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Journal articles on the topic 'Genome conformation'
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1
Wang, Yanbo, John Mallon, Haobo Wang, et al. "Real-time observation of Cas9 postcatalytic domain motions." Proceedings of the National Academy of Sciences 118, no. 2 (2020): e2010650118. http://dx.doi.org/10.1073/pnas.2010650118.
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CRISPR-Cas9 fromStreptococcus pyogenesis an RNA-guided DNA endonuclease, which has become the most popular genome editing tool. Coordinated domain motions of Cas9 prior to DNA cleavage have been extensively characterized but our understanding of Cas9 conformations postcatalysis is limited. Because Cas9 can remain stably bound to the cleaved DNA for hours, its postcatalytic conformation may influence genome editing mechanisms. Here, we use single-molecule fluorescence resonance energy transfer to characterize the HNH domain motions of Cas9 that are coupled with cleavage activity of the target strand (TS) or nontarget strand (NTS) of DNA substrate. We reveal an NTS-cleavage-competent conformation following the HNH domain conformational activation. The 3′ flap generated by NTS cleavage can be rapidly digested by a 3′ to 5′ single-stranded DNA-specific exonuclease, indicating Cas9 exposes the 3′ flap for potential interaction with the DNA repair machinery. We find evidence that the HNH domain is highly flexible post-TS cleavage, explaining a recent observation that the HNH domain was not visible in a postcatalytic cryo-EM structure. Our results illuminate previously unappreciated regulatory roles of DNA cleavage activity on Cas9’s conformation and suggest possible biotechnological applications.
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Sanford, Thomas J., Harriet V. Mears, Teodoro Fajardo, Nicolas Locker, and Trevor R. Sweeney. "Circularization of flavivirus genomic RNA inhibits de novo translation initiation." Nucleic Acids Research 47, no. 18 (2019): 9789–802. http://dx.doi.org/10.1093/nar/gkz686.
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Abstract Members of the Flaviviridae family, including dengue virus (DENV) and yellow fever virus, cause serious disease in humans, whilst maternal infection with Zika virus (ZIKV) can induce microcephaly in newborns. Following infection, flaviviral RNA genomes are translated to produce the viral replication machinery but must then serve as a template for the transcription of new genomes. However, the ribosome and viral polymerase proceed in opposite directions along the RNA, risking collisions and abortive replication. Whilst generally linear, flavivirus genomes can adopt a circular conformation facilitated by long-range RNA–RNA interactions, shown to be essential for replication. Using an in vitro reconstitution approach, we demonstrate that circularization inhibits de novo translation initiation on ZIKV and DENV RNA, whilst the linear conformation is translation-competent. Our results provide a mechanism to clear the viral RNA of ribosomes in order to promote efficient replication and, therefore, define opposing roles for linear and circular conformations of the flavivirus genome.
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Shepherd, Jeremiah J., Lingxi Zhou, William Arndt, Yan Zhang, W. Jim Zheng, and Jijun Tang. "Exploring genomes with a game engine." Faraday Discuss. 169 (2014): 443–53. http://dx.doi.org/10.1039/c3fd00152k.
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More and more evidence indicates that the 3D conformation of eukaryotic genomes is a critical part of genome function. However, due to the lack of accurate and reliable 3D genome structural data, this information is largely ignored and most of these studies have to use information systems that view the DNA in a linear structure. Visualizing genomes in real time 3D can give researchers more insight, but this is fraught with hardware limitations since each element contains vast amounts of information that cannot be processed on the fly. Using a game engine and sophisticated video game visualization techniques enables us to construct a multi-platform real-time 3D genome viewer. The game engine-based viewer achieves much better rendering speed and can handle much larger amounts of data compared to our previous implementation using OpenGL. Combining this viewer with 3D genome models from experimental data could provide unprecedented opportunities to gain insight into the conformation–function relationships of a genome.
