G-quadruplexes (G4s) formed by guanine-rich nucleic acids play a role in essential biological processes such as transcription and replication. Besides the >1.5 million putative G-4-forming sequences ...(PQSs), the human genome features >640 million single-nucleotide variations (SNVs), the most common type of genetic variation among people or populations. An SNV may alter a G4 structure when it falls within a PQS motif. To date, genome-wide PQS-SNV interactions and their impact have not been investigated. Herein, we present a study on the PQS-SNV interactions and the impact they can bring to G4 structures and, subsequently, gene expressions. Based on build 154 of the Single Nucleotide Polymorphism Database (dbSNP), we identified 5 million gains/losses or structural conversions of G4s that can be caused by the SNVs. Of these G4 variations (G4Vs), 3.4 million are within genes, resulting in an average load of >120 G4Vs per gene, preferentially enriched near the transcription start site. Moreover, >80% of the G4Vs overlap with transcription factor-binding sites and >14% with enhancers, giving an average load of 3 and 7.5 for the two regulatory elements, respectively. Our experiments show that such G4Vs can significantly influence the expression of their host genes. These results reveal genome-wide G4Vs and their impact on gene activity, emphasizing an understanding of genetic variation, from a structural perspective, of their physiological function and pathological implications. The G4Vs may also provide a unique category of drug targets for individualized therapeutics, health risk assessment, and drug development.
•We performed integrative analysis of genetic variations DNA excision repair pathway and their association with chemosensitivity and survival outcome in AML.•ERCC8 rs158572 is deemed the most ...clinically impactful due to its association with MRD positivity and refractory group.•XPC rs2228001 is correlated with the high WBC count and overall survival (OS) of AML.
Acute myeloid leukemia (AML) is a hematologic malignancy with a high recurrence rate and poor long-term prognosis. DNA excision repair systems, such as base excision repair (BER) and nucleotide excision repair (NER), play a major role in maintaining genomic stability and integrity. Further intensive investigations are necessary to uncover additional AML prognosis loci. In this study, we analyzed 16 candidate SNPs within NER and BER pathways in AML patients. Our results showed the GT/GG genotype of the XPC rs2228001 polymorphism was significantly associated with WBC count in dominant models (OR = 0.41, 95 % CI = 0.18–0.96, p = 0.039). Additionally, the rs25487 and rs3213245 SNPs in the XRCC1 gene, in both co-dominant and dominant models, were significantly associated with PLT count in AML (p < 0.05). The GG genotype of rs1130409 in APEX1 was more prone to adverse cytogenetics in both the codominant and recessive models (p < 0.05). Furthermore, the GA genotypes of ERCC8 rs158572 in codominant model was significantly correlated with refractory group (p < 0.05). ERCC8 rs158572 and XRCC1 rs3213245 in both codominant and dominant models were significantly correlated with the MRD positivity (p < 0.05). Kaplan-Meier analysis revealed an link between overall survival (OS) and the co-dominant, dominant, and recessive models of rs2228001 in XPC. Additionally, patients with the GG and GT/GG genotype in the co-dominant, dominant model and recessive model in XPC rs2228001 exhibited significantly longer survival (p < 0.05). Multivariate Cox analyses indicated that rs2228001 in both co-dominant and dominant models were independent favorable factors impacting patient OS (OR < 1). Our findings suggest that genetic polymorphisms in DNA excision repair pathway genetic polymorphisms contribute to the chemosensitivity and prognosis of acute myeloid leukemia.
Recent scientific advances in
ex situ
system design and operation make it possible to complete gametogenic cycles of broadcast spawning corals. Breeding corals in aquaria is a critical advance for ...population management, particularly genetic rescue and assisted gene flow efforts. Genetic rescue projects for corals are already underway to bring threatened species into
ex situ
culture and propagation, thereby preserving standing genetic variation. However, while breeding corals is increasingly feasible, the consequences of the aquarium environment on the genetic and phenotypic composition of coral populations is not yet known. The aquarium environment may in itself be a selective pressures on corals, but it also presents relaxed selective pressures in other respects. In 2019 and 2020, gravid
Acropora hyacinthus
coral colonies were collected from Palauan reefs and shipped to the California Academy of Sciences (CAS) in San Francisco. In both years, gametes were batch-fertilized to produce larvae that were then settled and reared to recruits. As of April 2021, when they were sampled for sequencing, 23 corals produced at CAS in 2019 and 16 corals produced at CAS in 2020 had survived for two years and one year, respectively. We sequenced the full genomes of the 39 offspring corals and their 15 potential parents to a median 26x depth of coverage. We find clear differential parentage, with some parents producing the vast majority of offspring, while the majority of parents produced no surviving offspring. After scanning 12.9 million single nucleotide polymorphisms (SNPs), we found 887 SNPs that may be under selection in the aquarium environment, and we identified the genes and pathways these SNPs may affect. We present recommendations for preserving standing genetic variation in aquarium-bred corals based on the results of this pilot project.
