotal tumor suppressor genes. This network analysis elucidates critical proteins, including SIRT1, CBP, p300, ATM, DAXX, HSP 90-alpha, Mdm2, RPA70, 14-3-3 protein sigma, p53, and ASPP2, pivotal in regulating cell cycle dynamics, DNA damage response, and transcriptional regulation. Our study underscores the paramount importance of deciphering TP53 dynamics in cancer, providing invaluable insights into tumor behavior, disease-free survival, and potential therapeutic avenues. Full article

Numerous studies have shown genetic variation at the LCORL-NCAPG locus is strongly associated with growth traits in beef cattle. However, a causative molecular variant has yet to be identified. To define all possible candidate variants, 34 Charolais-sired calves were whole-genome sequenced, including 17 homozygous for a long-range haplotype associated with increased growth (QQ) and 17 homozygous for potential ancestral haplotypes for this region (qq). The Q haplotype was refined to an 814 kb region between chr6:37,199,897–38,014,080 and contained 218 variants not found in qq individuals. These variants include an insertion in an intron of NCAPG, a previously documented mutation in NCAPG (rs109570900), two coding sequence mutations in LCORL (rs109696064 and rs384548488), and 15 variants located within ATAC peaks that were predicted to affect transcription factor binding. Notably, rs384548488 is a frameshift variant likely resulting in loss of function for long isoforms of LCORL. To test the association of the coding sequence variants of LCORL with phenotype, 405 cattle from five populations were genotyped. The two variants were in complete linkage disequilibrium. Statistical analysis of the three populations that contained QQ animals revealed significant (p < 0.05) associations with genotype and birth weight, live weight, carcass weight, hip height, and average daily gain. These findings affirm the link between this locus and growth in beef cattle and describe DNA variants that define the haplotype. However, further studies will be required to define the true causative mutation. Full article

Induced pluripotent stem cells (iPSCs) are a powerful tool for biomedical research, but their production presents challenges and safety concerns. Yamanaka and Takahashi revolutionised the field by demonstrating that somatic cells could be reprogrammed into pluripotent cells by overexpressing four key factors for a sufficient time. iPSCs are typically generated using viruses or virus-based methods, which have drawbacks such as vector persistence, risk of insertional mutagenesis, and oncogenesis. The application of less harmful nonviral vectors is limited as conventional plasmids cannot deliver the levels or duration of the factors necessary from a single transfection. Hence, plasmids that are most often used for reprogramming employ the potentially oncogenic Epstein–Barr nuclear antigen 1 (EBNA-1) system to ensure adequate levels and persistence of expression. In this study, we explored the use of nonviral SMAR DNA vectors to reprogram human fibroblasts into iPSCs. We show for the first time that iPSCs can be generated using nonviral plasmids without the use of EBNA-1 and that these DNA vectors can provide sufficient expression to induce pluripotency. We describe an optimised reprogramming protocol using these vectors that can produce high-quality iPSCs with comparable pluripotency and cellular function to those generated with viruses or EBNA-1 vectors. Full article

MicroRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in regulating gene expression at the post-transcriptional level. These regulatory molecules are integral to many biological processes and have been implicated in the pathogenesis of various diseases, including Human Immunodeficiency Virus (HIV) infection. This review aims to cover the current understanding of the multifaceted roles miRNAs assume in the context of HIV infection and pathogenesis. The discourse is structured around three primary focal points: (i) elucidation of the mechanisms through which miRNAs regulate HIV replication, encompassing both direct targeting of viral transcripts and indirect modulation of host factors critical for viral replication; (ii) examination of the modulation of miRNA expression by HIV, mediated through either viral proteins or the activation of cellular pathways consequent to viral infection; and (iii) assessment of the impact of miRNAs on the immune response and the progression of disease in HIV-infected individuals. Further, this review delves into the potential utility of miRNAs as biomarkers and therapeutic agents in HIV infection, underscoring the challenges and prospects inherent to this line of inquiry. The synthesis of current evidence positions miRNAs as significant modulators of the host-virus interplay, offering promising avenues for enhancing the diagnosis, treatment, and prevention of HIV infection. Full article

