scholarly journals 3127 The effect of common genetic variants in the oxytocin receptor gene on oxytocin response.

2019 ◽  
Vol 3 (s1) ◽  
pp. 115-115
Author(s):  
Manasi Malik ◽  
Naiqi Shi ◽  
Geraldine Serwald ◽  
Grace Y. Lee ◽  
Antonina I. Frolova ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Genetic Variants ◽  
Oxytocin Receptor ◽  
Labor Induction ◽  
Allelic Expression ◽  
Receptor Function ◽  
Allelic Expression Imbalance ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Common Genetic Variants

OBJECTIVES/SPECIFIC AIMS: Previous studies suggest that genetic variants in the oxytocin receptor (OXTR) may alter oxytocin dose requirement for labor induction and may increase risk for preterm labor and neurodevelopmental disorders. However, the mechanisms of actions of these variants remain unknown. The goal of this study was to functionally characterize common missense and noncoding variants in OXTR. First, we aimed to determine the effects of missense variants on two major aspects of receptor function: calcium signaling and β-arrestin recruitment. Second, we used allelic expression imbalance assays in an effort to identify regulatory single nucleotide polymorphisms (SNPs) in noncoding regions of OXTR that alter OXTR mRNA expression. METHODS/STUDY POPULATION: We used the Exome Aggregation Consortium database to identify the 12 most prevalent missense single nucleotide variants in OXTR. To determine the functional effects of these variants, we transfected human embryonic kidney cells (a common model system used to study receptor function) with wild type OXTR, variant OXTR, or empty vector control. We used the calcium-sensitive dye Fluo4 to quantify intracellular calcium flux in response to oxytocin treatment, and used bioluminescence resonance energy transfer assays to measure recruitment of the signaling partner β-arrestin to the receptor. To investigate potential effects of noncoding SNPs on OXTR mRNA expression, we quantified allele-specific expression of OXTR in human uterine tissue obtained from participants at the time of Cesarean section. We used next-generation sequencing (Illumina MiSeq) to count alleles of a reporter SNP in OXTR exon 3. RESULTS/ANTICIPATED RESULTS: Of the 12 most prevalent missense single nucleotide variants, four were predicted to be deleterious by PolyPhen variant annotation software. We anticipate that these variants will alter receptor signaling through calcium or β-arrestin pathways. We further observed that a reporter SNP in OXTR exon 3 exhibits significant allelic expression imbalance in a subset of our myometrial tissue samples, indicating that OXTR expression may be regulated by a functional SNP. Our current work focuses on discovering the functional SNPs in OXTR responsible for the pattern of allelic expression imbalance seen in mRNA. In the future, we will seek to explore the effects of these variants on uterine function by using genome editing of uterine smooth muscle cells. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that both missense and noncoding variants may affect OXTR expression and function. Future studies may suggest that OXTR sequencing, genotyping, or expression analysis would be useful to identify individuals likely to respond or fail to respond to safe doses of oxytocin for labor induction. Personalizing approaches for labor induction in this way would increase the safety of oxytocin and potentially reduce maternal morbidity and mortality.

scholarly journals Common genetic variants and pathways in diabetes and associated complications and vulnerability of populations with different ethnic origins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sabrina Samad Shoily ◽  
Tamim Ahsan ◽  
Kaniz Fatema ◽  
Abu Ashfaqur Sajib
Keyword(s):  
Diabetes Mellitus ◽  
Chronic Kidney Disease ◽  
Genetic Variants ◽  
Nucleotide Polymorphisms ◽  
Differential Distribution ◽  
East Asians ◽  
Single Nucleotide ◽  
Common Genetic Variants ◽  
Haplotype Frequencies ◽  
Variant Alleles

