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Journal articles on the topic 'Structural variants'
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Welsch, Christoph, Sabine Schweizer, Tetsuro Shimakami, Francisco S. Domingues, Seungtaek Kim, Stanley M. Lemon, and Iris Antes. "Ketoamide Resistance and Hepatitis C Virus Fitness in Val55 Variants of the NS3 Serine Protease." Antimicrobial Agents and Chemotherapy 56, no. 4 (January 17, 2012): 1907–15. http://dx.doi.org/10.1128/aac.05184-11.
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ABSTRACTDrug-resistant viral variants are a major issue in the use of direct-acting antiviral agents in chronic hepatitis C. Ketoamides are potent inhibitors of the NS3 protease, with V55A identified as mutation associated with resistance to boceprevir. Underlying molecular mechanisms are only partially understood. We applied a comprehensive sequence analysis to characterize the natural variability at Val55 within dominant worldwide patient strains. A residue-interaction network and molecular dynamics simulation were applied to identify mechanisms for ketoamide resistance and viral fitness in Val55 variants. An infectious H77S.3 cell culture system was used for variant phenotype characterization. We measured antiviral 50% effective concentration (EC50) and fold changes, as well as RNA replication and infectious virus yields from viral RNAs containing variants. Val55 was found highly conserved throughout all hepatitis C virus (HCV) genotypes. The conservative V55A and V55I variants were identified from HCV genotype 1a strains with no variants in genotype 1b. Topology measures from a residue-interaction network of the protease structure suggest a potential Val55 key role for modulation of molecular changes in the protease ligand-binding site. Molecular dynamics showed variants with constricted binding pockets and a loss of H-bonded interactions upon boceprevir binding to the variant proteases. These effects might explain low-level boceprevir resistance in the V55A variant, as well as the Val55 variant, reduced RNA replication capacity. Higher structural flexibility was found in the wild-type protease, whereas variants showed lower flexibility. Reduced structural flexibility could impact the Val55 variant's ability to adapt for NS3 domain-domain interaction and might explain the virus yield drop observed in variant strains.
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Ahdesmäki, Miika J., Brad A. Chapman, Pablo Cingolani, Oliver Hofmann, Aleksandr Sidoruk, Zhongwu Lai, Gennadii Zakharov, et al. "Prioritisation of structural variant calls in cancer genomes." PeerJ 5 (April 4, 2017): e3166. http://dx.doi.org/10.7717/peerj.3166.
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Sensitivity of short read DNA-sequencing for gene fusion detection is improving, but is hampered by the significant amount of noise composed of uninteresting or false positive hits in the data. In this paper we describe a tiered prioritisation approach to extract high impact gene fusion events from existing structural variant calls. Using cell line and patient DNA sequence data we improve the annotation and interpretation of structural variant calls to best highlight likely cancer driving fusions. We also considerably improve on the automated visualisation of the high impact structural variants to highlight the effects of the variants on the resulting transcripts. The resulting framework greatly improves on readily detecting clinically actionable structural variants.
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Laddach, Anna, Joseph Chi Fung Ng, and Franca Fraternali. "Pathogenic missense protein variants affect different functional pathways and proteomic features than healthy population variants." PLOS Biology 19, no. 4 (April 28, 2021): e3001207. http://dx.doi.org/10.1371/journal.pbio.3001207.
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Missense variants are present amongst the healthy population, but some of them are causative of human diseases. A classification of variants associated with “healthy” or “diseased” states is therefore not always straightforward. A deeper understanding of the nature of missense variants in health and disease, the cellular processes they may affect, and the general molecular principles which underlie these differences is essential to offer mechanistic explanations of the true impact of pathogenic variants. Here, we have formalised a statistical framework which enables robust probabilistic quantification of variant enrichment across full-length proteins, their domains, and 3D structure-defined regions. Using this framework, we validate and extend previously reported trends of variant enrichment in different protein structural regions (surface/core/interface). By examining the association of variant enrichment with available functional pathways and transcriptomic and proteomic (protein half-life, thermal stability, abundance) data, we have mined a rich set of molecular features which distinguish between pathogenic and population variants: Pathogenic variants mainly affect proteins involved in cell proliferation and nucleotide processing and are enriched in more abundant proteins. Additionally, rare population variants display features closer to common than pathogenic variants. We validate the association between these molecular features and variant pathogenicity by comparing against existing in silico variant impact annotations. This study provides molecular details into how different proteins exhibit resilience and/or sensitivity towards missense variants and provides the rationale to prioritise variant-enriched proteins and protein domains for therapeutic targeting and development. The ZoomVar database, which we created for this study, is available at fraternalilab.kcl.ac.uk/ZoomVar. It allows users to programmatically annotate missense variants with protein structural information and to calculate variant enrichment in different protein structural regions.
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Khanna, Tarun, Gordon Hanna, Michael J. E. Sternberg, and Alessia David. "Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants." Human Genetics 140, no. 5 (January 27, 2021): 805–12. http://dx.doi.org/10.1007/s00439-020-02246-z.
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AbstractThe interpretation of human genetic variation is one of the greatest challenges of modern genetics. New approaches are urgently needed to prioritize variants, especially those that are rare or lack a definitive clinical interpretation. We examined 10,136,597 human missense genetic variants from GnomAD, ClinVar and UniProt. We were able to perform large-scale atom-based mapping and phenotype interpretation of 3,960,015 of these variants onto 18,874 experimental and 84,818 in house predicted three-dimensional coordinates of the human proteome. We demonstrate that 14% of amino acid substitutions from the GnomAD database that could be structurally analysed are predicted to affect protein structure (n = 568,548, of which 566,439 rare or extremely rare) and may, therefore, have a yet unknown disease-causing effect. The same is true for 19.0% (n = 6266) of variants of unknown clinical significance or conflicting interpretation reported in the ClinVar database. The results of the structural analysis are available in the dedicated web catalogue Missense3D-DB (http://missense3d.bc.ic.ac.uk/). For each of the 4 M variants, the results of the structural analysis are presented in a friendly concise format that can be included in clinical genetic reports. A detailed report of the structural analysis is also available for the non-experts in structural biology. Population frequency and predictions from SIFT and PolyPhen are included for a more comprehensive variant interpretation. This is the first large-scale atom-based structural interpretation of human genetic variation and offers geneticists and the biomedical community a new approach to genetic variant interpretation.
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Liao, Wen-Wei, Mobin Asri, Jana Ebler, Daniel Doerr, Marina Haukness, Glenn Hickey, Shuangjia Lu, et al. "A draft human pangenome reference." Nature 617, no. 7960 (May 10, 2023): 312–24. http://dx.doi.org/10.1038/s41586-023-05896-x.
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AbstractHere the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.
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Neuser, Sonja, Ilona Krey, Annemarie Schwan, Rami Abou Jamra, Tobias Bartolomaeus, Jan Döring, Steffen Syrbe, et al. "Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain." European Journal of Human Genetics 30, no. 1 (October 25, 2021): 101–10. http://dx.doi.org/10.1038/s41431-021-00982-y.
