scholarly journals A De Novo MITF Deletion Explains a Novel Splashed White Phenotype in an American Paint Horse

2020 ◽  
Vol 111 (3) ◽  
pp. 287-293
Author(s):  
K Gary Magdesian ◽  
Jocelyn Tanaka ◽  
Rebecca R Bellone
Keyword(s):  
Protein Function ◽  
De Novo ◽  
Coat Color ◽  
Causal Variant ◽  
Color Pattern ◽  
De Novo Mutation ◽  
Nucleotide Polymorphisms ◽  
Helix Loop Helix ◽  
Blue Eyes

Abstract Splashed white is a coat color pattern in horses characterized by extensive white patterning on the legs, belly, and face often accompanied by blue eyes and deafness. Three mutations in microphthalmia-associated transcription factor (MITF) and two mutations in Paired Box 3 (PAX3) have been identified that explain splashed white patterns (SW1–SW5). An American Paint Horse stallion with a splashed white phenotype and blue eyes, whose parents were not white patterned, was negative for the 5 known splashed white variants and other known white spotting alleles. This novel splashed white phenotype (SW6) was hypothesized to be caused by a de novo mutation in MITF or PAX3. Analysis of whole-genome sequencing using the EquCab3.0 reference genome for comparison identified an 8.7 kb deletion in MITF on ECA16 (NC_009159.3:g.21551060-21559770del). The deletion encompassed part of intron 7 through the 3′ UTR of exon 9 of MITF, including the helix-loop-helix DNA-binding domain (ENSECAT00000006375.3). This variant is predicted to truncate protein and impair binding to DNA. Sanger sequencing confirmed the stallion was heterozygous for the MITF deletion. No single nucleotide polymorphisms (SNPs) or structural variants were identified in PAX3 or any of the other candidate genes that were unique to the stallion or predicted to affect protein function. Genotyping five of the stallion’s splashed white offspring, including one all white foal, found that they were also heterozygous for the deletion. Given the role of MITF in producing white pattern phenotypes, and the predicted deleterious effect of this mutation, this 8.7 kb deletion is the likely causal variant for SW6.

scholarly journals Clinical Perspectives of ERCC1 in Bladder Cancer

2020 ◽  
Vol 21 (22) ◽  
pp. 8829
Author(s):  
Konstantinos Koutsoukos ◽  
Angeliki Andrikopoulou ◽  
Nikos Dedes ◽  
Flora Zagouri ◽  
Aristotelis Bamias ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Dna Adducts ◽  
Protein Function ◽  
Excision Repair ◽  
Locally Advanced ◽  
Platinum Resistance ◽  
Nucleotide Polymorphisms ◽  
Repair Capacity ◽  
Dna Repair Capacity

ERCC1 is a key regulator of nucleotide excision repair (NER) pathway that repairs bulky DNA adducts, including intrastrand DNA adducts and interstrand crosslinks (ICLs). Overexpression of ERCC1 has been linked to increased DNA repair capacity and platinum resistance in solid tumors. Multiple single nucleotide polymorphisms (SNPs) have been detected in ERCC1 gene that may affect ERCC1 protein expression. Platinum-based treatment remains the cornerstone of urothelial cancer treatment. Given the expanding application of neoadjuvant and adjuvant chemotherapy in locally advanced bladder cancer, there is an emerging need for biomarkers that could distinguish potential responders to cisplatin treatment. Extensive research has been done regarding the prognostic and predictive role of ERCC1 gene expression and polymorphisms in bladder cancer. Moreover, novel compounds have been recently developed to target ERCC1 protein function in order to maximize sensitivity to cisplatin. We aim to review all the existing literature regarding the role of the ERCC1 gene in bladder cancer and address future perspectives for its clinical application.

scholarly journals Genetic characterization of coat color genes in Brazilian Crioula sheep from a conservation nucleus

2017 ◽  
Vol 52 (8) ◽  
pp. 615-622 ◽  
Author(s):  
Lilian Cristina Gomes Cavalcanti ◽  
José Carlos Ferrugem Moraes ◽  
Danielle Assis de Faria ◽  
Concepta Margaret McManus ◽  
Alcebiades Renato Nepomuceno ◽  
...  
Keyword(s):  
Coat Color ◽  
Color Variation ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Epistatic Interactions ◽  
Low Frequencies ◽  
Melanocortin 1 Receptor ◽  
Tyrosinase Related Protein

