Search Results (10,110)

Background/purpose: A comprehensive review of the degree of disorder in all genes in the Retinal Information Network (RetNet) Database is implicated in inherited retinal diseases (IRDs). Their association with a missense variation was evaluated. Methods: IRD genes from RetNet were included in this study. Publicly available data on the genome aggregation database (gnomAD) were used to analyze the number of total and pathogenic missense variants. Metapredict, an accurate and high-performance predictor that reproduces consensus disorder scores, was used to calculate disorder. Main outcome measures: The main outcome measures were percent disorder, percent pathogenicity, number of total missense variants, and percent total missense variation. Results: We included 287 RetNet genes with relevant data available from gnomAD. Mean percent disorder was 26.3% ± 26.0%, mean percent pathogenicity was 5.2% ± 11.0%, mean number of total missense variants was 424.4 ± 450.0, and mean percent total missense was 50.0% ± 13.4%. The percent disorder followed a bimodal distribution with the highest number of occurrences in the 0 to 10th disorder decile. The five outlier proteins in the first disorder decile with a higher-than-expected number of total missense variation were identified (HMCN1, ADGRV, USH2A, DYNC2H1, LAMA1, and SLC38A8). When excluded, % total missense was significantly associated with percent disorder (R = 0.238 and p = 0.0240). Conclusions: This novel study examining all genes implicated in IRDs found that the majority genes had a disorder in the 0 to 10th decile and were relatively intolerant to missense variation. This may have future utility when interpreting variants of undetermined significance and missense variants. Full article

Patients with human papillomavirus-negative head and neck squamous cell carcinoma (HPV-negative HNSCC) have worse outcomes than HPV-positive HNSCC. In our study, we used a published dataset and investigated the microbes enriched in molecularly classified tumor groups. We showed that microbial signatures could distinguish Hypoxia/Immune phenotypes similar to the gene expression signatures. Furthermore, we identified three highly-correlated microbes with immune processes that are crucial for immunotherapy response. The survival of patients in a molecularly heterogenous group shows significant differences based on the co-abundance of the three microbes. Overall, we present evidence that tumor-associated microbiota are critical components of the tumor ecosystem that may impact tumor microenvironment and immunotherapy response. The results of our study warrant future investigation to experimentally validate the conclusions, which have significant impacts on clinical decision-making, such as treatment selection. Full article

We have developed MAGI-ACMG, a classification algorithm that allows the classification of sequencing variants (single nucleotide or small indels) according to the recommendations of the American College of Medical Genetics (ACMG) and the Association for Clinical Genomic Science (ACGS). The MAGI-ACMG classification algorithm uses information retrieved through the VarSome Application Programming Interface (API), integrates the AutoPVS1 tool in order to evaluate more precisely the attribution of the PVS1 criterion, and performs the customized assignment of specific criteria. In addition, we propose a sub-classification scheme for variants of uncertain significance (VUS) according to their proximity either towards the “likely pathogenic” or “likely benign” classes. We also conceived a pathogenicity potential criterion (P_POT) as a proxy for segregation criteria that might be added to a VUS after posterior testing, thus allowing it to upgrade its clinical significance in a diagnostic reporting setting. Finally, we have developed a user-friendly web application based on the MAGI-ACMG algorithm, available to geneticists for variant interpretation. Full article

Weighted gene co-expression network analysis (WGCNA) is a research method in systematic biology. It is widely used to identify gene modules related to target traits in multi-sample transcriptome data. In order to further explore the molecular mechanism of maize response to low-temperature stress at the seedling stage, B144 (cold stress tolerant) and Q319 (cold stress sensitive) provided by the Maize Research Institute of Heilongjiang Academy of Agricultural Sciences were used as experimental materials, and both inbred lines were treated with 5 °C for 0 h, 12 h, and 24 h, with the untreated material as a control. Eighteen leaf samples were used for transcriptome sequencing, with three biological replicates. Based on the above transcriptome data, co-expression networks of weighted genes associated with low-temperature-tolerance traits were constructed by WGCNA. Twelve gene modules significantly related to low-temperature tolerance at the seedling stage were obtained, and a number of hub genes involved in low-temperature stress regulation pathways were discovered from the four modules with the highest correlation with target traits. These results provide clues for further study on the molecular genetic mechanisms of low-temperature tolerance in maize at the seedling stage. Full article