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AbstractBiallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot–Marie–Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Pathological examination of a male fetus in the 18th gestational week revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities. Prenatal trio-exome sequencing identified compound heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sister fetus. Through RNA analyses, we characterized exon 4 skipping affecting the PNKP forkhead-associated (FHA) and phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the paternal c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the splice donor variant c.1029+2T>C intrans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro); c.151G>C, p.(Val51Leu)). RNA-seq showed complex splicing for c.1029+2T>C and c.151G>C. Structural modeling revealed significant clustering of missense variants in the FHA domain with variants generating structural damage. Our clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modeling, we highlight the mutational complexity and exemplify a PNKP-variant characterization framework.
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Chowdhury, Murad, Brent S. Pedersen, Fritz J. Sedlazeck, Aaron R. Quinlan, and Ryan M. Layer. "Searching thousands of genomes to classify somatic and novel structural variants using STIX." Nature Methods 19, no. 4 (April 2022): 445–48. http://dx.doi.org/10.1038/s41592-022-01423-4.
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AbstractStructural variants are associated with cancers and developmental disorders, but challenges with estimating population frequency remain a barrier to prioritizing mutations over inherited variants. In particular, variability in variant calling heuristics and filtering limits the use of current structural variant catalogs. We present STIX, a method that, instead of relying on variant calls, indexes and searches the raw alignments from thousands of samples to enable more comprehensive allele frequency estimation.
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Hain, Carsten, Rudolf Stadler, and Jörn Kalinowski. "Unraveling the Structural Variations of Early-Stage Mycosis Fungoides—CD3 Based Purification and Third Generation Sequencing as Novel Tools for the Genomic Landscape in CTCL." Cancers 14, no. 18 (September 14, 2022): 4466. http://dx.doi.org/10.3390/cancers14184466.
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Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL). At present, knowledge of genetic changes in early-stage MF is insufficient. Additionally, low tumor cell fraction renders calling of copy-number variations as the predominant mutations in MF challenging, thereby impeding further investigations. We show that enrichment of T cells from a biopsy of a stage I MF patient greatly increases tumor fraction. This improvement enables accurate calling of recurrent MF copy-number variants such as ARID1A and CDKN2A deletion and STAT5 amplification, undetected in the unprocessed biopsy. Furthermore, we demonstrate that application of long-read nanopore sequencing is especially useful for the structural variant rich CTCL. We detect the structural variants underlying recurrent MF copy-number variants and show phasing of multiple breakpoints into complex structural variant haplotypes. Additionally, we record multiple occurrences of templated insertion structural variants in this sample. Taken together, this study suggests a workflow to make the early stages of MF accessible for genetic analysis, and indicates long-read sequencing as a major tool for genetic analysis for MF.
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KHACHATRYAN, Lalik. "STRUCTURAL TYPES OF ARMENIAN LANGUAGE VARIANT- UNITS IN THE TRANSLATION BOOKS OF THE BIBLE." Main Issues Of Pedagogy And Psychology 17, no. 1 (April 28, 2020): 126–36. http://dx.doi.org/10.24234/miopap.v17i1.372.
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The correlative study of variants’ form and meaning in the Bible books shows that some types of variants; word-variants, phonetic-variants, grammatical variants, that give some idea about present linguistic reality from the synchronic point. The marginal components of word variants are words which have different manifestations of the form. Phonetic variants have been formed through sound- interchange. Grammatical variants are formed by different declensional forms.
The results of the investigation can serve as a means of comparison for both the interlinguistic and interlinguistic typological investigation. From the subject of the study, we can conclude that variant-units found in the Bible are a heritage from the prewritten period. They have been transferred to old Armenian with the lexical structure of prewritten Armenian and were reflected in the first Armenian translation manuscript- in the Bible.
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Flynn, C. P., and J. A. Eades. "Structural variants in heteroepitaxial growth." Thin Solid Films 389, no. 1-2 (June 2001): 116–37. http://dx.doi.org/10.1016/s0040-6090(01)00768-4.
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Ketten, Darlene R., James Simmons, Hiroshi Riquimaroux, Scott Cramer, and Julie Arruda. "Cochlear structural variants in echolocators." Journal of the Acoustical Society of America 131, no. 4 (April 2012): 3423. http://dx.doi.org/10.1121/1.4708838.
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Kumar, Anil, and S. Ramakrishnan. "Structural Variants of Hyperbranched Polyesters." Macromolecules 29, no. 7 (January 1996): 2524–30. http://dx.doi.org/10.1021/ma950948r.
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JUX, N. "ChemInform Abstract: Porphyrin Structural Variants." ChemInform 23, no. 5 (August 22, 2010): no. http://dx.doi.org/10.1002/chin.199205326.
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Xiao, Binghe, Shaohua Zhang, Maierdanjiang Ainiwaer, Houyi Liu, Li Ning, Yingying Hong, Yang Sun, and Yinghong Ji. "Deep learning–based assessment of missense variants in theCOG4gene presented with bilateral congenital cataract." BMJ Open Ophthalmology 10, no. 1 (January 2025): e001906. https://doi.org/10.1136/bmjophth-2024-001906.
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ObjectiveWe compared the protein structure and pathogenicity of clinically relevant variants of theCOG4gene with AlphaFold2 (AF2), Alpha Missense (AM), and ThermoMPNN for the first time.Methods and analysisThe sequences of clinically relevant Cog4 missense variants (one novel identified p.Y714F and three pre-existing p.G512R, p.R729W and p.L769R from Uniprot Q9H9E3) were imported into AF2 for protein structural prediction, and the pathogenicity was estimated using AM and ThermoMPNN. Different pathogenicity metrics were aggregated with principal component analysis (PCA) and further analysed at three levels (amino acid position, substitution and post-translation) based on all possible Cog4 missense variants (n=14 915).ResultsLocalised protein structural impact including change of conformation and amino acid polarity, breakage of hydrogen bond and salt-bridge, and formation of alpha-helix were identified among clinically relevant Cog4 variants. The global structural comparison with multidimensional scaling demonstrated variants with similar protein structures (AF2) tended to exhibit similar clinical and biological phenotypes. The Cog4 p.Y714F variant exhibited greater protein structural similarity to mutated Cog4 found in Saul‒Wilson syndrome (p.G512R) and shared similar clinical phenotype (congenital cataract and psychomotor retardation). PCA of included pathogenic metrics demonstrated p.Y714F occurred at a critical position in Cog4 amino acid sequence with disrupted post-translational phosphorylation.ConclusionDeep learning algorithms, including AF2, AM and ThermoMPNN, can be useful for evaluating variant of uncertain significance (VUS) by structural and pathogenicity prediction. Despite classified as VUS (American College of Medical Genetics and Genomics criteria: PM1, PP4), the pathogenicity in this Cog4 variant cannot be ruled out and warrants further investigation.
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Barile, Anna, Philippa Mills, Martino L. di Salvo, Claudio Graziani, Victoria Bunik, Peter Clayton, Roberto Contestabile, and Angela Tramonti. "Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy." International Journal of Molecular Sciences 22, no. 21 (November 6, 2021): 12013. http://dx.doi.org/10.3390/ijms222112013.