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Fujishiro, Shin, Naoko Tokuda, and Masaki Sasai. "2P267 Computational chromosome conformation sampling of human diploid genome(21B. Genome biology:Genome structure,Poster)." Seibutsu Butsuri 54, supplement1-2 (2014): S239. http://dx.doi.org/10.2142/biophys.54.s239_3.
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Brigham, Benjamin S., Jonathan P. Kitzrow, Joshua-Paolo C. Reyes, Karin Musier-Forsyth, and James B. Munro. "Intrinsic conformational dynamics of the HIV-1 genomic RNA 5′UTR." Proceedings of the National Academy of Sciences 116, no. 21 (2019): 10372–81. http://dx.doi.org/10.1073/pnas.1902271116.
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The highly conserved 5′ untranslated region (5′UTR) of the HIV-1 RNA genome is central to the regulation of virus replication. NMR and biochemical experiments support a model in which the 5′UTR can transition between at least two conformational states. In one state the genome remains a monomer, as the palindromic dimerization initiation site (DIS) is sequestered via base pairing to upstream sequences. In the second state, the DIS is exposed, and the genome is competent for kissing loop dimerization and packaging into assembling virions where an extended dimer is formed. According to this model the conformation of the 5′UTR determines the fate of the genome. In this work, the dynamics of this proposed conformational switch and the factors that regulate it were probed using multiple single-molecule and in-gel ensemble FRET assays. Our results show that the HIV-1 5′UTR intrinsically samples conformations that are stabilized by both viral and host factor binding. Annealing of tRNALys3, the primer for initiation of reverse transcription, can promote the kissing dimer but not the extended dimer. In contrast, HIV-1 nucleocapsid (NC) promotes formation of the extended dimer in both the absence and presence of tRNALys3. Our data are consistent with an ordered series of events that involves primer annealing, genome dimerization, and virion assembly.
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You, Chuihuai, Tianzhen Cui, Chang Zhang, Shoujian Zang, Yachun Su, and Youxiong Que. "Assembly of the Complete Mitochondrial Genome of Gelsemium elegans Revealed the Existence of Homologous Conformations Generated by a Repeat Mediated Recombination." International Journal of Molecular Sciences 24, no. 1 (2022): 527. http://dx.doi.org/10.3390/ijms24010527.
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Gelsemium elegans (G. elegans) is a Chinese medicinal plant with substantial economic and feeding values. There is a lack of detailed studies on the mitochondrial genome of G. elegans. In this study, the mitochondrial genome of G. elegans was sequenced and assembled, and its substructure was investigated. The mitochondrial genome of G. elegans is represented by two circular chromosomes of 406,009 bp in length with 33 annotated protein-coding genes, 15 tRNA genes, and three rRNA genes. We detected 145 pairs of repeats and found that four pairs of repeats could mediate the homologous recombination into one major conformation and five minor conformations, and the presence of conformations was verified by PCR amplification and Sanger sequencing. A total of 124 SSRs were identified in the G. elegans mitochondrial genome. The homologous segments between the chloroplast and mitochondrial genomes accounted for 5.85% of the mitochondrial genome. We also predicted 477 RNA potential editing sites and found that the nad4 gene was edited 38 times, which was the most frequent occurrence. Taken together, the mitochondrial genome of G. elegans was assembled and annotated. We gained a more comprehensive understanding on the genome of this medicinal plant, which is vital for its effective utilization and genetic improvement, especially for cytoplasmic male sterility breeding and evolution analysis in G. elegans.
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Bentley, Kirsten, Jonathan P. Cook, Andrew K. Tuplin, and David J. Evans. "Structural and functional analysis of the roles of the HCV 5′ NCR miR122-dependent long-range association and SLVI in genome translation and replication." PeerJ 6 (November 6, 2018): e5870. http://dx.doi.org/10.7717/peerj.5870.