Salt stress has a detrimental impact on food crop production, with its severity escalating due to both natural and man-made factors. As one of the most important food crops, wheat is susceptible to salt stress, resulting in abnormal plant growth and reduced yields; therefore, damage from salt stress should be of great concern. Additionally, the utilization of land in coastal areas warrants increased attention, given diminishing supplies of fresh water and arable land, and the escalating demand for wheat. A comprehensive understanding of the physiological and molecular changes in wheat under salt stress can offer insights into mitigating the adverse effects of salt stress on wheat. In this review, we summarized the genes and molecular mechanisms involved in ion transport, signal transduction, and enzyme and hormone regulation, in response to salt stress based on the physiological processes in wheat. Then, we surveyed the latest progress in improving the salt tolerance of wheat through breeding, exogenous applications, and microbial pathways. Breeding efficiency can be improved through a combination of gene editing and multiple omics techniques, which is the fundamental strategy for dealing with salt stress. Possible challenges and prospects in this process were also discussed. Full article

Wintergrazer-70 and Ganyin No1 are high-yield forage varieties suitable for cultivation in high-altitude areas of Tibet (4300 m above sea level). Ganyin No1 was developed from Wintergrazer-70, with the latter serving as its parent variety. Ganyin No1 was identified as a spring variety, and subsequent RNA sequencing was conducted. RNA sequencing analysis identified 4 differentially expressed genes related to vernalization and 28 genes related to photoperiod regulation. The Sc7296g5-i1G3 gene is related to the flowering inhibition of rye, which may be related to the phenotypic difference in the Ganyin No1 variety in winter and spring. This finding provides valuable insights for future research on Ganyin No1, especially in addressing feed shortages in Tibet during winter and spring. Full article

Hearing loss (HL) is a common and multi-complex etiological deficit that can occur at any age and can be caused by genetic variants, aging, toxic drugs, noise, injury, viral infection, and other factors. Recently, a high incidence of genetic etiologies in congenital HL has been reported, and the usefulness of genetic testing has been widely accepted in congenital-onset or early-onset HL. In contrast, there have been few comprehensive reports on the relationship between late-onset HL and genetic causes. In this study, we performed next-generation sequencing analysis for 91 HL patients mainly consisting of late-onset HL patients. As a result, we identified 23 possibly disease-causing variants from 29 probands, affording a diagnostic rate for this study of 31.9%. The highest diagnostic rate was observed in the congenital/early-onset group (42.9%), followed by the juvenile/young adult-onset group (31.7%), and the middle-aged/aged-onset group (21.4%). The diagnostic ratio decreased with age; however, genetic etiologies were involved to a considerable degree even in late-onset HL. In particular, the responsible gene variants were found in 19 (55.9%) of 34 patients with a familial history and progressive HL. Therefore, this phenotype is considered to be a good candidate for genetic evaluation based on this diagnostic panel. Full article

The Hetian Qing donkey is an excellent local donkey breed in Xinjiang. It is of great significance to accelerate breeding and the speed of breeding and rejuvenation, as well as to understand the genetic basis of the strategies and population. This study collected a total of 4 male donkeys and 28 female donkeys. It then obtained genotype data through Simplified Genomic Sequencing (GBS) technology for data analysis. The results detected a total of 55,399 SNP loci, and the genotype detection rate of individuals was ≥90%. A total of 45,557 SNP loci were identified through quality control, of which 95.5% were polymorphic. The average minimum allele frequency was 0.250. The average observed heterozygosity was 0.347. The average expected heterozygosity was 0.340. The average IBS (state homologous) genetic distance was 0.268. ROH: 49 (homozygous fragments), with 73.47% of the length between 1 and 5 Mb. The average per-strip ROH length was 1.75 Mb. The mean inbreeding coefficient was 0.003. The 32 Hetian green donkeys could be divided into six families. The number of individuals in each family is significant. To sum up, the Hetian Qing donkey population has low heterozygosity, few families, and large differences in the number of individuals in each family, which can easily cause a loss of genetic diversity. In the subsequent process of seed protection, seed selection should be conducted according to the divided pedigree to ensure the long-term protection of the genetic resources of Hetian green donkeys. Full article