Campanula carpatica is an ornamental flowering plant belonging to the family Campanulaceae. The complete chloroplast genome of C. carpatica was obtained using Illumina HiSeq X and Oxford Nanopore (Nanopore GridION) platforms. The chloroplast genome exhibited a typical circular structure with a total length of 169,341 bp, comprising a large single-copy region of 102,323 bp, a small single-copy region of 7744 bp, and a pair of inverted repeats (IRa/IRb) of 29,637 bp each. Out of a total 120 genes, 76 were protein-coding genes, 36 were transfer RNA genes, and eight were ribosomal RNA genes. The genomic characteristics of C. carpatica are similar to those of other Campanula species in terms of repetitive sequences, sequence divergence, and contraction/expansion events in the inverted repeat regions. A phylogenetic analysis of 63 shared genes in 16 plant species revealed that Campanula zangezura is the closest relative of C. carpatica. Phylogenetic analysis indicated that C. carpatica was within the Campanula clade, and C. pallida occupied the outermost position of that clade. Full article

Telomeres are terminal DNA regions of chromosomes that prevent chromosomal fusion and degradation during cell division. In cattle, leukocyte telomere length (LTL) is associated with longevity, productive lifespan, and disease susceptibility. However, the genetic basis of LTL in this species is less studied than in humans. In this study, we utilized the whole-genome resequencing data of 239 animals from 17 cattle breeds for computational leukocyte telomere length estimation and subsequent genome-wide association study of LTL. As a result, we identified 42 significant SNPs, of which eight were found in seven genes (EXOC6B, PTPRD, RPS6KC1, NSL1, AGBL1, ENSBTAG00000052188, and GPC1) when using covariates for two major breed groups (Turano–Mongolian and European). Association analysis with covariates for breed effect detected 63 SNPs, including 13 in five genes (EXOC6B, PTPRD, RPS6KC1, ENSBTAG00000040318, and NELL1). The PTPRD gene, demonstrating the top signal in analysis with breed effect, was previously associated with leukocyte telomere length in cattle and likely is involved in the mechanism of alternative lengthening of telomeres. The single nucleotide variants found could be tested for marker-assisted selection to improve telomere-length-associated traits. Full article

Post-transplant diabetes mellitus (PTDM) is a common complication that occurs in kidney transplant patients, increasing the risk of infection, cardiovascular disease and loss of graft function. Currently, factors that increase the risk of this complication are being sought, among them polymorphisms in genes that regulate carbohydrate metabolism and influence pancreatic β-cell function. The aim of this study was to evaluate the association of selected polymorphisms of genes affecting carbohydrate metabolism, such as CDKAL1 rs10946398, GCK rs1799884, GCKR rs780094 and DGKB/TMEM195 rs2191349, with the development of post-transplant diabetes in kidney transplant patients. This study included 201 Caucasian patients after kidney transplantation treated with tacrolimus. An association was observed between the CDKAL1 rs10946398 gene polymorphism and PTDM. Among patients with PTDM, there was an increased prevalence of the CC genotype in the PTDM group compared to the group without PTDM. The chance of PTDM in those with the CC genotype was 2.60 times higher compared to those with the AC + AA genotypes (CC vs. AC + AA OR (95% CI): 2.60 (1.02–6.61), p = 0.040). Multivariate logistic regression analysis showed that advanced age and the CC genotype (rare homozygote) of CDKAL1 rs10946398 were risk factors for the development of PTDM at 1 year after transplantation. There was no statistically significant association between GCK rs1799884, GCKR rs780094 or DGKB/TMEM195 rs2191349 polymorphisms and the development of post-transplant diabetes mellitus in kidney transplant patients. The results of this study suggest that the CDKAL1 rs10946398 CC genotype is associated with the increased risk of PTDM development in patients after kidney graft transplantation treated with tacrolimus. Full article

Nuclear and cytoplasmic DNA barcoding regions are useful for plant identification, breeding, and phylogenesis. In this study, the genetic diversity of 17 Diplotaxis species, was investigated with 5 barcode markers. The allelic variation was based on the sequences of chloroplast DNA markers including the spacer between trnL and trnF and tRNA-Phe gene (trnL-F), the rubisco (rbcl), the maturase K (matk), as well as the internal transcribed spacer (ITS) region of the nuclear ribosomal DNA. A highly polymorphic marker (HRM500) derived from a comparison of cytoplasmic genome sequences in Brassicaceae, was also included. Subsequently, a real-time PCR method coupled with HRM analysis was implemented to better resolve taxonomic relationships and identify assays suitable for species identification. Integration of the five barcode regions revealed a grouping of the species according to the common chromosomal set number. Clusters including species with n = 11 (D. duveryrieriana or cretacea, D. tenuifolia, D. simplex and D. acris), n = 8 (D. ibicensis, D. brevisiliqua and D. ilorcitana), and n = 9 (D. brachycarpa, D. virgata, D. assurgens, and D. berthautii) chromosomes were identified. Both phylogenetic analysis and the genetic structure of the collection identified D. siifolia as the most distant species. Previous studies emphasized this species’ extremely high glucosinolate content, particularly for glucobrassicin. High-resolution melting analysis showed specific curve patterns useful for the discrimination of the species, thus determining ITS1 as the best barcode for fingerprinting. Findings demonstrate that the approach used in this study is effective for taxa investigations and genetic diversity studies. Full article