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The hepatitis C virus RNA genome possesses a variety of conserved structural elements, in both coding and non-coding regions, that are important for viral replication. These elements are known or predicted to modulate key life cycle events, such as translation and genome replication, some involving conformational changes induced by long-range RNA–RNA interactions. One such element is SLVI, a stem-loop (SL) structure located towards the 5′ end of the core protein-coding region. This element forms an alternative RNA–RNA interaction with complementary sequences in the 5′ untranslated regions that are independently involved in the binding of the cellular microRNA 122 (miR122). The switch between ‘open’ and ‘closed’ structures involving SLVI has previously been proposed to modulate translation, with lower translation efficiency associated with the ‘closed’ conformation. In the current study, we have used selective 2′-hydroxyl acylation analysed by primer extension to validate this RNA–RNA interaction in the absence and presence of miR122. We show that the long-range association (LRA) only forms in the absence of miR122, or otherwise requires the blocking of miR122 binding combined with substantial disruption of SLVI. Using site-directed mutations introduced to promote open or closed conformations of the LRA we demonstrate no correlation between the conformation and the translation phenotype. In addition, we observed no influence on virus replication compared to unmodified genomes. The presence of SLVI is well-documented to suppress translation, but these studies demonstrate that this is not due to its contribution to the LRA. We conclude that, although there are roles for SLVI in translation, the LRA is not a riboswitch regulating the translation and replication phenotypes of the virus.
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Gu, Bowen, Ruifan Sun, Xingqiang Fang, et al. "Genome-Wide Association Study of Body Conformation Traits by Whole Genome Sequencing in Dazu Black Goats." Animals 12, no. 5 (2022): 548. http://dx.doi.org/10.3390/ani12050548.
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Identifying associations between genetic markers and economic traits has practical benefits for the meat goat industry. To better understand the genomic regions and biological pathways contributing to body conformation traits of meat goats, a genome-wide association study was performed using Dazu black goats (DBGs), a Chinese indigenous goat breed. In particular, 150 DBGs were genotyped by whole-genome sequencing, and six body conformation traits, including body height (BH), body length (BL), cannon circumference (CC), chest depth (CD), chest width (CW), and heart girth (HG), were examined. In total, 53 potential SNPs were associated with these body conformation traits. A bioinformatics analysis was performed to evaluate the genes located close to the significant SNPs. Finally, 42 candidate genes (e.g., PSTPIP2, C7orf57, CCL19, FGF9, SGCG, FIGN, and SIPA1L) were identified as components of the genetic architecture underlying body conformation traits. Our results provide useful biological information for the improvement of growth performance and have practical applications for genomic selection in goats.
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Bolovan-Fritts, Cynthia A., Edward S. Mocarski, and Jean A. Wiedeman. "Peripheral Blood CD14+ Cells From Healthy Subjects Carry a Circular Conformation of Latent Cytomegalovirus Genome." Blood 93, no. 1 (1999): 394–98. http://dx.doi.org/10.1182/blood.v93.1.394.
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Abstract The majority of the human population harbors latent cytomegalovirus. Although CD14+ peripheral blood mononuclear cells have been implicated as sites of latency, the conformation of the latent viral genome in these cells is unknown. In this study, the conformation of viral genomic DNA was assessed in CD14+ cells from healthy virus seropositive carriers using an electrophoretic separation on native agarose gels in combination with polymerase chain reaction detection. Here we show that the viral genome migrates as a circular plasmid with a mobility equivalent to a circular 230-kb Shigella flexneri megaplasmid marker. Neither linear nor complex or integrated forms of the viral genome were detected. This report provides further evidence that the CD14+ cell population is an important site of viral latency in the naturally infected human host. Detection of the viral genome as a circular plasmid during latency suggests that this virus maintains its genome in a manner analogous to other herpesviruses where latent viral genome conformation has been studied.
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Bolovan-Fritts, Cynthia A., Edward S. Mocarski, and Jean A. Wiedeman. "Peripheral Blood CD14+ Cells From Healthy Subjects Carry a Circular Conformation of Latent Cytomegalovirus Genome." Blood 93, no. 1 (1999): 394–98. http://dx.doi.org/10.1182/blood.v93.1.394.401k44_394_398.