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Several variants of the enzyme pyridox(am)ine 5′-phosphate oxidase (PNPO), responsible for a rare form of vitamin B6-dependent neonatal epileptic encephalopathy known as PNPO deficiency (PNPOD), have been reported. However, only a few of them have been characterised with respect to their structural and functional properties, despite the fact that the knowledge of how variants affect the enzyme may clarify the disease mechanism and improve treatment. Here, we report the characterisation of the catalytic, allosteric and structural properties of recombinantly expressed D33V, R161C, P213S, and E50K variants, among which D33V (present in approximately 10% of affected patients) is one of the more common variants responsible for PNPOD. The D33V and E50K variants have only mildly altered catalytic properties. In particular, the E50K variant, given that it has been found on the same chromosome with other known pathogenic variants, may be considered non-pathogenic. The P213S variant has lower thermal stability and reduced capability to bind the FMN cofactor. The variant involving Arg161 (R161C) largely decreases the affinity for the pyridoxine 5′-phosphate substrate and completely abolishes the allosteric feedback inhibition exerted by the pyridoxal 5′-phosphate product.
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Bodenbender, Jan-Philipp, Valerio Marino, Leon Bethge, Katarina Stingl, Tobias B. Haack, Saskia Biskup, Susanne Kohl, Laura Kühlewein, Daniele Dell’Orco, and Nicole Weisschuh. "Biallelic Variants in TULP1 Are Associated with Heterogeneous Phenotypes of Retinal Dystrophy." International Journal of Molecular Sciences 24, no. 3 (January 31, 2023): 2709. http://dx.doi.org/10.3390/ijms24032709.
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Biallelic pathogenic variants in TULP1 are mostly associated with severe rod-driven inherited retinal degeneration. In this study, we analyzed clinical heterogeneity in 17 patients and characterized the underlying biallelic variants in TULP1. All patients underwent thorough ophthalmological examinations. Minigene assays and structural analyses were performed to assess the consequences of splice variants and missense variants. Three patients were diagnosed with Leber congenital amaurosis, nine with early onset retinitis pigmentosa, two with retinitis pigmentosa with an onset in adulthood, one with cone dystrophy, and two with cone-rod dystrophy. Seventeen different alleles were identified, namely eight missense variants, six nonsense variants, one in-frame deletion variant, and two splice site variants. For the latter two, minigene assays revealed aberrant transcripts containing frameshifts and premature termination codons. Structural analysis and molecular modeling suggested different degrees of structural destabilization for the missense variants. In conclusion, we report the largest cohort of patients with TULP1-associated IRD published to date. Most of the patients exhibited rod-driven disease, yet a fraction of the patients exhibited cone-driven disease. Our data support the hypothesis that TULP1 variants do not fold properly and thus trigger unfolded protein response, resulting in photoreceptor death.
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Doñate Puertas, Rosa, Gilles Millat, Isabelle Ernens, Vincent Gache, Samuel Chauveau, Elodie Morel, Emilie Christin, Nathalie Couturier, Yvan Devaux, and Philippe Chevalier. "Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation." BioMed Research International 2018 (September 10, 2018): 1–12. http://dx.doi.org/10.1155/2018/4862480.
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Atrial fibrillation (AF) is a common arrhythmia for which the genetic studies mainly focused on the genes involved in electrical remodeling, rather than left atrial muscle remodeling. To identify rare variants involved in atrial myopathy using mutational screening, a high-throughput next-generation sequencing (NGS) workflow was developed based on a custom AmpliSeq™ panel of 55 genes potentially involved in atrial myopathy. This workflow was applied to a cohort of 94 patients with AF, 76 with atrial dilatation and 18 without. Bioinformatic analyses used NextGENe® software and in silico tools for variant interpretation. The AmpliSeq custom-made panel efficiently explored 96.58% of the targeted sequences. Based on in silico analysis, 11 potentially pathogenic missense variants were identified that were not previously associated with AF. These variants were located in genes involved in atrial tissue structural remodeling. Three patients were also carriers of potential variants in prevalent arrhythmia-causing genes, usually associated with AF. Most of the variants were found in patients with atrial dilatation (n=9, 82%). This NGS approach was a sensitive and specific method that identified 11 potentially pathogenic variants, which are likely to play roles in the predisposition to left atrial myopathy. Functional studies are needed to confirm their pathogenicity.
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Abu-Rub, Lubna I., Tara Al-Barazenji, Sumaya Abiib, Ayat S. Hammad, Alaa Abbas, Khalid Hussain, and Mashael Al-Shafai. "Identification of KSR2 Variants in Pediatric Patients with Severe Early-Onset Obesity from Qatar." Genes 15, no. 8 (July 23, 2024): 966. http://dx.doi.org/10.3390/genes15080966.
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The kinase suppressor of Ras 2 (KSR2) gene is associated with monogenic obesity, and loss-of-function variants in KSR2 have been identified in individuals with severe early-onset obesity. This study investigated KSR2 variants in 9 pediatric patients with severe early-onset obesity in Qatar using whole genome sequencing among a cohort of 240 individuals. We focused on KSR2 variants with a minor allele frequency (MAF) below 1% and a Combined Annotation Dependent Depletion (CADD) score above 13 to identify potential causative variants. Our analysis identified four KSR2 variants: one intronic (c.1765-8G>A) and three missense variants (c.1057G>A, c.1673G>A, and c.923T>C) in nine patients. The intronic variant c.1765-8G>A was the most frequent (seen in six individuals) and had a CADD score of 21.10, suggesting possible pathogenicity. This variant showed a significantly higher allele frequency in the Qatari population compared to the Genome Aggregation Database (gnomAD), indicating a possible founder effect. Molecular modeling of the missense variants revealed structural changes in the protein structure. The study concludes that these four KSR2 variants are associated with monogenic obesity, with an autosomal dominant inheritance pattern. The c.1765-8G>A variant’s prevalence in Qatar underscores its importance in genetic screening for severe obesity. This research advances the understanding of genetic factors in severe early-onset obesity and may inform better management strategies.
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Lee-Chen, G. J., and M. Woodworth-Gutai. "Evolutionarily selected replication origins: functional aspects and structural organization." Molecular and Cellular Biology 6, no. 9 (September 1986): 3077–85. http://dx.doi.org/10.1128/mcb.6.9.3077-3085.1986.
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A selective replicative pressure occurs during the evolution of simian virus 40 variants. When the replication origin is duplicated as an inverted repeat, there is a dramatic enhancement of replication. Having regulatory sequences located between the inverted repeat of ori magnifies their enhancing effect on replication. A passage 20 variant and a passage 45 variant containing three pairs of an inverted repeat of ori replicated more efficiently than a passage 13 variant containing nine copies of ori arranged in tandem. A 69-base-pair cellular sequence inserted between inverted repeats of ori of both passage 40 and 45 variants enhanced simian virus 40 DNA replication. Differences in replication efficiencies became greater as the total number of replicating species was increased in the transfection mixture, under conditions where T antigen is limiting. In a competitive environment, sequences flanking the replication origin may be inhibitory to replication.
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Lee-Chen, G. J., and M. Woodworth-Gutai. "Evolutionarily selected replication origins: functional aspects and structural organization." Molecular and Cellular Biology 6, no. 9 (September 1986): 3077–85. http://dx.doi.org/10.1128/mcb.6.9.3077.
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A selective replicative pressure occurs during the evolution of simian virus 40 variants. When the replication origin is duplicated as an inverted repeat, there is a dramatic enhancement of replication. Having regulatory sequences located between the inverted repeat of ori magnifies their enhancing effect on replication. A passage 20 variant and a passage 45 variant containing three pairs of an inverted repeat of ori replicated more efficiently than a passage 13 variant containing nine copies of ori arranged in tandem. A 69-base-pair cellular sequence inserted between inverted repeats of ori of both passage 40 and 45 variants enhanced simian virus 40 DNA replication. Differences in replication efficiencies became greater as the total number of replicating species was increased in the transfection mixture, under conditions where T antigen is limiting. In a competitive environment, sequences flanking the replication origin may be inhibitory to replication.