Vitamin A, an essential fat-soluble micronutrient, plays a critical role in the body, by regulating vision, immune responses, and normal development, for instance. Vitamin A deficiency (VAD) is a ...major cause of xerophthalmia and increases the risk of death from infectious diseases. It is also emerging that prenatal exposure to VAD is associated with disease risks later in life. The overall prevalence of VAD has significantly declined over recent decades; however, the rate of VAD is still high in many low- and mid-income countries and even in high-income countries among specific ethnic/race groups. While VAD occurs when dietary intake is insufficient to meet demands, establishing a strong association between food insecurity and VAD, and vitamin A supplementation is the primary solution to treat VAD, genetic contributions have also been reported to effect serum vitamin A levels. In this review, we discuss genetic variations associated with vitamin A status and vitamin A bioactivity-associated genes, specifically those linked to uptake of the vitamin in the small intestine and its storage in the liver, as well as their potential contribution to vitamin A deficiency risks among different ethnic groups.
Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that is highly prevalent in almost all human populations and is associated with many human cancers, such as nasopharyngeal carcinoma (NPC), ...Hodgkin's disease, and gastric carcinoma. However, in these EBV-associated cancers, only NPC exhibits remarkable ethnic and geographic distribution. We hypothesized that EBV genomic variations might contribute to the pathogenesis of different human cancers in different geographic areas. In this study, we collected 18 NPC biopsy specimens from the Hunan Province in southern China and
assembled 18 NPC biopsy specimen-derived EBV (NPC-EBV) genomes, designated HN1 to HN18. This was achieved through target enrichment of EBV DNA by hybridization, followed by next-generation sequencing, to reveal sequence diversity. These EBV genomes harbored 20,570 variations totally, including 20,328 substitutions, 88 insertions, and 154 deletions, compared to the EBV reference genome. Phylogenetic analysis revealed that all NPC-EBV genomes were distinct from other EBV genomes. Furthermore, HN1 to HN18 had some nonsynonymous variations in EBV genes including genes encoding latent, early lytic, and tegument proteins, such as substitutions within transmembrane domains 1 and 3 of LMP1, FoP_duplication, and zf-AD domains of ENBA1, in addition to aberrations in noncoding regions, especially in BamHI A rightward transcript microRNAs. These variations might have potential biological significance. In conclusion, we reported a genome-wide view of sequence variation in EBV isolated from primary NPC biopsy specimens obtained from the Hunan Province. This might contribute to further understanding of how genomic variations contribute to carcinogenesis, which would impact the treatment of EBV-associated cancer.
Nasopharyngeal carcinoma (NPC) is highly associated with Epstein-Barr virus (EBV) infection and exhibits remarkable ethnic and geographic distribution. Hunan Province in southern China has a high incidence rate of NPCs. Here, we report 18 novel EBV genome sequences from viruses isolated from primary NPC biopsy specimens in this region, revealing whole-genome sequence diversity.
Drought is a big challenge for agricultural production. Root attributes are the important target traits for breeding high-yielding sustainable wheat varieties against ever changing climatic ...conditions. However, the transcriptomic of wheat concerning root architecture remained obscure. Here, we explored RNA-Seq based transcriptome to dissect putative genes involved in root system variations in naturally occurring six genotypes (drought-tolerant and sensitive) of wheat. Global RNA-Seq based root transcriptome analysis revealed single nucleotide polymorphisms (SNPs) variations and differentially expressed genes. Putative 56 SNPs were identified related to 15 genes involved in root architecture. Enrichment of these genes using GO terms demonstrated that differentially expressed genes (DEGs) are divided into sub-categories implicated in molecular functions, cellular components and biological processes. The KEGG analysis of DEGs in each comparison of genotype include metabolic, biosynthesis of secondary metabolites, microbial metabolism in diverse environments and biosynthesis of antibiotics. A deeper insight into DEGs unveiled various pathways involved in drought response and positive gravitropism. These genes belong to various transcription factor families such as DOF, C3H, MYB, and NAC involved in root developmental and stress-related pathways. Local White and UZ-11-CWA-8, which are drought-tolerant genotypes, harbor over-representation of most of DEGs or transcription factors. Notably, a microtubule-associated protein MAPRE1 belonging to RP/EB family recruited in positive gravitropism was enriched. Real-time PCR analysis revealed expression of MAPRE1 and PAL genes is consistent with RNA-seq data. The presented data and genetic resources seem valuable for providing genes involved in the root system architecture of drought-tolerant and susceptible genotypes.
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•RNA-Seq based transcriptome dissect the putative genes involved in root system.•Putative 56 SNPs were identified related to 15 genes involved in root architecture.•MAPRE1 involved in root architecture under drought.
Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in ...childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract.
The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway.
We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate “in silico” analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range.
The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).