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The majority of the human population harbors latent cytomegalovirus. Although CD14+ peripheral blood mononuclear cells have been implicated as sites of latency, the conformation of the latent viral genome in these cells is unknown. In this study, the conformation of viral genomic DNA was assessed in CD14+ cells from healthy virus seropositive carriers using an electrophoretic separation on native agarose gels in combination with polymerase chain reaction detection. Here we show that the viral genome migrates as a circular plasmid with a mobility equivalent to a circular 230-kb Shigella flexneri megaplasmid marker. Neither linear nor complex or integrated forms of the viral genome were detected. This report provides further evidence that the CD14+ cell population is an important site of viral latency in the naturally infected human host. Detection of the viral genome as a circular plasmid during latency suggests that this virus maintains its genome in a manner analogous to other herpesviruses where latent viral genome conformation has been studied.
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Tjong, Harianto, Wenyuan Li, Reza Kalhor, et al. "Population-based 3D genome structure analysis reveals driving forces in spatial genome organization." Proceedings of the National Academy of Sciences 113, no. 12 (2016): E1663—E1672. http://dx.doi.org/10.1073/pnas.1512577113.
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Conformation capture technologies (e.g., Hi-C) chart physical interactions between chromatin regions on a genome-wide scale. However, the structural variability of the genome between cells poses a great challenge to interpreting ensemble-averaged Hi-C data, particularly for long-range and interchromosomal interactions. Here, we present a probabilistic approach for deconvoluting Hi-C data into a model population of distinct diploid 3D genome structures, which facilitates the detection of chromatin interactions likely to co-occur in individual cells. Our approach incorporates the stochastic nature of chromosome conformations and allows a detailed analysis of alternative chromatin structure states. For example, we predict and experimentally confirm the presence of large centromere clusters with distinct chromosome compositions varying between individual cells. The stability of these clusters varies greatly with their chromosome identities. We show that these chromosome-specific clusters can play a key role in the overall chromosome positioning in the nucleus and stabilizing specific chromatin interactions. By explicitly considering genome structural variability, our population-based method provides an important tool for revealing novel insights into the key factors shaping the spatial genome organization.
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Hrebík, Dominik, Tibor Füzik, Mária Gondová, et al. "ICAM-1 induced rearrangements of capsid and genome prime rhinovirus 14 for activation and uncoating." Proceedings of the National Academy of Sciences 118, no. 19 (2021): e2024251118. http://dx.doi.org/10.1073/pnas.2024251118.
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Most rhinoviruses, which are the leading cause of the common cold, utilize intercellular adhesion molecule-1 (ICAM-1) as a receptor to infect cells. To release their genomes, rhinoviruses convert to activated particles that contain pores in the capsid, lack minor capsid protein VP4, and have an altered genome organization. The binding of rhinoviruses to ICAM-1 promotes virus activation; however, the molecular details of the process remain unknown. Here, we present the structures of virion of rhinovirus 14 and its complex with ICAM-1 determined to resolutions of 2.6 and 2.4 Å, respectively. The cryo-electron microscopy reconstruction of rhinovirus 14 virions contains the resolved density of octanucleotide segments from the RNA genome that interact with VP2 subunits. We show that the binding of ICAM-1 to rhinovirus 14 is required to prime the virus for activation and genome release at acidic pH. Formation of the rhinovirus 14–ICAM-1 complex induces conformational changes to the rhinovirus 14 capsid, including translocation of the C termini of VP4 subunits, which become poised for release through pores that open in the capsids of activated particles. VP4 subunits with altered conformation block the RNA–VP2 interactions and expose patches of positively charged residues. The conformational changes to the capsid induce the redistribution of the virus genome by altering the capsid–RNA interactions. The restructuring of the rhinovirus 14 capsid and genome prepares the virions for conversion to activated particles. The high-resolution structure of rhinovirus 14 in complex with ICAM-1 explains how the binding of uncoating receptors enables enterovirus genome release.