Abstract: The objective of this work was to identify single nucleotide polymorphisms (SNPs) in resequencing data from MC1R, ASIP, and TYRP1 genes derived from Crioula sheep (Ovis aris) with different coat colors. Polymorphisms in the ASIP (agouti-signaling protein), MC1R (melanocortin 1 receptor), and TRYP1 (tyrosinase-related protein 1) genes were analyzed in 115 sheep from Embrapa’s conservation nucleus of crioula sheep, in Brazil. A total of 7,914 bp were sequenced per animal, and 14 SNPs were identified. Two additional assays were performed to detect duplications and deletions in the ASIP gene. Ninety-five percent of the coat color variation was explained by epistatic interactions observed between specific alleles in the MC1R and ASIP genes. Evidence suggests an important role of TYRP1 variants for wool color, despite their low frequencies. The marker panel was efficient enough in predicting coat color in the studied animals and, therefore, can be used to implement a marker-assisted selection program in the conservation nucleus of sheep of the crioula breed.

scholarly journals Structural Variants in SARS-CoV-2 Occur at Template-Switching Hotspots

2020 ◽  
Author(s):  
Brianna Chrisman ◽  
Kelley Paskov ◽  
Nate Stockham ◽  
Kevin Tabatabaei ◽  
Jae-Yoon Jung ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Evolutionary Dynamics ◽  
De Novo ◽  
Template Switching ◽  
Nucleotide Polymorphisms ◽  
Structural Variants ◽  
Consensus Sequences ◽  
The Relationship ◽  
Folded Rna

ABSTRACTThe evolutionary dynamics of SARS-CoV-2 have been carefully monitored since the COVID-19 pandemic began in December 2019, however, analysis has focused primarily on single nucleotide polymorphisms and largely ignored the role of structural variants (SVs) as well as recombination in SARS-CoV-2 evolution. Using sequences from the GISAID database, we catalogue over 100 insertions and deletions in the SARS-CoV-2 consensus sequences. We hypothesize that these indels are artifacts of imperfect homologous recombination between SARS-CoV-2 replicates, and provide four independent pieces of evidence. (1) The SVs from the GISAID consensus sequences are clustered at specific regions of the genome. (2) These regions are also enriched for 5’ and 3’ breakpoints in the transcription regulatory site (TRS) independent transcriptome, presumably sites of RNA-dependent RNA polymerase (RdRp) template-switching. (3) Within raw reads, these structural variant hotspots have cases of both high intra-host heterogeneity and intra-host homogeneity, suggesting that these structural variants are both consequences of de novo recombination events within a host and artifacts of previous recombination. (4) Within the RNA secondary structure, the indels occur in “arms” of the predicted folded RNA, suggesting that secondary structure may be a mechanism for TRS-independent template-switching in SARS-CoV-2 or other coronaviruses. These insights into the relationship between structural variation and recombination in SARS-CoV-2 can improve our reconstructions of the SARS-CoV-2 evolutionary history as well as our understanding of the process of RdRp template-switching in RNA viruses.

scholarly journals Indels in SARS-CoV-2 occur at template-switching hotspots

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Brianna Sierra Chrisman ◽  
Kelley Paskov ◽  
Nate. Stockham ◽  
Kevin Tabatabaei ◽  
Jae-Yoon Jung ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Rna Polymerase ◽  
Evolutionary Dynamics ◽  
De Novo ◽  
Template Switching ◽  
Nucleotide Polymorphisms ◽  
Rna Dependent Rna Polymerase ◽  
Consensus Sequences ◽  
Insertions And Deletions