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Mkrtchian, A. A., K. S. Grammatikati, P. G. Kazakova, S. I. Mitrofanov, P. U. Zemsky, A. A. Ivashechkin, M. N. Pilipenko, et al. "Comparative Analysis of Structural Variant Callers on the Short-Read Whole-Genome Sequencing Data." Генетика 59, no. 6 (June 1, 2023): 687–707. http://dx.doi.org/10.31857/s0016675823060115.
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In this study three structural variant callers (Manta, Smoove, Delly) were analysed on the whole-genome sequencing data using four different alignment algorithms: DRAGEN, GDC DNA-Seq Alignment Workflow, GDC DNA-Seq Alignment Workflow + GDC DNA-Seq Co-Cleaning Workflow, NovoAlign, different lengths of raw reads: 2 × 150 bp and 2 × 250 bp, different mean genome coverage values. Results were compared to etalon results of GIAB team. Structural variants validation was hold also with Sanger sequencing. Structural variants deletions and insertions as it turned out were best determined with Manta tool. We’ve got 89–96% of accuracy and 59–70% of sensitivity for analysed deletions, and also 96–99% of accuracy and 15–36% of sensitivity for insertions. Smoove and Delly showed less accurate and sensitive results (Smoove: 91–95% of accuracy and 8–54% of sensitivity for deletions, Delly: 78–87% of accuracy and 31–66% of sensitivity for deletions, 99–100% of accuracy and 1–13% of sensitivity for insertions). Simultaneous using of two or even three structural variant callers didn’t give a rise of accuracy and sensitivity for deletions. Analysis showed that accuracy and sensitivity of structural variant callers rise with the rising of mean genome coverage value, increasing of reads length from 150 to 250 bp influence in to varying degrees on the accuracy and sensitivity of individual tools. Another inference of this study was that accuracy of structural variants callers vary depends on structural variants size range. For example, Manta finds better deletions in the range from 200 and more bp, Delly – from 1000 to 10 000 bp, Smoove – from 200 to 10 000 bp.
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Heller, David, and Martin Vingron. "SVIM: structural variant identification using mapped long reads." Bioinformatics 35, no. 17 (January 21, 2019): 2907–15. http://dx.doi.org/10.1093/bioinformatics/btz041.
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Abstract Motivation Structural variants are defined as genomic variants larger than 50 bp. They have been shown to affect more bases in any given genome than single-nucleotide polymorphisms or small insertions and deletions. Additionally, they have great impact on human phenotype and diversity and have been linked to numerous diseases. Due to their size and association with repeats, they are difficult to detect by shotgun sequencing, especially when based on short reads. Long read, single-molecule sequencing technologies like those offered by Pacific Biosciences or Oxford Nanopore Technologies produce reads with a length of several thousand base pairs. Despite the higher error rate and sequencing cost, long-read sequencing offers many advantages for the detection of structural variants. Yet, available software tools still do not fully exploit the possibilities. Results We present SVIM, a tool for the sensitive detection and precise characterization of structural variants from long-read data. SVIM consists of three components for the collection, clustering and combination of structural variant signatures from read alignments. It discriminates five different variant classes including similar types, such as tandem and interspersed duplications and novel element insertions. SVIM is unique in its capability of extracting both the genomic origin and destination of duplications. It compares favorably with existing tools in evaluations on simulated data and real datasets from Pacific Biosciences and Nanopore sequencing machines. Availability and implementation The source code and executables of SVIM are available on Github: github.com/eldariont/svim. SVIM has been implemented in Python 3 and published on bioconda and the Python Package Index. Supplementary information Supplementary data are available at Bioinformatics online.
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Ali, Muhammad Zeeshan, Arshad Farid, Safeer Ahmad, Muhammad Muzammal, Mohammed Al Mohaini, Abdulkhaliq J. Alsalman, Maitham A. Al Hawaj, et al. "In Silico Analysis Identified Putative Pathogenic Missense nsSNPs in Human SLITRK1 Gene." Genes 13, no. 4 (April 11, 2022): 672. http://dx.doi.org/10.3390/genes13040672.
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Human DNA contains several variations, which can affect the structure and normal functioning of a protein. These variations could be single nucleotide polymorphisms (SNPs) or insertion-deletions (InDels). SNPs, as opposed to InDels, are more commonly present in DNA and may cause genetic disorders. In the current study, several bioinformatic tools were used to prioritize the pathogenic variants in the SLITRK1 gene. Out of all of the variants, 16 were commonly predicted to be pathogenic by these tools. All the variants had very low frequency, i.e., <0.0001 in the global population. The secondary structure of all filtered variants was predicted, but no structural change was observed at the site of variation in any variant. Protein stability analysis of these variants was then performed, which determined a decrease in protein stability of 10 of the variants. Amino acid conservation analysis revealed that all the amino acids were highly conserved, indicating their structural and functional importance. Protein 3D structure of wildtype SLITRK1 and all of its variants was predicted using I-TASSER, and the effect of variation on 3D structure of the protein was observed using the Missense3D tool, which presented the probable structural loss in three variants, i.e., Asn529Lys, Leu496Pro and Leu94Phe. The wildtype SLITRK1 protein and these three variants were independently docked with their close interactor protein PTPRD, and remarkable differences were observed in the docking sites of normal and variants, which will ultimately affect the functional activity of the SLITRK1 protein. Previous studies have shown that mutations in SLITRK1 are involved in Tourette syndrome. The present study may assist a molecular geneticist in interpreting the variant pathogenicity in research as well as diagnostic setup.
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Francisco-Velilla, Rosario, Azman Embarc-Buh, Francisco del Caño-Ochoa, Salvador Abellan, Marçal Vilar, Sara Alvarez, Alberto Fernandez-Jaen, et al. "Functional and structural deficiencies of Gemin5 variants associated with neurological disorders." Life Science Alliance 5, no. 7 (April 7, 2022): e202201403. http://dx.doi.org/10.26508/lsa.202201403.
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Dysfunction of RNA-binding proteins is often linked to a wide range of human disease, particularly with neurological conditions. Gemin5 is a member of the survival of the motor neurons (SMN) complex, a ribosome-binding protein and a translation reprogramming factor. Recently, pathogenic mutations in Gemin5 have been reported, but the functional consequences of these variants remain elusive. Here, we report functional and structural deficiencies associated with compound heterozygosity variants within the Gemin5 gene found in patients with neurodevelopmental disorders. These clinical variants are located in key domains of Gemin5, the tetratricopeptide repeat (TPR)–like dimerization module and the noncanonical RNA-binding site 1 (RBS1). We show that the TPR-like variants disrupt protein dimerization, whereas the RBS1 variant confers protein instability. All mutants are defective in the interaction with protein networks involved in translation and RNA-driven pathways. Importantly, the TPR-like variants fail to associate with native ribosomes, hampering its involvement in translation control and establishing a functional difference with the wild-type protein. Our study provides insights into the molecular basis of disease associated with malfunction of the Gemin5 protein.