AbstractDiabetes mellitus is a complex and heterogeneous metabolic disorder which is often pre- or post-existent with complications such as cardiovascular disease, hypertension, inflammation, chronic kidney disease, diabetic retino- and nephropathies. However, the frequencies of these co-morbidities vary among individuals and across populations. It is, therefore, not unlikely that certain genetic variants might commonly contribute to these conditions. Here, we identified four single nucleotide polymorphisms (rs5186, rs1800795, rs1799983 and rs1800629 in AGTR1, IL6, NOS3 and TNFA genes, respectively) to be commonly associated with each of these conditions. We explored their possible interplay in diabetes and associated complications. The variant allele and haplotype frequencies at these polymorphic loci vary among different super-populations (African, European, admixed Americans, South and East Asians). The variant alleles are particularly highly prevalent in different European and admixed American populations. Differential distribution of these variants in different ethnic groups suggests that certain drugs might be more effective in selective populations rather than all. Therefore, population specific genetic architectures should be considered before considering a drug for these conditions.

scholarly journals scSNV: accurate dscRNA-seq SNV co-expression analysis using duplicate tag collapsing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Gavin W. Wilson ◽  
Mathieu Derouet ◽  
Gail E. Darling ◽  
Jonathan C. Yeung
Keyword(s):  
Genetic Variants ◽  
False Positive ◽  
Variant Calling ◽  
Call Rate ◽  
Rna Seq ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Variant Call ◽  
Two Samples ◽  
Co Detection

AbstractIdentifying single nucleotide variants has become common practice for droplet-based single-cell RNA-seq experiments; however, presently, a pipeline does not exist to maximize variant calling accuracy. Furthermore, molecular duplicates generated in these experiments have not been utilized to optimally detect variant co-expression. Herein, we introduce scSNV designed from the ground up to “collapse” molecular duplicates and accurately identify variants and their co-expression. We demonstrate that scSNV is fast, with a reduced false-positive variant call rate, and enables the co-detection of genetic variants and A>G RNA edits across twenty-two samples.

scholarly journals AllelePred: A Simple Allele Frequencies Ensemble Predictor for Different Single Nucleotide Variants

2021 ◽  
Author(s):  
Turki Sobahy ◽  
Meshari Alazmi
Keyword(s):  
Genetic Variants ◽  
Single Gene ◽  
Genomic Medicine ◽  
Vital Role ◽  
Ensemble Prediction ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Single Gene Disorders ◽  
Medical Diagnostic ◽  
Coding Variants

Genomic medicine stands to be revolutionized through the understanding of single nucleotide variants (SNVs) and their expression in single-gene disorders (mendelian diseases). Computational tools can play a vital role in the exploration of such variations and their pathogenicity. Consequently, we developed the ensemble prediction tool AllelePred to identify deleterious SNVs and disease causative genes. In comparison to other tools, our classifier achieves higher accuracy, precision, F1 score, and coverage for different types of coding variants. Furthermore, this research analyzes and structures 168,945 broad spectrum genetic variants from the genomes of the Saudi population to denote the accuracy of the model. When compared, AllelePred was able to structure the unlabeled Saudi genetic variants of the dataset to mimic the data characteristics of the known labeled data. On this basis, we accumulated a list of highly probable deleterious variants that we recommend for further experimental validation prior to medical diagnostic usage.<br>

scholarly journals Discovery of human ACE2 variants with altered recognition by the SARS-CoV-2 spike protein

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251585
Author(s):  
Pete Heinzelman ◽  
Philip A. Romero
Keyword(s):  
Clinical Trial ◽  
Genetic Variants ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Spike Protein ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Novel Variants ◽  
The Future ◽  
Fundamental Research

Understanding how human ACE2 genetic variants differ in their recognition by SARS-CoV-2 can facilitate the leveraging of ACE2 as an axis for treating and preventing COVID-19. In this work, we experimentally interrogate thousands of ACE2 mutants to identify over one hundred human single-nucleotide variants (SNVs) that are likely to have altered recognition by the virus, and make the complementary discovery that ACE2 residues distant from the spike interface influence the ACE2-spike interaction. These findings illuminate new links between ACE2 sequence and spike recognition, and could find substantial utility in further fundamental research that augments epidemiological analyses and clinical trial design in the contexts of both existing strains of SARS-CoV-2 and novel variants that may arise in the future.