Tiller number is an important trait associated with yield in rice. Tiller number in Korean japonica rice was analyzed under greenhouse conditions in 160 recombinant inbred lines (RILs) derived from a cross between the temperate japonica varieties Odae and Unbong40 to identify quantitative trait loci (QTLs). A genetic map comprising 239 kompetitive allele-specific PCR (KASP) and 57 cleaved amplified polymorphic sequence markers was constructed. qTN3, a major QTL for tiller number, was identified at 132.4 cm on chromosome 3. This QTL was also detected under field conditions in a backcross population; thus, qTN3 was stable across generations and environments. qTN3 co-located with QTLs associated with panicle number per plant and culm diameter, indicating it had pleiotropic effects. The qTN3 regions of Odae and Unbong40 differed in a known functional variant (4 bp TGTG insertion/deletion) in the 5ʹ UTR of OsTB1, a gene underlying variation in tiller number and culm strength. Investigation of variation in genotype and tiller number revealed that varieties with the insertion genotype had lower tiller numbers than those with the reference genotype. A high-resolution melting marker was developed to enable efficient marker-assisted selection. The QTL qTN3 will therefore be useful in breeding programs developing japonica varieties with optimal tiller numbers for increased yield. Full article

Ticks are small, blood-sucking arachnids, known vectors of various diseases, and found throughout the world. They are distributed basically in almost all regions of China. At present, there is not much information regarding tick species on Hainan Island. They were subjected to morphological identification and imaging on an individual basis. Molecular phylogenetic analyses, based on cox1 and 16S rRNA genes, were utilized to identify the species and determine their approximate phylogenetic origin and genetic diversity. The genomic DNA of tick species was extracted, and cytochrome oxidase subunit 1 (cox1) and 16S ribosomal RNA (rRNA) genes were amplified and sequenced. The identification of five tick species, namely Rhipicephalus microplus, Rhipicephalus sanguineus, Rhipicephalus haemaphysaloides, Haemaphysalis cornigera and Haemaphysalis mageshimaensis, was carried out by morphological analysis. When employing the cox1 and 16S rRNA phylogenetic tree, all isolates of R. microplus from Hainan Island were classified as clade A and B, respectively. R. sanguineus was recognized as a member of the tropical lineage by phylogenetic analysis on the cox1 and 16S rRNA genes. Three phylogenetic groups of R. haemaphysaloides were recognized and found to be related closely to strains from China. H. cornigera and H. mageshimaensis formed one phylogenetic group, presumably from tick strains prevalent in Japan and China. The haplotype network analysis indicated that R. microplus is classed into 26 and 6 haplotypes, which correspond to cox1 and 16S rRNA gene assemblages, respectively. In addition, four cox1 haplotypes were detected in R. sanguineus. This is the first evidence that suggests genetic diversity, host range and geographical distribution of hard ticks in Hainan Island, China. Full article

The mitogenomic evolution of old-world cichlids is still largely incomplete in Western Africa. In this present study, the complete mitogenome of the Cameroon endemic cichlid, Coptodon camerunensis, was determined by next-generation sequencing. The mitogenome was 16,557 bp long and encoded with 37 genes (13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and a control region). The C. camerunensis mitogenome is AT-biased (52.63%), as exhibited in its congener, Coptodon zillii (52.76% and 53.04%). The majority of PCGs start with an ATG initiation codon, except COI, which starts with a GTG codon and five PCGs and ends with the TAA termination codon and except seven PCGs with an incomplete termination codon. In C. camerunensis mitogenome, most tRNAs showed classical cloverleaf secondary structures, except tRNA-serine with a lack of DHU stem. Comparative analyses of the conserved blocks of two Coptodonini species control regions revealed that the CSB-II block was longer than other blocks and contained highly variable sites. Using 13 concatenated PCGs, the mitogenome-based Bayesian phylogeny easily distinguished all the examined old-world cichlids. Except for Oreochromini and Coptodinini tribe members, the majority of the taxa exhibited monophyletic clustering within their respective lineages. C. camerunensis clustered closely with Heterotilapia buttikoferi (tribe Heterotilapiini) and had paraphyletic clustering with its congener, C. zillii. The Oreochromini species also displayed paraphyletic grouping, and the genus Oreochromis showed a close relationship with Coptodinini and Heterotilapiini species. In addition, illustrating the known distribution patterns of old-world cichlids, the present study is congruent with the previous hypothesis and proclaims that prehistoric geological evolution plays a key role in the hydroclimate of the African continent during Mesozoic, which simultaneously disperses and/or colonizes cichlids in different ichthyological provinces and Rift Lake systems in Africa. The present study suggests that further mitogenomes of cichlid species are required, especially from western Africa, to understand their unique evolution and adaptation. Full article