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Gerlevik, Umut, Mahmut Cerkez Ergoren, Osman Uğur Sezerman, and Sehime Gulsun Temel. "Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility." PeerJ 10 (March 21, 2022): e12947. http://dx.doi.org/10.7717/peerj.12947.
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Background Impaired meiosis can result in absence of sperm in the seminal fluid. This condition, namely non-obstructive azoospermia (NOA), is one of the reasons of male infertility. Despite the low number of studies on meiosis 1-associated protein (M1AP) in the literature, M1AP is known to be crucial for spermatogenesis. Recently, seven variants (five missense, one frameshift, one splice-site) have been reported in the M1AP gene as associated with NOA, cryptozoospermia and oligozoospermia in two separate studies. However, all missense variants were evaluated as variant of uncertain significance by these studies. Therefore, we aimed to analyze their structural impacts on the M1AP protein that could lead to NOA. Methods We firstly performed an evolutionary conservation analysis for the variant positions. Afterwards, a comprehensive molecular modelling study was performed for the M1AP structure. By utilizing this model, protein dynamics were sampled for the wild-type and variants by performing molecular dynamics (MD) simulations. Results All variant positions are highly conserved, indicating that they are potentially important for function. In MD simulations, none of the variants led to a general misfolding or loss of stability in the protein structure, but they did cause severe modifications in the conformational dynamics of M1AP, particularly through changes in local interactions affecting flexibility, hinge and secondary structure. Conclusions Due to critical perturbations in protein dynamics, we propose that these variants may cause NOA by affecting important interactions regulating meiosis, particularly in wild-type M1AP deficiency since the variants are reported to be homozygous or bi-allelic in the infertile individuals. Our results provided reasonable insights about the M1AP structure and the effects of the variants to the structure and dynamics, which should be further investigated by experimental studies to validate.
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Chaley, M. B., and V. A. Kutyrkin. "Coronavirus Genus Recognition Based on Prototype Virus Variants." Mathematical Biology and Bioinformatics 17, no. 1 (March 15, 2022): 10–27. http://dx.doi.org/10.17537/2022.17.10.
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Method named as variant approach to recognizing genus of coronavirus that is based on frequency of codon distribution in viral ORF1ab and genes of structural proteins (S, M and N) was proposed in the work. This method uses modified statistics whose efficiency was demonstrated earlier for flavivirus species recognition. To recognize genus of coronavirus the variant approach considers both various combinations of several structural coronavirus genes and individual structural genes. Finally, coronavirus genus is determined in the result of analysis of all variants considered. The method proposed was developed with the help of learning sample from prototype viral variants of Alphacoronavirus, Betacoronavirus, Deltacoronavirus and Gammacoronavirus genus. Application of the variant approach to recognizing genus of coronavirus has demonstrated the approach high assurance at level of 95 %. Among all variants of joint analysis, the most reliability (98 %) in recognizing genus has been achieved if codon frequency of the ORF1ab was used. Variant approach has revealed a phenomenon of mosaic structure in coronavirus genomes, i.e., when the results of genus recognition for a few genes differ from final conclusion about coronavirus genus. It seems that such phenomenon reflects homologous recombinations of the genes between various species of the coronaviruses and plasticity of their genomes in evolutionary processes.
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Kumai, Takumi, Shin-ya Nishio, Hideaki Moteki, Akihiro Katada, and Shin-ichi Usami. "Auditory Neuropathy Caused by a Structural Variation in the OTOF Gene, Identified Using Oxford Nanopore Adaptive Sampling." Genes 16, no. 2 (January 21, 2025): 116. https://doi.org/10.3390/genes16020116.
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Background/Objectives: The OTOF gene is reported to be the causative gene for non-syndromic recessive sensorineural hearing loss and auditory neuropathy spectrum disorder. About 300 variants have been reported, but there have been no reports to date on copy gain variants. Methods: We identified a copy gain variant in the OTOF gene through short-read next-generation sequencing analysis from one patient with auditory neuropathy. We also performed long-read next-generation sequencing analysis using the Oxford Nanopore Technologies adaptive sampling procedure. Results: The four-year-old male carried a duplication of chr2: 26,477,852 to 26,483,106 (a 5254-base duplication including exon 14 to exon 18 of the OTOF gene NM_001287489) and a c.5385C>A single nucleotide variant. We also confirmed that these two variants were located in the trans configuration based on haplotype phasing results using the long-read next-generation sequencing data. Conclusions: This is the first report of an auditory neuropathy patient with a large duplication variant in the OTOF gene. The identified variants were novel, but based on the clinical phenotype of the patient, these variants seem to be the genetic cause of this patient’s phenotype. Oxford Nanopore Technologies adaptive sampling is a powerful tool for the analysis of structural variants (particularly for determining the breakpoint and direction) and haplotype phasing.
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Kleinert, Philip, and Martin Kircher. "A framework to score the effects of structural variants in health and disease." Genome Research 32, no. 4 (February 23, 2022): 766–77. http://dx.doi.org/10.1101/gr.275995.121.
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Although technological advances improved the identification of structural variants (SVs) in the human genome, their interpretation remains challenging. Several methods utilize individual mechanistic principles like the deletion of coding sequence or 3D genome architecture disruptions. However, a comprehensive tool using the broad spectrum of available annotations is missing. Here, we describe CADD-SV, a method to retrieve and integrate a wide set of annotations to predict the effects of SVs. Previously, supervised learning approaches were limited due to a small number and biased set of annotated pathogenic or benign SVs. We overcome this problem by using a surrogate training objective, the Combined Annotation Dependent Depletion (CADD) of functional variants. We use human- and chimpanzee-derived SVs as proxy-neutral and contrast them with matched simulated variants as proxy-deleterious, an approach that has proven powerful for short sequence variants. Our tool computes summary statistics over diverse variant annotations and uses random forest models to prioritize deleterious structural variants. The resulting CADD-SV scores correlate with known pathogenic and rare population variants. We further show that we can prioritize somatic cancer variants as well as noncoding variants known to affect gene expression. We provide a website and offline-scoring tool for easy application of CADD-SV.
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Pös, Ondrej, Jaroslav Budis, Zuzana Kubiritova, Marcel Kucharik, Frantisek Duris, Jan Radvanszky, and Tomas Szemes. "Identification of Structural Variation from NGS-Based Non-Invasive Prenatal Testing." International Journal of Molecular Sciences 20, no. 18 (September 7, 2019): 4403. http://dx.doi.org/10.3390/ijms20184403.
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Copy number variants (CNVs) are an important type of human genome variation, which play a significant role in evolution contribute to population diversity and human genetic diseases. In recent years, next generation sequencing has become a valuable tool for clinical diagnostics and to provide sensitive and accurate approaches for detecting CNVs. In our previous work, we described a non-invasive prenatal test (NIPT) based on low-coverage massively parallel whole-genome sequencing of total plasma DNA for detection of CNV aberrations ≥600 kbp. We reanalyzed NIPT genomic data from 5018 patients to evaluate CNV aberrations in the Slovak population. Our analysis of autosomal chromosomes identified 225 maternal CNVs (47 deletions; 178 duplications) ranging from 600 to 7820 kbp. According to the ClinVar database, 137 CNVs (60.89%) were fully overlapping with previously annotated variants, 66 CNVs (29.33%) were in partial overlap, and 22 CNVs (9.78%) did not overlap with any previously described variant. Identified variants were further classified with the AnnotSV method. In summary, we identified 129 likely benign variants, 13 variants of uncertain significance, and 83 likely pathogenic variants. In this study, we use NIPT as a valuable source of population specific data. Our results suggest the utility of genomic data from commercial CNV analysis test as background for a population study.