scholarly journals Driving mosaicism: somatic variants in reference population databases and effect on variant interpretation in rare genetic disease

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Vladimir Avramović ◽  
Simona Denise Frederiksen ◽  
Marjana Brkić ◽  
Maja Tarailo-Graovac
Keyword(s):  
Cell Proliferation ◽  
Genetic Variants ◽  
Allelic Imbalance ◽  
Autosomal Dominant ◽  
Reference Population ◽  
Mendelian Disease ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
The Impact ◽  
Population Databases

Abstract Background Genetic variation databases provide invaluable information on the presence and frequency of genetic variants in the ‘untargeted’ human population, aggregated with the primary goal to facilitate the interpretation of clinically important variants. The presence of somatic variants in such databases can affect variant assessment in undiagnosed rare disease (RD) patients. Previously, the impact of somatic mosaicism was only considered in relation to two Mendelian disease-associated genes. Here, we expand the analyses to identify additional mosaicism-prone genes in blood-derived reference population databases. Results To identify additional mosaicism-prone genes relevant to RDs, we focused on known/previously established ClinVar pathogenic and likely pathogenic single-nucleotide variants, residing in genes associated with early onset, severe autosomal dominant diseases. We asked whether any of these variants are present in a higher-than-expected frequency in the reference population databases and whether there is evidence of somatic origin (i.e., allelic imbalance) rather than germline heterozygosity (~ half of the reads supporting alternative allele). The mosaicism-prone genes identified were further categorized according to the processes they are involved in. Beyond the previously reported ASXL1 and DNMT3A, we identified 7 additional autosomal dominant RD-associated genes with known pathogenic single-nucleotide variants present in the reference population databases and good evidence of allelic imbalance: BRAF, CBL, FGFR3, IDH2, KRAS, PTPN11 and SETBP1. From this group of 9 genes, the majority (n = 7) was important for hematopoiesis. In addition, 4 of these genes were involved in cell proliferation. Further assessment of the known 156 hematopoietic genes led to identification of 48 genes (21 not yet associated with RDs) with at least some evidence of mosaicism detectable in reference population databases. Conclusions These results stress the importance of considering genes involved in hematopoiesis and cell proliferation when interpreting the presence and frequency of genetic variants in blood-derived reference population databases, both public and private. This is especially important when considering new variants of uncertain significance in known hematopoietic/cell proliferation RD genes and future novel gene–disease associations involving this class of genes.

High Throughput Transcriptome Sequencing of Pediatric Relapsed Acute Lymphoblastic Leukemia (ALL) Identifies Relapse Specific Mutations and Expression

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3233-3233
Author(s):  
Julia A. Meyer ◽  
Laura E. Hogan ◽  
Jinhua Wang ◽  
Jun J. Yang ◽  
Jay Patel ◽  
...  
Keyword(s):  
High Throughput ◽  
Genetic Variants ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Illumina Genome Analyzer ◽  
Sequencing Analysis ◽  
Single Nucleotide Variants ◽  
Specific Expression ◽  
Single Nucleotide