•Inflammatory Bowel Disease and Genetic heterogeneity with different severity levels.•Very early onset is associated with more genetic variants.•Genetic variants and in silico analysis to predict the variant impact on the protein.
Bovine herpesvirus type 1 (BoHV-1) is one of the most critical pathogens in cattle and is prevalent in China. BoHV-1 is divided into two gene types, BoHV-1.1 and 1.2, which are further differentiated ...into two subtypes, BoHV-1.2a and 1.2b. However, the phylogenetic analysis of BoHV-1 isolates has not been reported in China. To perform a molecular epidemiological survey based on isolates from cattle in China, 102 lung tissue samples of calves under ten months of age with respiratory disease (BRD) that died from 2016 to 2019 in China were used to isolate BoHV-1 with Madin-Darby bovine kidney (MDBK) cells. Part of the BoHV-1 isolates were applied to the phylogenetic analysis based on the region of the glycoprotein C (gC) gene of BoHV-1. Thirty BoHV-1 isolates were obtained, and the gC gene of 13 isolates was amplified by polymerase chain reaction (PCR) methods and sequenced. The result of the phylogenetic analysis according to the 451-nucleotide portion of the gC gene found that all of 13 isolates belonged to the BoHV-1.2b gene subtype, but these isolates had located two different phylogenetic tree branches. The gC gene sequence homology of isolates in group1 was higher with a reference strain of BoHV-1.2b EVI14 up to 98.0–100%, while in group 2, this was higher with reference strain BoHV-1.2b B589 up to 97.8–99.8%. The deduced amino acid sequence of gC from isolates in group 2 had two amino acid mutations with interference strain BoHV-1.2b K22 or BoHV-1.1 COOPER. The cytopathic effects (CPEs) of BoHV-1 isolates in group 2 were ulcered on the centration like a volcano on MDBK cell, and different from traditional CPEs of BoHV-1. Overall, BoHV-1.2b seems to be the primary strain of BoHV-1 in cattle in China and is also a critical cause of BRD. These BoHV-1.2b isolates had significant genetic variations.
•The paper firstly reported the molecular epidemiology study of BoHV-1 strains from naturally infected cattle in China.•Bovine herpesvirus type 1.2b is prevalent gene type of BoHV-1 in cattle with respiratory disease in China.•Bovine herpesvirus type 1.2b isolates had significant genetic variations, further divided into two groups.•The cytopathic effects (CPEs) of BoHV-1 isolates in group 2 were different from traditional BoHV-1 CPEs.
The translin-associated factor X (TSNAX) gene, located adjacent to the DISC1 gene, has been implicated in schizophrenia. While cognitive impairment determines long-term the functional outcome of ...schizophrenia, the role of TSNAX in cognitive dysfunction of schizophrenia patients remains elusive. This study aimed to explore the genetic effect of TSNAX on cognitive functions of schizophrenia.
We recruited 286 chronic schizophrenia patients who had been stabilized with antipsychotics for at least 2 months and genotyped three TSNAX SNPs (rs1630250, rs766288, rs6662926). Clinical symptoms and seven cognitive domains were assessed. The score of cognitive tests was standardized to T score.
Clinical symptoms were similar among genotypes of all the three SNPs. The GLM analysis demonstrated that TSNAX genetic polymorphisms influenced cognitive function of schizophrenia patients after adjustment for gender, age, and education. The patients with the rs1630250 C/G genotype performed better than the G/G homozygotes in the Trail Making A (p = 0.034). Those with the rs766288 G/T genotype also performed better than the G/G homozygotes in the Trail Making A (p = 0.012). The patients with the G/G genotype of rs6662926 also performed better than the C/C homozygotes in verbal learning and memory test (p = 0.044).
This study suggests that the TSNAX gene variation may influence the cognitive functions of the patients with schizophrenia.
•TSNAX variations affected the cognitive functions of the schizophrenia patients.•The rs1630250 C/G heterozygotes exceeded the G/G homozygotes in Trail Making A.•The rs766288 C/A heterozygotes surpassed the C/C homozygotes in Trail Making A.•The rs6662926 G/G homozygotes excelled the C/C homozygotes in verbal memory.•These genetic effects were primary, because clinical symptoms were not affected.
Polygenetic Risk Scores are used to evaluate an individual's vulnerability to developing specific diseases or conditions based on their genetic composition, by taking into account numerous genetic ...variations. This article provides an overview of the concept of Polygenic Risk Scores (PRS). We elucidate the historical advancements of PRS, their advantages and shortcomings in comparison with other predictive methods, and discuss their conceptual limitations in light of the complexity of biological systems. Furthermore, we provide a survey of published tools for computing PRS and associated resources. The various tools and software packages are categorized based on their technical utility for users or prospective developers. Understanding the array of available tools and their limitations is crucial for accurately assessing and predicting disease risks, facilitating early interventions, and guiding personalized healthcare decisions. Additionally, we also identify potential new avenues for future bioinformatic analyzes and advancements related to PRS.
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