AbstractThe evolutionary dynamics of SARS-CoV-2 have been carefully monitored since the COVID-19 pandemic began in December 2019. However, analysis has focused primarily on single nucleotide polymorphisms and largely ignored the role of insertions and deletions (indels) as well as recombination in SARS-CoV-2 evolution. Using sequences from the GISAID database, we catalogue over 100 insertions and deletions in the SARS-CoV-2 consensus sequences. We hypothesize that these indels are artifacts of recombination events between SARS-CoV-2 replicates whereby RNA-dependent RNA polymerase (RdRp) re-associates with a homologous template at a different loci (“imperfect homologous recombination”). We provide several independent pieces of evidence that suggest this. (1) The indels from the GISAID consensus sequences are clustered at specific regions of the genome. (2) These regions are also enriched for 5’ and 3’ breakpoints in the transcription regulatory site (TRS) independent transcriptome, presumably sites of RNA-dependent RNA polymerase (RdRp) template-switching. (3) Within raw reads, these indel hotspots have cases of both high intra-host heterogeneity and intra-host homogeneity, suggesting that these indels are both consequences of de novo recombination events within a host and artifacts of previous recombination. We briefly analyze the indels in the context of RNA secondary structure, noting that indels preferentially occur in “arms” and loop structures of the predicted folded RNA, suggesting that secondary structure may be a mechanism for TRS-independent template-switching in SARS-CoV-2 or other coronaviruses. These insights into the relationship between structural variation and recombination in SARS-CoV-2 can improve our reconstructions of the SARS-CoV-2 evolutionary history as well as our understanding of the process of RdRp template-switching in RNA viruses.

scholarly journals Computational Analysis of Single Nucleotide polymorphisms (SNPs) in Human TCell Acute Lymphocytic Leukemia Protein 1 (TAL1) Gene/Comprehensive Study

2018 ◽  
Author(s):  
Shaza W. Shantier ◽  
Hashim E. Elmansi ◽  
Mihad E. Elnnewery ◽  
Hind K. Osman ◽  
Isam-Aldin A. Alhassan ◽  
...  
Keyword(s):  
Protein Function ◽  
Computational Analysis ◽  
Lymphocytic Leukemia ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Post Translational Modifications ◽  
Diamond Blackfan Anemia ◽  
Helix Loop Helix ◽  
Therapeutic Measures ◽  
Near Future

AbstractBackgroundTAL1is a proto-oncogene whose distorted modifications in committed T-cell Precursors is related with the development of T-ALL, it also found to be related to many other human hematological diseases such as lymphoblastic lymphoma, immunodeficiency 18, acute myeloid leukemia and diamond-blackfan Anemia.ObjectivesThis study aims to predict the effect of nsSNPs onTAL1protein structure functionMethodsRetrieved nSNPs in the coding and3’UTRregions were analyzed using different in silico tools. Interactions ofTAL1with functionally similar genes were investigated using Genemania. Post-translational modifications in several sites of the protein were also investigated.ResultsOut of ninety nsSNPs identified, only eight were found damaging to protein function of which one is located in the basis helix-loop-helix domain (bHLH). Two SNPs were anticipated by PolymiRTs to prompt disturbance or creation of miR binding sites.ConclusionThe present study is the first ever computational analysis ofTAL1’s nsSNPs hence this effort might be of help in the near future for inventing early diagnostic and therapeutic measures for T-ALL

P002 Specific genome editing to model hypermethylation of the SP140 gene that associates to Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S129-S130
Author(s):  
I Hageman ◽  
A Li Yim ◽  
V Joustra ◽  
M Ghiboub ◽  
K Gecse ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Protein Function ◽  
Regulatory Region ◽  
Methyl Groups ◽  
Nucleotide Polymorphisms ◽  
Dna Hypermethylation ◽  
A Genome