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Roy, Urmi. "Computational Investigation of Selected Spike Protein Mutations in SARS-CoV-2: Delta, Omicron, and Some Circulating Subvariants." Pathogens 13, no. 1 (December 21, 2023): 10. http://dx.doi.org/10.3390/pathogens13010010.
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Among the multiple SARS-CoV-2 variants recently reported, the Delta variant has generated the most perilous and widespread effects. Another variant, Omicron, has been identified specifically for its high transmissibility. Omicron contains numerous spike (S) protein mutations and numbers much larger than those of its predecessor variants. In this report, the author has discussed some essential structural aspects and time-based structure changes of a selected set of spike protein mutations within the Delta and Omicron variants. The expected impact of multiple point mutations within the spike protein’s receptor-binding domain (RBD) and S1 of these variants are examined. Additionally, the RBDs of the more recently emerged subvariants BA.4, BA.5, and BA.2.12.1 are discussed. Within the latter group, BA.5 represents the most prevalent form of SARS-CoV-2 globally until recently. This computational work also briefly explores the temporal mutation profile for the currently circulating variants of interest (VOIs), variants under monitoring (VUMs), and variants being monitored (VBMs) including XBB.1.5, BQ.1, BA.2.75, CH.1.1, XBB, XBF, EG.5 (or Eris), and BA.2.86 (or Pirola). It is expected that these structural data can facilitate the tasks of identifying drug targets and neutralizing antibodies for the evolving variants/subvariants of SARS-CoV-2.
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Tembrink, Marco, Wanda Maria Gerding, Stefan Wieczorek, Thomas Mika, Roland Schroers, Huu Phuc Nguyen, Deepak Ben Vangala, and Verena Nilius-Eliliwi. "Novel NUP98::ASH1L Gene Fusion in Acute Myeloid Leukemia Detected by Optical Genome Mapping." Cancers 15, no. 11 (May 27, 2023): 2942. http://dx.doi.org/10.3390/cancers15112942.
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Optical genome mapping (OGM) recently has demonstrated the potential to improve genetic diagnostics in acute myeloid leukemia (AML). In this study, OGM was utilized as a tool for the detection of genome-wide structural variants and disease monitoring. A previously unrecognized NUP98::ASH1L fusion was detected in an adult patient with secondary AML. OGM identified the fusion of NUP98 to Absent, Small, or Homeotic-Like Histone Lysine Methyltransferase (ASH1L) as result of a complex structural rearrangement between chromosomes 1 and 11. A pipeline for the measurement of rare structural variants (Rare Variant Pipeline, Bionano Genomics, San Diego, USA) was used for detection. As NUP98 and other fusions are relevant for disease classification, this demonstrates the necessity for methods such as OGM for cytogenetic diagnostics in AML. Furthermore, other structural variants showed discordant variant allele frequencies at different time points over the course of the disease and treatment pressure, indicating clonal evolution. These results support OGM to be a valuable tool for primary diagnostics in AML as well as longitudinal testing for disease monitoring and deepening our understanding of genetically heterogenous diseases.
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Giraldo-Ramirez, Sebastián, Santiago Rendon-Marin, and Julián Ruiz-Saenz. "Phylogenetic, Evolutionary and Structural Analysis of Canine Parvovirus (CPV-2) Antigenic Variants Circulating in Colombia." Viruses 12, no. 5 (April 30, 2020): 500. http://dx.doi.org/10.3390/v12050500.
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Canine parvovirus (CPV-2) is the causative agent of haemorrhagic gastroenteritis in canids. Three antigenic variants—CPV-2a, CPV-2b and CPV-2c—have been described, which are determined by variations at residue 426 of the VP2 capsid protein. In Colombia, the CPV-2a and CPV-2b antigenic variants have previously been reported through partial VP2 sequencing. Mutations at residues Asn428Asp and Ala514Ser of variant CPV-2a were detected, implying the appearance of a possible new CPV-2a variant in Colombia. The purpose of the present study was to characterise the full VP2 capsid protein in samples from Antioquia, Colombia. We conducted a cross-sectional study with 56 stool samples from dogs showing clinical symptoms of parvoviral disease. Following DNA extraction from the samples, VP2 amplification was performed using PCR and positive samples were sequenced. Sequence and phylogenetic analyses were performed by comparison with the VP2 gene sequences of the different CPV-2 worldwide. VP2 was amplified in 51.8% of the analysed samples. Sequencing and sequence alignment showed that 93.1% of the amplified samples belonged to the new CPV-2a antigenic variant previously. Analysing the amino acid sequences revealed that all CPV-2a contain Ala297Asn mutations, which are related to the South America I clade, and the Ala514Ser mutation, which allows characterization as a new CPV-2a sub-variant. The Colombian CPV-2b variant presented Phe267Tyr, Tyr324Ile and Thr440Ala, which are related to the Asia-I clade variants. The CPV-2c was not detected in the samples. In conclusion, two antigenic CPV-2 variants of two geographically distant origins are circulating in Colombia. It is crucial to continue characterising CPV-2 to elucidate the molecular dynamics of the virus and to detect new CPV-2 variants that could be becoming highly prevalent in the region.
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Othman, Houcemeddine, Jorge E. B. da Rocha, and Scott Hazelhurst. "Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations." International Journal of Molecular Sciences 22, no. 15 (July 21, 2021): 7786. http://dx.doi.org/10.3390/ijms22157786.
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Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigated the impact of such variants on protein structure to assess their functional importance. We used genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability seemed to act on the plasticity of the protein. The impact on drug binding might be drug dependant. We concluded that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.
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Ruigrok, Mike, Bing Xue, Andrew Catanach, Mengjie Zhang, Linley Jesson, Marcus Davy, and Maren Wellenreuther. "The Relative Power of Structural Genomic Variation versus SNPs in Explaining the Quantitative Trait Growth in the Marine Teleost Chrysophrys auratus." Genes 13, no. 7 (June 23, 2022): 1129. http://dx.doi.org/10.3390/genes13071129.