Currently, more than 55 million people around the world suffer from dementia, and Alzheimer’s Disease and Related Dementias (ADRD) accounts for nearly 60–70% of all those cases. The spread of Alzheimer’s Disease (AD) pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of ADRD’s causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA), in the induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that the NSCs’ ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR-corrected p-value ≤ 0.05 and fold change absolute ≥ 2.0) differentially expressed (DE). The pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF-6), and inositol-requiring enzyme-1 (IRE1), were significantly activated and cooperatively regulated the NSCs’ transcriptional response to ER stress. Our results show that IRE1/X-box binding protein 1 (XBP1) mediated transcriptional regulation of the E2F transcription factor 1 (E2F1) gene, and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in ER stress-challenged NSCs. The ER stress-challenged NSCs also showed the activation of C/EBP homologous protein (CHOP)-mediated apoptosis and the dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that the ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD. Full article

Genome-wide prenatal cell-free DNA (cfDNA) screening can be used to screen for a wide range of fetal chromosomal anomalies in pregnant patients. In this study, we describe our clinical experience with a genome-wide cfDNA assay in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RAAs), and copy-number variations (CNVs) in about 6000 patients over a three-year period at our hospital’s Prenatal Diagnostic Unit in Spain. Overall, 204 (3.3%) patients had a high-risk call, which included 76 trisomy 21, 21 trisomy 18, 7 trisomy 13, 29 SCAs, 31 RAAs, 31 CNVs, and 9 cases with multiple anomalies. The diagnostic outcomes were obtained for the high-risk cases when available, allowing for the calculation of positive predictive values (PPVs). Calculated PPVs were 95.9% for trisomy 21, 77.8% for trisomy 18, 66.7% for trisomy 13, 10.7% for RAAs, and 10.7% for CNVs. Pregnancy and birth outcomes were also collected for the majority of RAA and CNV cases. Adverse perinatal outcomes for some of these cases included preeclampsia, fetal growth restriction, preterm birth, reduced birth weight, and major congenital structural abnormalities. In conclusion, our study showed strong performance for genome-wide cfDNA screening in a large cohort of pregnancy patients in Spain. Full article

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the presence of the Philadelphia chromosome, a product of the reciprocal translocation t(9;22)(q34;q11), in the BCR and ABL genes. These rearrangements in both genes lead to the formation of various fusion mRNA products, with preferential expression of b2a2, b3a2, and other BCR::ABL1 mRNA variants, combined with additional chromosomal abnormalities. Notably, the distribution and frequency of different mRNA variants vary in different populations. However, studies concerning this in Mexico are limited, and the results have been inconclusive. This study therefore aimed to determine the distribution of BCR::ABL1 mRNA variants in different clinical phases of CML and their effect on hematological parameters and patient survival. This study included 33 patients, whose demographic, clinical, and molecular data on BCR::ABL1 mRNA variants and hematological parameters were collected to identify potential associations. A total of 84.8% (n = 28) of patients had BCR::ABL1 translocation and increased platelet and basophil counts. The most frequent mRNA variant was b3a2 (64.3%), followed by b2a2 (28.6%) and e1a2 (3.6%). Concerning the clinical phases of CML, 75.8% (n = 25), 21.2% (n = 7), and 3% (n = 1) of patients were in the chronic, blast, and accelerated phases, respectively. Moreover, the b3a2 mRNA variant was more commonly identified in patients in the chronic phase. No correlation was observed between mRNA variant expression and patient survival. However, b2a2 was indicative of patients with longer survival as well as those treated with imatinib or nilotinib. Additionally, platelet count could be a marker of BCR::ABL1 translocation. Full article