Environmental heat stress triggers a series of compensatory mechanisms in sheep that are dependent on their genetic regulation of thermotolerance. Our objective was to identify genes and regulatory pathways associated with thermotolerance in ewes exposed to heat stress. We performed next-generation RNA sequencing on blood collected from 16 pregnant ewes, which were grouped as tolerant and non-tolerant to heat stress according to a physiological indicator. Additional samples were collected to measure complete blood count. A total of 358 differentially expressed genes were identified after applying selection criteria. Gene expression analysis detected 46 GO terms and 52 KEGG functional pathways. The top-three signaling pathways were p53, RIG-I-like receptor and FoxO, which suggested gene participation in biological processes such as apoptosis, cell signaling and immune response to external stressors. Network analysis revealed ATM, ISG15, IRF7, MDM4, DHX58 and TGFβR1 as over-expressed genes with high regulatory potential. A co-expression network involving the immune-related genes ISG15, IRF7 and DXH58 was detected in lymphocytes and monocytes, which was consistent with hematological findings. In conclusion, transcriptomic analysis revealed a non-viral immune mechanism involving apoptosis, which is induced by external stressors and appears to play an important role in the molecular regulation of heat stress tolerance in ewes. Full article

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, and it is typically caused by PKD1 and PKD2 heterozygous variants. Nonetheless, the extensive phenotypic variability observed among affected individuals, even within the same family, suggests a more complex pattern of inheritance. We describe an ADPKD family in which the proband presented with an earlier and more severe renal phenotype (clinical diagnosis at the age of 14 and end-stage renal disease aged 24), compared to the other affected family members. Next-generation sequencing (NGS)-based analysis of polycystic kidney disease (PKD)-associated genes in the proband revealed the presence of a pathogenic PKD2 variant and a likely pathogenic variant in PKD1, according to the American College of Medical Genetics and Genomics (ACMG) criteria. The PKD2 nonsense p.Arg872Ter variant was segregated from the proband’s father, with a mild phenotype. A similar mild disease presentation was found in the proband’s aunts and uncle (the father’s siblings). The frameshift p.Asp3832ProfsTer128 novel variant within PKD1 carried by the proband in addition to the pathogenic PKD2 variant was not found in either parent. This report highlights that the co-inheritance of two or more PKD genes or alleles may explain the extensive phenotypic variability among affected family members, thus emphasizing the importance of NGS-based techniques in the definition of the prognostic course. Full article

Recurrent implantation failure (RIF) is defined as a failure to achieve pregnancy after multiple embryo transfers. Implantation is closely related to inflammatory gradients, and interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) play a key role in maternal and trophoblast inflammation during implantation. Signal transducer and activator of transcription 3 (STAT3) interacts with cytokines and plays a critical role in implantation through involvement in the inflammation of the embryo and placenta. Therefore, we investigated 151 RIF patients and 321 healthy controls in Korea and analyzed the association between the polymorphisms (STAT3 rs1053004, IL-1β rs16944, IL-6 rs1800796, and TNF-α rs1800629, 1800630) and RIF prevalence. In this paper, we identified that STAT3 rs1053004 (AG, adjusted odds rate [AOR] = 0.623; p = 0.027; GG, AOR = 0.513; p = 0.043; Dominant, AOR = 0.601, p = 0.011), IL-6 rs1800796 (GG, AOR = 2.472; p = 0.032; Recessive, AOR = 2.374, p = 0.037), and TNF-α rs1800629 (GA, AOR = 2.127, p = 0.010, Dominant, AOR = 2.198, p = 0.007) have a significant association with RIF prevalence. This study is the first to investigate the association of each polymorphism with RIF prevalence in Korea and to compare their effect based on their function on inflammation. Full article

Limb-girdle muscular dystrophies are a group of genetic disorders classically manifesting with progressive proximal muscle weakness. Affected individuals present with atrophy and weakness of the muscles of the shoulders and hips, and in some cases, intellectual disability or developmental delay has also been reported. Limb-girdle muscular dystrophy-3 is a recessive disorder caused by biallelic variants in the SGCA gene. Similarly, symptoms include proximal muscle weakness, elevated CPK, calf muscle pseudohypertrophy, and mobility issues. Cardiac symptoms and respiratory insufficiency are also common symptoms. This case report details a 3-year-old male with muscular weakness, elevated CK, and a neurodevelopmental disorder in whom a homozygous missense variant in c.229C>T (p.Arg77Cys) associated with limb-girdle muscular dystrophy-3 was found. This report shows the association between SGCA c.229C>T and neurodevelopmental disorders as observed in other muscular dystrophies. Full article