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Background: Genetic diversity provides the basic substrate for evolution. Genetic variation consists of changes ranging from single base pairs (single-nucleotide polymorphisms, or SNPs) to larger-scale structural variants, such as inversions, deletions, and duplications. SNPs have long been used as the general currency for investigations into how genetic diversity fuels evolution. However, structural variants can affect more base pairs in the genome than SNPs and can be responsible for adaptive phenotypes due to their impact on linkage and recombination. In this study, we investigate the first steps needed to explore the genetic basis of an economically important growth trait in the marine teleost finfish Chrysophrys auratus using both SNP and structural variant data. Specifically, we use feature selection methods in machine learning to explore the relative predictive power of both types of genetic variants in explaining growth and discuss the feature selection results of the evaluated methods. Methods: SNP and structural variant callers were used to generate catalogues of variant data from 32 individual fish at ages 1 and 3 years. Three feature selection algorithms (ReliefF, Chi-square, and a mutual-information-based method) were used to reduce the dataset by selecting the most informative features. Following this selection process, the subset of variants was used as features to classify fish into small, medium, or large size categories using KNN, naïve Bayes, random forest, and logistic regression. The top-scoring features in each feature selection method were subsequently mapped to annotated genomic regions in the zebrafish genome, and a permutation test was conducted to see if the number of mapped regions was greater than when random sampling was applied. Results: Without feature selection, the prediction accuracies ranged from 0 to 0.5 for both structural variants and SNPs. Following feature selection, the prediction accuracy increased only slightly to between 0 and 0.65 for structural variants and between 0 and 0.75 for SNPs. The highest prediction accuracy for the logistic regression was achieved for age 3 fish using SNPs, although generally predictions for age 1 and 3 fish were very similar (ranging from 0–0.65 for both SNPs and structural variants). The Chi-square feature selection of SNP data was the only method that had a significantly higher number of matches to annotated genomic regions of zebrafish than would be explained by chance alone. Conclusions: Predicting a complex polygenic trait such as growth using data collected from a low number of individuals remains challenging. While we demonstrate that both SNPs and structural variants provide important information to help understand the genetic basis of phenotypic traits such as fish growth, the full complexities that exist within a genome cannot be easily captured by classical machine learning techniques. When using high-dimensional data, feature selection shows some increase in the prediction accuracy of classification models and provides the potential to identify unknown genomic correlates with growth. Our results show that both SNPs and structural variants significantly impact growth, and we therefore recommend that researchers interested in the genotype–phenotype map should strive to go beyond SNPs and incorporate structural variants in their studies as well. We discuss how our machine learning models can be further expanded to serve as a test bed to inform evolutionary studies and the applied management of species.
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Larsen, Ole Halfdan, Alisa D. Kjaergaard, Anne-Mette Hvas, and Peter H. Nissen. "Genetic Variants in the Protein S (PROS1) Gene and Protein S Deficiency in a Danish Population." TH Open 05, no. 04 (October 2021): e479-e488. http://dx.doi.org/10.1055/s-0041-1736636.
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AbstractProtein S (PS) deficiency is a risk factor for venous thromboembolism (VTE) and can be caused by variants of the gene encoding PS (PROS1). This study aimed to evaluate the clinical value of molecular analysis of the PROS1 gene in PS-deficient participants. We performed Sanger sequencing of the coding region of the PROS1 gene and multiplex ligation-dependent probe amplification to exclude large structural rearrangements. Free PS was measured by a particle-enhanced immunoassay, while PS activity was assessed by a clotting method.A total of 87 PS-deficient participants and family members were included. In 22 index participants, we identified 13 PROS1 coding variants. Five variants were novel. In 21 index participants, no coding sequence variants or structural rearrangements were identified. The free PS level was lower in index participants carrying a PROS1 variant compared with index participants with no variant (0.51 [0.32–0.61] vs. 0.62 [0.57–0.73] × 103 IU/L; p < 0.05). The p.(Thr78Met) variant was associated with only slightly decreased free PS levels (0.59 [0.53–0.66] × 103 IU/L) compared with the p.(Glu390Lys) variant (0.27 [0.24–0.37] × 103 IU/L, p < 0.01). The frequency of VTE in participants with a coding PROS1 variant was 43 and 17% in the group with normal PROS1 gene (p = 0.05).In conclusion, we report 13 PROS1 coding variants including five novel variants. PS levels differ by PROS1 variant and the frequency of VTE was higher when a coding PROS1 variant was present. Hence, molecular analysis of the PROS1 gene may add clinical value in the diagnostic work-up of PS deficiency.
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Mizejewski, Gerald J. "The Different Biologically Active Forms of Alpha-Fetoprotein as Functional Biomarkers in Pregnancy, Disease and Cancer: A Review and Update." International Journal of Clinical and Molecular Oncology 2, no. 1 (December 22, 2023): 1–11. http://dx.doi.org/10.59657/2993-0197.brs.23.005.
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Human alpha-fetoprotein (HAFP) has been known to manifest in multiple structural forms as previously reported in the biomedical literature. Such structural forms of HAFP have included isoforms, epitopes, carbohydrate and pH heterogenetic forms, and structural variants. However, within the last decade, studies have reported variant forms of HAFP not necessarily of a structural nature as reported in the literature. These newer forms of HAFP are largely functional forms in contrast to structural variants. Such functional forms are a result of slightly denatured intermediates (molten globule forms), conformational variants, misfolded proteins, conformationally transformed HAFP molecules, non-secreted forms, and synthetic peptide segments/sequences derived from the HAFP polypeptide. These latter bioactive functional forms of HAFP have been discussed in the present report. Such recently described forms of the oncofetal protein are deemed of importance since they can be utilized as functional bioactive markers during pregnancy, perinatal, perineurium and juvenile stages, in addition to benign and/or malignant tumor growths in adults.
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Lin, Xin, Yuanhao Yang, Phillip E. Melton, Vikrant Singh, Steve Simpson-Yap, Kathryn P. Burdon, Bruce V. Taylor, and Yuan Zhou. "Integrating Genetic Structural Variations and Whole-Genome Sequencing Into Clinical Neurology." Neurology Genetics 8, no. 4 (May 27, 2022): e200005. http://dx.doi.org/10.1212/nxg.0000000000200005.
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Advances in genome sequencing technologies have unlocked new possibilities in identifying disease-associated and causative genetic markers, which may in turn enhance disease diagnosis and improve prognostication and management strategies. With the capability of examining genetic variations ranging from single-nucleotide mutations to large structural variants, whole-genome sequencing (WGS) is an increasingly adopted approach to dissect the complex genetic architecture of neurologic diseases. There is emerging evidence for different structural variants and their roles in major neurologic and neurodevelopmental diseases. This review first describes different structural variants and their implicated roles in major neurologic and neurodevelopmental diseases, and then discusses the clinical relevance of WGS applications in neurology. Notably, WGS-based detection of structural variants has shown promising potential in enhancing diagnostic power of genetic tests in clinical settings. Ongoing WGS-based research in structural variations and quantifying mutational constraints can also yield clinical benefits by improving variant interpretation and disease diagnosis, while supporting biomarker discovery and therapeutic development. As a result, wider integration of WGS technologies into health care will likely increase diagnostic yields in difficult-to-diagnose conditions and define potential therapeutic targets or intervention points for genome-editing strategies.
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Hernandez, Ciria C., Ningning Hu, Wangzhen Shen, and Robert L. Macdonald. "Epileptic Encephalopathy GABRB Structural Variants Share Common Gating and Trafficking Defects." Biomolecules 13, no. 12 (December 14, 2023): 1790. http://dx.doi.org/10.3390/biom13121790.
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Variants in the GABRB gene, which encodes the β subunit of the GABAA receptor, have been implicated in various epileptic encephalopathies and related neurodevelopmental disorders such as Dravet syndrome and Angelman syndrome. These conditions are often associated with early-onset seizures, developmental regression, and cognitive impairments. The severity and specific features of these encephalopathies can differ based on the nature of the genetic variant and its impact on GABAA receptor function. These variants can lead to dysfunction in GABAA receptor-mediated inhibition, resulting in an imbalance between neuronal excitation and inhibition that contributes to the development of seizures. Here, 13 de novo EE-associated GABRB variants, occurring as missense mutations, were analyzed to determine their impact on protein stability and flexibility, channel function, and receptor biogenesis. Our results showed that all mutations studied significantly impact the protein structure, altering protein stability, flexibility, and function to varying degrees. Variants mapped to the GABA-binding domain, coupling zone, and pore domain significantly impact the protein structure, modifying the β+/α− interface of the receptor and altering channel activation and receptor trafficking. Our study proposes that the extent of loss or gain of GABAA receptor function can be elucidated by identifying the specific structural domain impacted by mutation and assessing the variability in receptor structural dynamics. This paves the way for future studies to explore and uncover links between the incidence of a variant in the receptor topology and the severity of the related disease.