Abstract Abstract 3233 Introduction: Relapsed ALL carries a very poor prognosis despite intensive therapy, indicating the need for new insights into disease mechanisms. We have previously used gene expression profiling (Hogan et al. ASH 2009) and copy number analysis (Yang et al. Blood 2008) in paired diagnosis and relapsed ALL samples to better understand the biologic mechanisms leading to recurrent disease. To create an integrated genomic profile of ALL, we have now focused on high throughput RNA sequencing to detect changes in the transcriptome from diagnosis to relapse. Patients/Methods: To date we have sequenced 6 matched diagnosis/relapse pairs (i.e. 12 marrow samples) from B-precursor ALL patients enrolled on Children's Oncology Group (COG) P9906 and AALL0232 trials. RNA libraries were prepared from poly-A selected RNA and sequenced using 54 base pair single end reads using the Illumina Genome Analyzer IIx. Each sample was sequenced in at least 7 lanes, generating an average of 100 million reads per sample. BWA (v0.5.8) was used to align the reads to the human genome, producing an average of 53 million mapped reads. Samtools (v0.1.8) was then used to predict genetic variants across the genome, filtering out variants with a low mapping quality (<Q20), sub-optimal alignment (X:1>0), low coverage (<8X), or overlap with known single nucleotide polymorphisms (SNPs) from dbSNP (r131) or the 1000 Genomes Project. Results: We observed a total of 119,000 genetic variants across all samples, with comparable overall mutational burden at relapse and diagnosis. To identify candidate lesions that may indicate a selection for common chemoresistance pathways, we focused our analysis on relapse-enriched, non-synonymous variants. 8,486 non-synonymous variants (insertions/deletions and single nucleotide variants [SNV]) were identified that occurred more often at relapse compared to diagnosis. Our analysis was focused on relapse-enriched SNVs that coded for non-synonymous changes, of which 154 were prioritized for validation. Validation was completed using matched genomic DNA samples and PCR products were directly sequenced. Mutation calls were made by manual review of tracings using the Mutation Surveyor program from Softgenetics. Thirty-three percent of predicted SNV loci were validated, but upon further sequencing of matched germline samples, five relapse specific mutations were confirmed. Mutations in COBRA1, FAM120A, RGS12, SND2, and SMEK2 were found in individual patient relapse samples. Validation is currently ongoing to confirm additional SNVs and an expanded validation of mutations will be completed in an additional 66 matched diagnosis/relapse pairs from COG 9906 and AALL 0232 and 0331 studies. Relapse specific isoforms identifying alternative exon usage was also detected in 15 genes, all of which were shared amongst multiple patients. In addition, a significant increase (p=6.7×10−6) was observed in the number of poly-adenylation sites in the genes of the relapse samples. Conclusions: While, isoform specific expression was shared amongst patients at relapse, all relapse specific mutations were private and our data to date indicate that a diversity of mechanisms contribute to relapsed disease. Further sequencing analysis of our expanded cohort of samples will determine the mutation and isoform expression prevalence, as well as the functional significance and the potential therapeutic relevance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Bone marrow stromal antigen 2 (BST-2) genetic variants influence expression levels and disease outcome in HIV-1 chronically infected patients

2021 ◽  
Author(s):  
Hlelolwenkosi Mlimi ◽  
Kewreshini K. Naidoo ◽  
Jenniffer Mabuka ◽  
Thumbi Ndung’u ◽  
Paradise Madlala
Keyword(s):  
Viral Load ◽  
Mrna Expression ◽  
Genetic Variants ◽  
Disease Outcome ◽  
Mrna Levels ◽  
Single Nucleotide ◽  
Cd4 Counts ◽  
Expression Levels ◽  
Hiv 1 ◽  
Mrna Expression Levels

Abstract BackgroundBone marrow stromal antigen 2 (BST-2) also known as Tetherin (CD317/HM1.24), is a host restriction factor that blocks the release of HIV-1 virions from infected cells. Previous studies reported that BST-2 genetic variants or single nucleotide polymorphims (SNPs) have a preventative role during HIV-1 infection. However, the influence of BST-2 SNPs on expression levels remains unknown. In this study, we investigated the inffluence of BST-2 SNPs on expression levels and disease outcome in HIV-1 subtype C chronically infected antiretroviral therapy naïve individuals.ResultsWe quantified BST-2 mRNA levels in peripheral blood mononuclear cells (PBMCs), determined BST-2 protein expression on the surface of CD4 + T cells using flow cytometry and genotyped single nucleotide polymorphisms (SNPs) rs919267, rs919266 and rs9576 using TaqMan assays from HIV-1 uninfected and infected participants. Determined the ability of plasma antibody levels to meadiate andibodydependenet cellular phagocytosis (ADCP) using gp120 consensus C and p24 subtype B/C protein. Fc receptor-mediated NK cell degranulation was evaluated as a surrogate for ADCC activity using plasma from HIV-1 positive participants. BST-2 mRNA expression levels in PBMCs and protein levels on CD4 + T cells were lower in HIV-1 infected compared to uninfected participants (p=0.075 and p=0.005, respectively). rs919267CT (p=0.042) and rs919267TT (p=0.045) were associated with lower BST-2 mRNA expression levels compared to rs919267CC in HIV-1 uninfected participants. In HIV-1 infected participants, rs919267CT associated with lower CD4 count, (p=0.003), gp120-IgG1 (p=0.040), gp120-IgG3 (p=0.016) levels and but higher viral load (p=0.001) while rs919267TT was associated with lower BST-2 mRNA levels (p=0.046), CD4 counts (p=0.001), gp120-IgG1 levels (p=0.033) but higher plasma viral load (p=0.007). Conversely, rs9576CA was associated with higher BST-2 mRNA expression levels (p=0.027), CD4 counts (p=0.079), gp120-IgG1 (p=0.009), -IgG3 (p=0.039) levels and but with lower viral load (p=0.037). However, there was not correlation between BST-2 SNPs, p24-IgG subclass, ADCC and ADCP activity. ConclusionOur findings show that bst- 2 SNPs mediate BST-2 expression and disease outcome, correlate with gp120-IgG1, gp120-IgG3 levels but p24-IgG levels, ADCC and ADCP activity. Future studies should investigate the role of BST-2 polymorphic variants on improving myeloid dentritic cell (DC) activation and MHC class II antigene presentation.