Abstract Background SP140 (Speckled 140 KDa) encodes an epigenetic reader protein with an immune restricted expression, that binds to epigenetically modified (acetylated and methylated) histones and thereby regulates expression of large gene sets, including pro-inflammatory cytokines, in innate immune cells. SP140 is implicated in CD because single nucleotide polymorphisms, as well as defective protein function are associated with CD and marks anti-TNF response. Through a genome-wide methylation screen of Crohn’s disease (CD) patients peripheral blood, we identified two hypermethylated positions in SP140 locus associated with CD patients. We hypothesise that this DNA hypermethylation at the SP140 locus controls SP140 expression in CD patients contributing to their colitis development. Methods To address the role of SP140 DNA methylation, we used CRISPR ‘dead’ Cas9 (dCas9) epigenome-editing for specifically adding methyl groups (dCas9-DNMT) or removing methyl groups (dCas9-TET) in monocyte cell line THP1. We developed guide RNAs complementary to the gene expression regulatory region of the SP140 gene. With lentiviral delivery, we transduced THP-1 cells with guide RNA-lentiviruses, and with dCas9-DNMT or dCas9-TET lentiviruses. We assessed the level of SP140 methylation using bisulphite Sanger sequencing and the effect of methylation intervention of SP140 using qPCR and ELISA for SP140, IL-6, TNFα, IL-1β. Results We observed that SP140 gene in THP-1 cells under control conditions contained little methylated CpG sites. We induced sp140 hypermethylation through transduction of dCas9-DNMT. We validated hypermethylation of the two SP140 CpGs in transduced THP1 cells, thus mimicking the observed hypermethylation in CD patients cells. SP140 hypermethylation in THP1 cells polarised into M1 macrophages and stimulated with lipoteichoic acid (TLR-2 ligand), displayed a decrease of TNFα and (p = 0.042) protein levels. Similarly, we showed a decrease of TNFα (p = 0.02) and IL-6 (p = 0.03) protein release after transduction dCas9-DNMT and stimulation with LPS or Zymosan (TLR-2/4 ligand). Conclusion In this study, we demonstrated that editing SP140 gene methylation through CRISPR-dCAS9 technology allows modelling of the relevance of epigenetic marks for CD aetiology. Through methylome editing, we could affect the expression of CD-associated pro-inflammatory genes. Our dCas9 technique will allow us to investigate the role of DNA-methylation in the aetiology of CD.

scholarly journals Genome wide transcriptome analysis reveals vital role of heat responsive genes in regulatory mechanisms of lentil (Lens culinaris Medikus)

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Dharmendra Singh ◽  
Chandan Kumar Singh ◽  
Jyoti Taunk ◽  
Vasudha Jadon ◽  
Madan Pal ◽  
...  
Keyword(s):  
Heat Stress ◽  
Transcriptome Analysis ◽  
Pollen Germination ◽  
De Novo ◽  
Nucleotide Polymorphisms ◽  
Sensitive Genotype ◽  
Tolerant Genotype

Abstract The present study reports the role of morphological, physiological and reproductive attributes viz. membrane stability index (MSI), osmolytes accumulations, antioxidants activities and pollen germination for heat stress tolerance in contrasting genotypes. Heat stress increased proline and glycine betaine (GPX) contents, induced superoxide dismutase (SOD), ascorbate peroxidase (APX) and glutathione peroxidase (GPX) activities and resulted in higher MSI in PDL-2 (tolerant) compared to JL-3 (sensitive). In vitro pollen germination of tolerant genotype was higher than sensitive one under heat stress. In vivo stressed pollens of tolerant genotype germinated well on stressed stigma of sensitive genotype, while stressed pollens of sensitive genotype did not germinate on stressed stigma of tolerant genotype. De novo transcriptome analysis of both the genotypes showed that number of contigs ranged from 90,267 to 104,424 for all the samples with N50 ranging from 1,755 to 1,844 bp under heat stress and control conditions. Based on assembled unigenes, 194,178 high-quality Single Nucleotide Polymorphisms (SNPs), 141,050 microsatellites and 7,388 Insertion-deletions (Indels) were detected. Expression of 10 genes was evaluated using quantitative Real Time Polymerase Chain Reaction (RT-qPCR). Comparison of differentially expressed genes (DEGs) under different combinations of heat stress has led to the identification of candidate DEGs and pathways. Changes in expression of physiological and pollen phenotyping related genes were also reaffirmed through transcriptome data. Cell wall and secondary metabolite pathways are found to be majorly affected under heat stress. The findings need further analysis to determine genetic mechanism involved in heat tolerance of lentil.

scholarly journals In silico analysis of SNPs in human phosphofructokinase, Muscle (PFKM) gene: An apparent therapeutic target of aerobic glycolysis and cancer

2020 ◽  
Author(s):  
Yogita Rani ◽  
Kamaljit kaur ◽  
Madhvi Sharma ◽  
Namarta Kalia
Keyword(s):  
Protein Function ◽  
Aerobic Glycolysis ◽  
In Silico Analysis ◽  
Nucleotide Polymorphisms ◽  
Cancer Etiology ◽  
Single Nucleotide ◽  
Cancer Types ◽  
Predictive Role ◽  
Dbsnp Database