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CHAKRAVARTHY, S., Y. BAO, V. A. ROBERTS, D. TREMETHICK, and K. LUGER. "Structural Characterization of Histone H2A Variants." Cold Spring Harbor Symposia on Quantitative Biology 69 (January 1, 2004): 227–34. http://dx.doi.org/10.1101/sqb.2004.69.227.
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Chakravarthy, S., Y. Bao, V. A. Roberts, D. Tremethick, and K. Luger. "Structural Characterization of Histone H2A Variants." Cold Spring Harbor Symposia on Quantitative Biology 69, no. 1 (January 2004): 1–8. http://dx.doi.org/10.1101/sqb.2004.69.28.
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Fuentes, Roven Rommel, Dmytro Chebotarov, Jorge Duitama, Sean Smith, Juan Fernando De la Hoz, Marghoob Mohiyuddin, Rod A. Wing, et al. "Structural variants in 3000 rice genomes." Genome Research 29, no. 5 (April 16, 2019): 870–80. http://dx.doi.org/10.1101/gr.241240.118.
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Cáceres, Mario. "Structural variants, much ado about nothing?" Briefings in Functional Genomics 14, no. 5 (September 2015): 303–4. http://dx.doi.org/10.1093/bfgp/elv031.
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Saini, Surinder S., and Azad Kaushik. "Origin of bovine IgM structural variants." Molecular Immunology 38, no. 5 (September 2001): 389–96. http://dx.doi.org/10.1016/s0161-5890(01)00063-3.
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Dobb, M. G., and R. M. Robson. "Structural characteristics of aramid fibre variants." Journal of Materials Science 25, no. 1 (January 1990): 459–64. http://dx.doi.org/10.1007/bf00714056.
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Milat, O., G. Van Tendeloo, S. Amelinckx, T. G. N. Babu, and C. Greaves. "Structural variants of Ca0.85CuO2(Ca5+xCu6O12)." Journal of Solid State Chemistry 101, no. 1 (November 1992): 92–114. http://dx.doi.org/10.1016/0022-4596(92)90205-a.
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Willson, Joseph. "Resolving the roles of structural variants." Nature Reviews Genetics 21, no. 9 (July 7, 2020): 507. http://dx.doi.org/10.1038/s41576-020-0264-6.
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Caputo, Emilia, and Luigi Mandrich. "SARS-CoV-2: Searching for the Missing Variants." Viruses 14, no. 11 (October 26, 2022): 2364. http://dx.doi.org/10.3390/v14112364.
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Structural and phylogenetic analysis of the spike glycoprotein highlighted that the last variants, annotated as omicron, have about 30 mutations compared to the initial version reported in China, while the delta variant, supposed to be the omicron ancestor, shows only 7 mutations. Moreover, the five omicron variants were isolated between November 2021 and January 2022, and the last variant BA.2.75, unofficially named centaurus, was isolated in May 2022. It appears that, since the isolation of the delta variant (October 2020) to the omicron BA.1 (November 2021), there was an interval of one year, whereas the five omicron variants were isolated in three months, and after a successive four months period, the BA.2.75 variant was isolated. So, what is the temporal and phylogenetic correlation among all these variants? The analysis of common mutations among delta and the omicron variants revealed: i) a phylogenetic correlation among these variants; ii) the existence of BA.1 and BA.2 omicron variants a few months before being isolated; iii) at least three possible intermediate variants during the evolution of omicron; iv) the evolution of the BA.2.12.1, BA.4 and BA.5 variants from omicron BA.2; v) the centaurus variant evolution from omicron BA.2.12.1.
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Malakov, Ivo, Velizar Zaharinov, Stiliyan Nikolov, and Reneta Dimitrova. "Computer-Aided Choosing of an Optimal Structural Variant of a Robot for Extracting Castings from Die Casting Machines." Actuators 12, no. 9 (September 15, 2023): 363. http://dx.doi.org/10.3390/act12090363.
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In the present article, the solution for choosing the optimal structural variant of an industrial robot for extracting castings from die casting machines is considered. For this purpose, the process of extracting the castings from the mold is analyzed. On this basis, functions are defined, and a functional structure of the robot is built. Alternative variants of devices for each function are developed. The set of possible structural variants are constructed, considering the compatibility between devices and the possibility of performing more than one function with one device. The problem of choosing an optimal structural variant is formulated, and its characteristic features are determined. The main stages of a methodology and application software for the problem’s solution are presented. After an analysis of requirements for the extractor, the set of criteria for evaluating the structural variants are determined. The set includes criteria that minimize the production costs, production floor space, as well as the energy costs in the operation process, which is of particular importance in the conditions of global energy crisis. A mathematical model of the problem is built. The formulated multi-criteria optimization problem is solved, both with equal objective functions and with different priority.
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Da Silva, Jorge Diogo, Natália Oliva-Teles, Nataliya Tkachenko, Joana Fino, Mariana Marques, Ana Maria Fortuna, and Dezso David. "A Novel Frameshift CHD4 Variant Leading to Sifrim-Hitz-Weiss Syndrome in a Proband with a Subclinical Familial t(17;19) and a Large Dup(2)(q14.3q21.1)." Biomedicines 11, no. 1 (December 21, 2022): 12. http://dx.doi.org/10.3390/biomedicines11010012.
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The genetic complexity of neurodevelopmental disorders (NDD), combined with a heterogeneous clinical presentation, makes accurate assessment of their molecular bases and pathogenic mechanisms challenging. Our purpose is to reveal the pathogenic variant underlying a complex NDD through identification of the “full” spectrum of structural genomic and genetic variants. Therefore, clinical phenotyping and identification of variants by genome and exome sequencing, together with comprehensive assessment of these and affected candidate genes, were carried out. A maternally-inherited familial translocation [t(17;19)(p13.1;p13.3)mat] disrupting the GSG1 like 2 gene (GSG1L2), a 3.2 Mb dup(2)(q14.3q21.1) encompassing the autosomal dominant OMIM phenotype-associated PROC and HS6ST1 gene, and a novel frameshift c.4442del, p.(Gly1481Valfs*21) variant within exon 30 of the Chromodomain helicase DNA binding protein 4 (CHD4) have been identified. Considering the pathogenic potential of each variant and the proband’s phenotype, we conclude that this case basically fits the Sifrim–Hitz–Weiss syndrome or CHD4-associated neurodevelopmental phenotype. Finally, our data highlight the need for identification of the “full” spectrum of structural genomic and genetic variants and of reverse comparative phenotyping, including unrelated patients with variants in same genes, for improved genomic healthcare of patients with NDD.
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Ås, Joel, Ilma Bertulyte, Nina Norgren, Anna Johansson, Niclas Eriksson, Henrik Green, Mia Wadelius, and Pär Hallberg. "Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs." PLOS ONE 19, no. 2 (February 29, 2024): e0299075. http://dx.doi.org/10.1371/journal.pone.0299075.
Full textAbstract:
A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.