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Cao, Pei, Yuan Huang, Mei Zong, and Zilong Xu. "De Novo Assembly and Comparative Analysis of the Complete Mitochondrial Genome of Chaenomeles speciosa (Sweet) Nakai Revealed the Existence of Two Structural Isomers." Genes 14, no. 2 (2023): 526. http://dx.doi.org/10.3390/genes14020526.
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As a valuable Chinese traditional medicinal species, Chaenomeles speciosa (Sweet) Nakai (C. speciosa) is a natural resource with significant economic and ornamental value. However, its genetic information is not well understood. In this study, the complete mitochondrial genome of C. speciosa was assembled and characterized to explore the repeat sequences, recombination events, rearrangements, and IGT, to predict RNA editing sites, and to clarify the phylogenetic and evolutionary relationship. The C. speciosa mitochondrial genome was found to have two circular chromosomes as its major conformation, with a total length of 436,464 bp and 45.2% GC content. The mitochondrial genome contained 54 genes, including 33 unique protein-coding genes, 18 tRNAs, and 3 rRNA genes. Seven pairs of repeat sequences involving recombination events were analyzed. Both the repeat pairs, R1 and R2, played significant roles in mediating the major and minor conformations. In total, 18 MTPTs were identified, 6 of which were complete tRNA genes. There were 454 RNA editing sites in the 33 protein-coding sequences predicted by the PREPACT3 program. A phylogenetic analysis based on 22 species of mitochondrial genomes was constructed and indicated highly conserved PCG sequences. Synteny analyses showed extensive genomic rearrangements in the mitochondrial genome of C. speciosa and closely related species. This work is the first to report the C. speciosa mitochondrial genome, which is of great significance for conducting additional genetic studies on this organism.
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Haque, Md Azizul, Mohammad Zahangir Alam, Asif Iqbal, Yun-Mi Lee, Chang-Gwon Dang, and Jong-Joo Kim. "Genome-Wide Association Studies for Body Conformation Traits in Korean Holstein Population." Animals 13, no. 18 (2023): 2964. http://dx.doi.org/10.3390/ani13182964.
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The objective of this study was to identify quantitative trait loci (QTL) and nearby candidate genes that influence body conformation traits. Phenotypic data for 24 body conformation traits were collected from a population of 2329 Korean Holstein cattle, and all animals were genotyped using the 50 K Illumina bovine SNP chip. A total of 24 genome-wide significant SNPs associated with 24 body conformation traits were identified by genome-wide association analysis. The selection of the most promising candidate genes was based on gene ontology (GO) terms and the previously identified functions that influence various body conformation traits as determined in our study. These genes include KCNA1, RYBP, PTH1R, TMIE, and GNAI3 for body traits; ANGPT1 for rump traits; MALRD1, INHBA, and HOXA13 for feet and leg traits; and CDK1, RHOBTB1, and SLC17A1 for udder traits, respectively. These findings contribute to our understanding of the genetic basis of body conformation traits in this population and pave the way for future breeding strategies aimed at enhancing desirable traits in dairy cattle.
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Keown, Jeremy R., Loïc Carrique, Benjamin E. Nilsson-Payant, Ervin Fodor, and Jonathan M. Grimes. "Structural characterization of the full-length Hantaan virus polymerase." PLOS Pathogens 20, no. 12 (2024): e1012781. https://doi.org/10.1371/journal.ppat.1012781.