ABSTRACTPhosphofructokinase, muscle (PFKM), a key glycolytic regulatory enzyme is a potential target for cancer therapeutic studies accredited to the employed inefficient phenomenon known as Warburg effect. PFKM is encoded by PFKM gene located at chromosome 12q13.11. Single nucleotide polymorphisms (SNPs) are known to profoundly affect gene expression and protein function. Therefore, the first attempt was made to computationally identify putative functional PFKM variants. These SNPs were further explored to find their probable association with different cancer types. A total of 9694 SNPs were retrieved from dbSNP database. Of which, only 85 validated SNPs with ≥10% minor allele frequency (MAF) were subjected to analysis by softwares including Ensembl Genome browser, FuncPred (SNPinfo), regulomeDB (v 2.0), SIFT and PolyPhen-2. The relative analysis of output obtained classified the selected-SNPs into 11 highly prioritized (HP), 20 moderately prioritized and 54 not/poorly prioritized SNPs. The 11 HP-SNPs were found to have the highest likelihood of being functionally important, evidenced by previous association of rs2269935, rs11168417, rs11609399 and rs2228500 HP-SNPs with cachexia, lung and breast cancer. The study warrants further experiments to confirm the predictive role of prioritized SNPs in cancer etiology and also provides directions to fellow researchers.

scholarly journals The First Report of Multicentric Carpotarsal Osteolysis Syndrome Caused by MAFB Mutation in Asian

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Pongsakorn Choochuen ◽  
Kitiwan Rojneuangnit ◽  
Thanitchet Khetkham ◽  
Sookkasem Khositseth
Keyword(s):  
Genetic Study ◽  
De Novo ◽  
Molecular Genetic ◽  
Osteoclast Differentiation ◽  
Female Adolescent ◽  
De Novo Mutation ◽  
Molecular Genetic Study ◽  
Stage Renal Disease ◽  
End Stage

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by aggressive osteolysis associated with progressive nephropathy. The early clinical presentation can mimic polyarticular juvenile idiopathic arthritis. Since 2012, MAFB mutations have been discovered in all MCTO patients. Therefore, the early diagnosis can be made based on genetic confirmation. We report the clinical manifestation of mineral bone disease and the molecular genetic study of a Thai female adolescent with MCTO. She presented with end-stage renal disease, bilateral wrist and ankle joint deformities, and subtle facial dysmorphic features. We identified a heterozygous missense MAFB mutation at nucleotide 197 from C to G (NM_005461.4; c.197C>G), predicting the change of amino acid at codon 66 from serine to cysteine (p.Ser66Cys), and the mutation was absent in the parents, indicating a de novo mutation. This report confirms the previous link between MAFB mutation and MCTO. Her unexplained hypercalcemia after a regular dose of calcium and active vitamin D supported an important role of MafB in the negative regulation of RANKL-mediated osteoclast differentiation. Therefore, we would encourage the physicians who take care of MCTO patients to closely monitor serum calcium level and perform a genetic study as a part of the management and investigation.

Posttransplant CMV infection and the role of immunosuppression (Sponsor: Novartis Pharma GmbH, Nürnberg)

2016 ◽  
Vol 04 (01) ◽  
pp. 4-10
Keyword(s):  
Lower Incidence ◽  
Paradigm Shift ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Expert Panel ◽  
Risk Of Infection ◽  
Cmv Infection ◽  
Expert Meeting ◽  
Selection Of

AbstractImmunosuppression permits graft survival after transplantation and consequently a longer and better life. On the other hand, it increases the risk of infection, for instance with cytomegalovirus (CMV). However, the various available immunosuppressive therapies differ in this regard. One of the first clinical trials using de novo everolimus after kidney transplantation [1] already revealed a considerably lower incidence of CMV infection in the everolimus arms than in the mycophenolate mofetil (MMF) arm. This result was repeatedly confirmed in later studies [2–4]. Everolimus is now considered a substance with antiviral properties. This article is based on the expert meeting “Posttransplant CMV infection and the role of immunosuppression”. The expert panel called for a paradigm shift: In a CMV prevention strategy the targeted selection of the immunosuppressive therapy is also a key element. For patients with elevated risk of CMV, mTOR inhibitor-based immunosuppression is advantageous as it is associated with a significantly lower incidence of CMV events.

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