scholarly journals Targeted Sequencing Identifies the Genetic Variants Associated with High-altitude Polycythemia in the Tibetan Population

2021 ◽  
Author(s):  
Zhiying Zhang ◽  
Lifeng Ma ◽  
Xiaowei Fan ◽  
Kun Wang ◽  
Lijun Liu ◽  
...  
Keyword(s):  
High Altitude ◽  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Oxygen Metabolism ◽  
Targeted Sequencing ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Pathway Enrichment ◽  
Excessive Proliferation ◽  
Stat Pathway

AbstractHigh-altitude polycythemia (HAPC) is characterized by excessive proliferation of erythrocytes, resulting from the hypobaric hypoxia condition in high altitude. The genetic variants and molecular mechanisms of HAPC remain unclear in highlanders. We recruited 141 Tibetan dwellers, including 70 HAPC patients and 71 healthy controls, to detect the possible genetic variants associated with the disease; and performed targeted sequencing on 529 genes associated with the oxygen metabolism and erythrocyte regulation, utilized unconditional logistic regression analysis and GO (gene ontology) analysis to investigate the genetic variations of HAPC. We identified 12 single nucleotide variants, harbored in 12 genes, associated with the risk of HAPC (4.7 ≤ odd ratios ≤ 13.6; 7.6E − 08 ≤ p-value ≤ 1E − 04). The pathway enrichment study of these genes indicated the three pathways, the PI3K-AKT pathway, JAK-STAT pathway, and HIF-1 pathway, are essential, which p-values as 3.70E − 08, 1.28 E − 07, and 3.98 E − 06, respectively. We are hopeful that our results will provide a reference for the etiology research of HAPC. However, additional genetic risk factors and functional investigations are necessary to confirm our results further.

scholarly journals Bisulfite-free epigenomics and genomics of single cells through methylation-sensitive restriction

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Christoph Niemöller ◽  
Julius Wehrle ◽  
Julian Riba ◽  
Rainer Claus ◽  
Nathalie Renz ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Myeloid Leukemia ◽  
Single Cells ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Powerful Means ◽  
Genetic Profiles

AbstractSingle-cell multi-omics are powerful means to study cell-to-cell heterogeneity. Here, we present a single-tube, bisulfite-free method for the simultaneous, genome-wide analysis of DNA methylation and genetic variants in single cells: epigenomics and genomics of single cells analyzed by restriction (epi-gSCAR). By applying this method, we obtained DNA methylation measurements of up to 506,063 CpGs and up to 1,244,188 single-nucleotide variants from single acute myeloid leukemia-derived cells. We demonstrate that epi-gSCAR generates accurate and reproducible measurements of DNA methylation and allows to differentiate between cell lines based on the DNA methylation and genetic profiles.

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