Soybean mosaic virus (SMV) is one of the main pathogens that can negatively affect soybean production and quality. To study the gene regulatory network of soybeans in response to SMV SC15, the resistant line X149 and susceptible line X97 were subjected to transcriptome analysis at 0, 2, 8, 12, 24, and 48 h post-inoculation (hpi). Differential expression analysis revealed that 10,190 differentially expressed genes (DEGs) responded to SC15 infection. Weighted gene co-expression network analysis (WGCNA) was performed to identify highly related resistance gene modules; in total, eight modules, including 2256 DEGs, were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of 2256 DEGs revealed that the genes significantly clustered into resistance-related pathways, such as the plant–pathogen interaction pathway, mitogen-activated protein kinases (MAPK) signaling pathway, and plant hormone signal transduction pathway. Among these pathways, we found that the flg22, Ca²⁺, hydrogen peroxide (H₂O₂), and abscisic acid (ABA) regulatory pathways were fully covered by 36 DEGs. Among the 36 DEGs, the gene Glyma.01G225100 (protein phosphatase 2C, PP2C) in the ABA regulatory pathway, the gene Glyma.16G031900 (WRKY transcription factor 22, WRKY22) in Ca²⁺ and H₂O₂ regulatory pathways, and the gene Glyma.04G175300 (calcium-dependent protein kinase, CDPK) in Ca²⁺ regulatory pathways were highly connected hub genes. These results indicate that the resistance of X149 to SC15 may depend on the positive regulation of flg22, Ca²⁺, H₂O₂, and ABA regulatory pathways. Our study further showed that superoxide dismutase (SOD) activity, H₂O₂ content, and catalase (CAT) and peroxidase (POD) activities were significantly up-regulated in the resistant line X149 compared with those in 0 hpi. This finding indicates that the H₂O₂ regulatory pathway might be dependent on flg22- and Ca²⁺-pathway-induced ROS generation. In addition, two hub genes, Glyma.07G190100 (encoding F-box protein) and Glyma.12G185400 (encoding calmodulin-like proteins, CMLs), were also identified and they could positively regulate X149 resistance. This study provides pathways for further investigation of SMV resistance mechanisms in soybean. Full article

Depression is heritable, differs by sex, and has environmental risk factors such as cigarette smoking. However, the effect of single nucleotide polymorphisms (SNPs) on depression through cigarette smoking and the role of sex is unclear. In order to examine the association of SNPs with depression and smoking in the UK Biobank with replication in the COPDGene study, we used counterfactual-based mediation analysis to test the indirect or mediated effect of SNPs on broad depression through the log of pack-years of cigarette smoking, adjusting for age, sex, current smoking status, and genetic ancestry (via principal components). In secondary analyses, we adjusted for age, sex, current smoking status, genetic ancestry (via principal components), income, education, and living status (urban vs. rural). In addition, we examined sex-stratified mediation models and sex-moderated mediation models. For both analyses, we adjusted for age, current smoking status, and genetic ancestry (via principal components). In the UK Biobank, rs6424532 [LOC105378800] had a statistically significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 4.0 × 10⁻⁴) among all participants and a marginally significant indirect effect among females (p = 0.02) and males (p = 4.0 × 10⁻³). Moreover, rs10501696 [GRM5] had a marginally significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 0.01) among all participants and a significant indirect effect among females (p = 2.2 × 10⁻³). In the secondary analyses, the sex-moderated indirect effect was marginally significant for rs10501696 [GRM5] on broad depression through the log of pack-years of cigarette smoking (p = 0.01). In the COPDGene study, the effect of an SNP (rs10501696) in GRM5 on depressive symptoms and medication was mediated by log of pack-years (p = 0.02); however, no SNPs had a sex-moderated mediated effect on depressive symptoms. In the UK Biobank, we found SNPs in two genes [LOC105378800, GRM5] with an indirect effect on broad depression through the log of pack-years of cigarette smoking. In addition, the indirect effect for GRM5 on broad depression through smoking may be moderated by sex. These results suggest that genetic regions associated with broad depression may be mediated by cigarette smoking and this relationship may be moderated by sex. Full article