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Hantaviridae are a family of segmented negative-sense RNA viruses that contains important human and animal pathogens. Hantaviridae contain a viral RNA-dependent RNA polymerase that replicates and transcribes the viral genome. Here we establish the expression and purification polymerase from the Old World Hantaan virus and characterise the structure using Cryo-EM. We determine a series of structures at resolutions between 2.7 and 3.3 Å of RNA free polymerase comprising the core, core and endonuclease, and a full-length polymerase. The full-length polymerase structure depicts the location of the cap binding and C-terminal domains which are arranged in a conformation that is incompatible with transcription and in a novel conformation not observed in previous conformations of cap-snatching viral polymerases. We further describe structures with 5′ vRNA promoter in the presence and absence of a nucleotide triphosphate. The nucleotide bound structure mimics a replication pre-initiation complex and the nucleotide stabilises the motif E in a conformation distinct from those previously observed. We observe motif E in four distinct conformations including β-sheet, two helical arrangements, and nucleotide primed arrangement. The insights gained here guide future mechanistic studies of both the transcription and replication activities of the hantavirus polymerase and for the development of therapeutic targets.
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Wlasnowolski, Michal, Michal Sadowski, Tymon Czarnota, et al. "3D-GNOME 2.0: a three-dimensional genome modeling engine for predicting structural variation-driven alterations of chromatin spatial structure in the human genome." Nucleic Acids Research 48, W1 (2020): W170—W176. http://dx.doi.org/10.1093/nar/gkaa388.
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Abstract Structural variants (SVs) that alter DNA sequence emerge as a driving force involved in the reorganisation of DNA spatial folding, thus affecting gene transcription. In this work, we describe an improved version of our integrated web service for structural modeling of three-dimensional genome (3D-GNOME), which now incorporates all types of SVs to model changes to the reference 3D conformation of chromatin. In 3D-GNOME 2.0, the default reference 3D genome structure is generated using ChIA-PET data from the GM12878 cell line and SVs data are sourced from the population-scale catalogue of SVs identified by the 1000 Genomes Consortium. However, users may also submit their own structural data to set a customized reference genome structure, and/or a custom input list of SVs. 3D-GNOME 2.0 provides novel tools to inspect, visualize and compare 3D models for regions that differ in terms of their linear genomic sequence. Contact diagrams are displayed to compare the reference 3D structure with the one altered by SVs. In our opinion, 3D-GNOME 2.0 is a unique online tool for modeling and analyzing conformational changes to the human genome induced by SVs across populations. It can be freely accessed at https://3dgnome.cent.uw.edu.pl/.
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Homma, Kengo, Hiromitsu Takahashi, Naomi Tsuburaya, Isao Naguro, Takao Fujisawa, and Hidenori Ichijo. "Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu,Zn-superoxide dismutase." Journal of Biological Chemistry 295, no. 10 (2020): 3148–58. http://dx.doi.org/10.1074/jbc.ra119.010239.
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Cu, Zn superoxide dismutase (SOD1) is one of the genes implicated in the devastating neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Although the precise mechanisms of SOD1 mutant (SOD1mut)-induced motoneuron toxicity are still unclear, defects in SOD1 proteostasis are known to have a critical role in ALS pathogenesis. We previously reported that the SOD1mut adopts a conformation that exposes a Derlin-1–binding region (DBR) and that DBR-exposed SOD1 interacts with Derlin-1, leading to motoneuron death. We also found that an environmental change, i.e. zinc depletion, induces a conformational change in WT SOD1 (SOD1WT) to the DBR-exposed conformation, suggesting the presence of an equilibrium state between the DBR-masked and DBR-exposed states even with SOD1WT. Here, we conducted a high-throughput screening based on time-resolved FRET to further investigate the SOD1WT conformational change, and we used a genome-wide siRNA screen to search for regulators of SOD1 proteostasis. This screen yielded 30 candidate genes that maintained an absence of the DBR-exposed SOD1WT conformation. Among these genes was one encoding DDB1- and CUL4-associated factor 4 (DCAF4), a substrate receptor of the E3 ubiquitin–protein ligase complex. Of note, we found that DCAF4 mediates the ubiquitination of an ALS-associated protein and autophagy receptor, optineurin (OPTN), and facilitates autophagic degradation of DBR-exposed SOD1. In summary, our screen identifies DCAF4 as being required for proper proteostasis of DBR-exposed SOD1, which may have potential relevance for the development of therapies for managing ALS.