The role of rice genomics in breeding progress is becoming increasingly important. Deeper research into the rice genome will contribute to the identification and utilization of outstanding functional genes, enriching the diversity and genetic basis of breeding materials and meeting the diverse demands for various improvements. Here, we review the significant contributions of rice genomics research to breeding progress over the last 25 years, discussing the profound impact of genomics on rice-genome sequencing, functional-gene exploration, and novel breeding methods, and we provide valuable insights for future research and breeding practices. Full article

TR2 and TR4 (NR2C1 and NR2C2, respectively) are evolutionarily conserved nuclear orphan receptors capable of binding direct repeat sequences in a stage-specific manner. Like other nuclear receptors, TR2 and TR4 possess important roles in transcriptional activation or repression with developmental stage and tissue specificity. TR2 and TR4 bind DNA and possess the ability to complex with available cofactors mediating developmental stage-specific actions in primitive and definitive erythrocytes. In erythropoiesis, TR2 and TR4 are required for erythroid development, maturation, and key erythroid transcription factor regulation. TR2 and TR4 recruit and interact with transcriptional corepressors or coactivators to elicit developmental stage-specific gene regulation during hematopoiesis. Full article

Galium genus belongs to the Rubiaceae family, which consists of approximately 14,000 species. In comparison to its well-known relatives, the plastomes of the Galium genus have not been explored so far. The plastomes of this genus have a typical, quadripartite structure, but differ in gene content, since the infA gene is missing in Galium palustre and Galium trfidum. An evaluation of the effectiveness of using entire chloroplast genome sequences as superbarcodes for accurate plant species identification revealed the high potential of this method for molecular delimitation within the genus and tribe. The trnE-UUC—psbD region showed the biggest number of diagnostides (diagnostic nucleotides) which might be new potential barcodes, not only in Galium, but also in other closely related genera. Relative synonymous codon usage (RSCU) appeared to be connected with the phylogeny of the Rubiaceae family, showing that during evolution, plants started preferring specific codons over others. Full article

Sarcopenia, defined as the age-associated loss of muscle mass and increased fragility with age, is increasing worldwide. The condition often precedes the development of Alzheimer’s disease, thereby decreasing the levels of mobility and physical activity in those affected. Indeed, the loss of muscle mass has, in some studies, been associated with an increased risk of Alzheimer’s disease and other dementias. However, a detailed understanding of the interplay between both conditions is not available and needs to be thoroughly addressed. In the following review, we focus on several genes, specifically APOE, BDNF, ACE, FTO, and FNDC5, that have been associated with both conditions. We also discuss the epigenetic regulation of each of these genes along with non-coding RNAs (ncRNAs) that may have a role in the development of both the sarcopenic and Alzheimer’s disease phenotypes. Finally, we assert that the application of systems biology will unravel the relationship between sarcopenia and Alzheimer’s disease and believe that the prevention of muscle loss in older age will reduce the incidence of debilitating cognitive decline. Full article

Background: Cervical cancer is among the highest-ranking types of cancer worldwide, with human papillomavirus (HPV) as the agent driving the malignant process. One aspect of the infection’s evolution is given by epigenetic modifications, mainly DNA methylation and chromatin alteration. These processes are guided by several chromatin remodeling complexes, including NuRD. The purpose of this study was to evaluate the genome-wide binding patterns of the NuRD complex components (MBD2 and MBD3) in the presence of active HPV16 E6 and E7 oncogenes and to determine the potential of identified genes through an experimental model to differentiate between cervical precursor lesions, with the aim of establishing their utility as biomarkers. Methods: The experimental model was built using the CaSki cell line and shRNA for E6 and E7 HPV16 silencing, ChIP-seq, qRT-PCR, and Western blot analyses. Selected genes’ expression was also assessed in patients. Results: Several genes have been identified to exhibit altered transcriptional activity due to the influence of HPV16 E6/E7 viral oncogenes acting through the MBD2/MBD3 NuRD complex, linking them to viral infection and cervical oncogenesis. Conclusions: The impacted genes primarily play roles in governing gene transcription, mRNA processing, and regulation of translation. Understanding these mechanisms offers valuable insights into the process of HPV-induced oncogenesis. Full article

Cytogenetic studies are essential in the diagnosis and follow up of patients with bone marrow failure syndromes (BMFSs), but obtaining good quality results is often challenging due to hypocellularity. Optical Genome Mapping (OGM), a novel technology capable of detecting most types chromosomal structural variants (SVs) at high resolution, is being increasingly used in many settings, including hematologic malignancies. Herein, we compared conventional cytogenetic techniques to OGM in 20 patients with diverse BMFSs. Twenty metaphases for the karyotype were only obtained in three subjects (15%), and no SVs were found in any of the samples. One patient with culture failure showed a gain in chromosome 1q by fluorescence in situ hybridization, which was confirmed by OGM. In contrast, OGM provided good quality results in all subjects, and SVs were detected in 14 of them (70%), mostly corresponding to cryptic submicroscopic alterations not observed by standard techniques. Therefore, OGM emerges as a powerful tool that provides complete and evaluable results in hypocellular BMFSs, reducing multiple tests into a single assay and overcoming some of the main limitations of conventional techniques. Furthermore, in addition to confirming the abnormalities detected by conventional techniques, OGM found new alterations beyond their detection limits. Full article

Uterine leiomyomas (ULs) are the most common benign tumor of the uterus. They can be associated with symptoms including abnormal uterine bleeding, pelvic pain, urinary frequency, and pregnancy complications. Despite the high prevalence of UL, its underlying pathophysiology mechanisms have historically been poorly understood. Several mechanisms of pathogenesis have been suggested, implicating various genes, growth factors, cytokines, chemokines, and microRNA aberrations. The purpose of this study is to summarize the current research on the relationship of genetics with UL. Specifically, we performed a literature review of published studies to identify how genetic aberrations drive pathophysiology, epidemiology, and therapeutic approaches of UL. With regards to pathophysiology, research has identified MED12 mutations, HMGA2 overexpression, fumarate hydratase deficiency, and cytogenetic abnormalities as contributors to the development of UL. Additionally, epigenetic modifications, such as histone acetylation and DNA methylation, have been identified as contributing to UL tumorigenesis. Specifically, UL stem cells have been found to contain a unique DNA methylation pattern compared to more differentiated UL cells, suggesting that DNA methylation has a role in tumorigenesis. On a population level, genome-wide association studies (GWASs) and epidemiologic analyses have identified 23 genetic loci associated with younger age at menarche and UL growth. Additionally, various GWASs have investigated genetic loci as potential drivers of racial disparities in UL incidence. For example, decreased expression of Cytohesin 4 in African Americans has been associated with increased UL risk. Recent studies have investigated various therapeutic options, including ten-eleven translocation proteins mediating DNA methylation, adenovirus vectors for drug delivery, and “suicide gene therapy” to induce apoptosis. Overall, improved understanding of the genetic and epigenetic drivers of UL on an individual and population level can propel the discovery of novel therapeutic options. Full article

The systematic revision of the family Peristediidae remains an unresolved issue due to their diverse and unique morphology. Despite the popularity of using mitochondrial genome research to comprehensively understand phylogenetic relationships in fish, genetic data for peristediid fish need to be included. Therefore, this study aims to investigate the mitochondrial genomic characteristics and intra-family phylogenetic relationships of Peristediidae by utilizing mitochondrial genome analysis. Therefore, this study aims to investigate the phylogenetic relationship of Peristediidae by utilizing mitochondrial genome analysis. The mitochondrial genome of four species of Peristediidae (Peristedion liorhynchus, Satyrichthys welchi, Satyrichthys rieffeli, and Scalicus amiscus) collected in the East China Sea was studied. The mitochondrial gene sequence lengths of four fish species were 16,533 bp, 16,526 bp, 16,527 bp, and 16,526 bp, respectively. They had the same mitochondrial structure and were all composed of 37 genes and one control region. Most PCGs used ATG as the start codon, and a few used GTG as the start codon. An incomplete stop codon (TA/T) occurred. The AT-skew and GC-skew values of 13 PCGs from four species were negative, and the GC-skew amplitude was greater than that of AT-skew. All cases of D-arm were found in tRNA-Ser (GCT). The Ka/Ks ratio analysis indicated that 13 PCGs were suffering purifying selection. Based on 12 PCGs (excluding ND6) sequences, a phylogenetic tree was constructed using Bayesian inference (BI) and maximum likelihood (ML) methods, providing a further supplement to the scientific classification of Peristediidae fish. According to the results of divergence time, the four species of fish had apparent divergence in the Early Cenozoic, which indicates that the geological events at that time caused the climax of species divergence and evolution. Full article