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Xiao, Ke, Dan Xiong, Gong Chen, et al. "RUNX1-mediated alphaherpesvirus-host trans-species chromatin interaction promotes viral transcription." Science Advances 7, no. 26 (2021): eabf8962. http://dx.doi.org/10.1126/sciadv.abf8962.
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Like most DNA viruses, herpesviruses precisely deliver their genomes into the sophisticatedly organized nuclei of the infected host cells to initiate subsequent transcription and replication. However, it remains elusive how the viral genome specifically interacts with the host genome and hijacks host transcription machinery. Using pseudorabies virus (PRV) as model virus, we performed chromosome conformation capture assays to demonstrate a genome-wide specific trans-species chromatin interaction between the virus and host. Our data show that the PRV genome is delivered by the host DNA binding protein RUNX1 into the open chromatin and active transcription zone. This facilitates virus hijacking host RNAPII to efficiently transcribe viral genes, which is significantly inhibited by either a RUNX1 inhibitor or RNA interference. Together, these findings provide insights into the chromatin interaction between viral and host genomes and identify new areas of research to advance the understanding of herpesvirus genome transcription.
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Totikov, Azamat, Andrey Tomarovsky, Lorena Derezanin, et al. "Chromosome-Level Genome Assemblies: Expanded Capabilities for Conservation Biology Research." Proceedings 76, no. 1 (2020): 10. http://dx.doi.org/10.3390/iecge-07149.
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Genome assemblies are becoming increasingly important for understanding genetic diversity in threatened species. However, due to limited budgets in the area of conservation biology, genome assemblies, when available, tend to be highly fragmented with tens of thousands of scaffolds. The recent advent of high throughput chromosome conformation capture (Hi-C) makes it possible to generate more contiguous assemblies containing scaffolds that are length of entire chromosomes. Such assemblies greatly facilitate analyses and visualization of genome-wide features. We compared genetic diversity in seven threatened species that had both draft genome assemblies and newer chromosome-level assemblies available. Chromosome-level assemblies allowed better estimation of genetic diversity, localization, and, especially, visualization of low heterozygosity regions in the genomes.
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Nayak, Vinod, Moshe Dessau, Kaury Kucera, Karen Anthony, Michel Ledizet, and Yorgo Modis. "Crystal Structure of Dengue Virus Type 1 Envelope Protein in the Postfusion Conformation and Its Implications for Membrane Fusion." Journal of Virology 83, no. 9 (2009): 4338–44. http://dx.doi.org/10.1128/jvi.02574-08.
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ABSTRACT Dengue virus relies on a conformational change in its envelope protein, E, to fuse the viral lipid membrane with the endosomal membrane and thereby deliver the viral genome into the cytosol. We have determined the crystal structure of a soluble fragment E (sE) of dengue virus type 1 (DEN-1). The protein is in the postfusion conformation even though it was not exposed to a lipid membrane or detergent. At the domain I-domain III interface, 4 polar residues form a tight cluster that is absent in other flaviviral postfusion structures. Two of these residues, His-282 and His-317, are conserved in flaviviruses and are part of the “pH sensor” that triggers the fusogenic conformational change in E, at the reduced pH of the endosome. In the fusion loop, Phe-108 adopts a distinct conformation, forming additional trimer contacts and filling the bowl-shaped concavity observed at the tip of the DEN-2 sE trimer.
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Zirkel, Anne, and Argyris Papantonis. "Transcription as a force partitioning the eukaryotic genome." Biological Chemistry 395, no. 11 (2014): 1301–5. http://dx.doi.org/10.1515/hsz-2014-0196.
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Abstract Eukaryotic genomes – until recently dealt with as if they were a cohort of linear DNA molecules – are perplexed three-dimensional structures, the exact conformation of which profoundly affects genome function. Recent advances in molecular biology and DNA sequencing technologies have led to a new understanding of the folding of chromatin in the nucleus. Changes in chromatin structure underlie deployment of new gene expression programs during development, differentiation, or disease. In this review, we revisit data pointing to, arguably, the major force that shapes genomes: transcription of DNA into RNA.