Background: Nutritional deficiencies are frequently observed in patients with head and neck cancer (HNC) undergoing radiation therapy. microRNAs (miRNAs) were found to play an important role in the development of metabolic disorders throughout regulation of genes involved in inflammatory responses. This study aimed to explore the correlation between pre-treatment miR-5682 expression and parameters reflecting nutritional deficits in laryngeal cancer (LC) patients subjected to radiotherapy (RT). Methods: Expression of miR-5682 was analyzed in plasma samples of 56 male LC individuals. Nutritional status of LC patients was assessed using anthropometric and laboratory parameters, bioelectrical impedance analysis (BIA) and clinical questionnaires. Results: A high expression of miR-5682 was associated with significantly lower values of BMI, fat mass, fat-free mass and plasma albumin at selected periods of RT course. miR-5682 allowed us to distinguish between patients classified with both SGA-C and low albumin level from other LC patients with 100% sensitivity and 69.6% specificity (AUC = 0.820; p < 0.0001). Higher expression of studied miRNA was significantly associated with shorter median overall survival (OS) in LC patients (HR = 2.26; p = 0.008). Conclusions: analysis of miR-5682 expression demonstrates a potential clinical utility in selection of LC patients suffering from nutritional deficiencies developing as a consequence of RT-based therapy. Full article

The ionic toxicity induced by salinization has adverse effects on the growth and development of crops. However, researches on ionic toxicity and salt tolerance in plants have focused primarily on cations such as sodium ions (Na⁺), with very limited studies on chloride ions (Cl⁻). Here, we cloned the homologous genes of Arabidopsis thaliana AtCLCc, GhCLCc-1A/D, from upland cotton (Gossypium hirsutum), which were significantly induced by NaCl or KCl treatments. Subcellular localization showed that GhCLCc-1A/D were both localized to the tonoplast. Complementation of Arabidopsis atclcc mutant with GhCLCc-1 rescued its salt-sensitive phenotype. In addition, the silencing of the GhCLCc-1 gene led to an increased accumulation of Cl⁻ in the roots, stems, and leaves of cotton seedlings under salt treatments, resulting in compromised salt tolerance. And ectopic expression of the GhCLCc-1 gene in Arabidopsis reduced the accumulation of Cl⁻ in transgenic lines under salt treatments, thereby enhancing salt tolerance. These findings elucidate that GhCLCc-1 positively regulates salt tolerance by modulating Cl⁻ accumulation and could be a potential target gene for improving salt tolerance in plants. Full article

Background: MUTYH germline monoallelic variants have been detected in a number of patients affected by breast/ovarian cancer or endometrial cancer, suggesting a potential susceptibility role, though their significance remains elusive since the disease mechanism is normally recessive. Hence, the aim of this research was to explore the hypothesis that a second hit could have arisen in the other allele in the tumor tissue. Methods: we used Sanger sequencing and immunohistochemistry to search for a second MUTYH variant in the tumoral DNA and to assess protein expression, respectively. Results: we detected one variant of unknown significance, one variant with conflicting interpretation of pathogenicity and three benign/likely benign variants; the MUTYH protein was not detected in the tumor tissue of half of the patients, and in others, its expression was reduced. Conclusions: our results fail to demonstrate that germinal monoallelic MUTYH variants increase cancer risk through a LOH (loss of heterozygosity) mechanism in the somatic tissue; however, the absence or partial loss of the MUTYH protein in many tumors suggests its dysregulation regardless of MUTYH genetic status. Full article