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Rajarajan, Prashanth, Tyler Borrman, Will Liao, et al. "Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk." Science 362, no. 6420 (2018): eaat4311. http://dx.doi.org/10.1126/science.aat4311.
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To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type–specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type–specific disease risk vulnerabilities in spatial genome organization.
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MacKay, Kimberly, and Anthony Kusalik. "Computational methods for predicting 3D genomic organization from high-resolution chromosome conformation capture data." Briefings in Functional Genomics 19, no. 4 (2020): 292–308. http://dx.doi.org/10.1093/bfgp/elaa004.
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Abstract The advent of high-resolution chromosome conformation capture assays (such as 5C, Hi-C and Pore-C) has allowed for unprecedented sequence-level investigations into the structure–function relationship of the genome. In order to comprehensively understand this relationship, computational tools are required that utilize data generated from these assays to predict 3D genome organization (the 3D genome reconstruction problem). Many computational tools have been developed that answer this need, but a comprehensive comparison of their underlying algorithmic approaches has not been conducted. This manuscript provides a comprehensive review of the existing computational tools (from November 2006 to September 2019, inclusive) that can be used to predict 3D genome organizations from high-resolution chromosome conformation capture data. Overall, existing tools were found to use a relatively small set of algorithms from one or more of the following categories: dimensionality reduction, graph/network theory, maximum likelihood estimation (MLE) and statistical modeling. Solutions in each category are far from maturity, and the breadth and depth of various algorithmic categories have not been fully explored. While the tools for predicting 3D structure for a genomic region or single chromosome are diverse, there is a general lack of algorithmic diversity among computational tools for predicting the complete 3D genome organization from high-resolution chromosome conformation capture data.
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Xu, Zhichao, and Jesse R. Dixon. "Genome reconstruction and haplotype phasing using chromosome conformation capture methodologies." Briefings in Functional Genomics 19, no. 2 (2019): 139–50. http://dx.doi.org/10.1093/bfgp/elz026.
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Abstract Genomic analysis of individuals or organisms is predicated on the availability of high-quality reference and genotype information. With the rapidly dropping costs of high-throughput DNA sequencing, this is becoming readily available for diverse organisms and for increasingly large populations of individuals. Despite these advances, there are still aspects of genome sequencing that remain challenging for existing sequencing methods. This includes the generation of long-range contiguity during genome assembly, identification of structural variants in both germline and somatic tissues, the phasing of haplotypes in diploid organisms and the resolution of genome sequence for organisms derived from complex samples. These types of information are valuable for understanding the role of genome sequence and genetic variation on genome function, and numerous approaches have been developed to address them. Recently, chromosome conformation capture (3C) experiments, such as the Hi-C assay, have emerged as powerful tools to aid in these challenges for genome reconstruction. We will review the current use of Hi-C as a tool for aiding in genome sequencing, addressing the applications, strengths, limitations and potential future directions for the use of 3C data in genome analysis. We argue that unique features of Hi-C experiments make this data type a powerful tool to address challenges in genome sequencing, and that future integration of Hi-C data with alternative sequencing assays will facilitate the continuing revolution in genomic analysis and genome sequencing.
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Bleker, Svenja, Michael Pawlita, and Jürgen A. Kleinschmidt. "Impact of Capsid Conformation and Rep-Capsid Interactions on Adeno-Associated Virus Type 2 Genome Packaging." Journal of Virology 80, no. 2 (2006): 810–20. http://dx.doi.org/10.1128/jvi.80.2.810-820.2006.
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ABSTRACT Single-stranded genomes of adeno-associated virus (AAV) are packaged into preformed capsids. It has been proposed that packaging is initiated by interaction of genome-bound Rep proteins to the capsid, thereby targeting the genome to the portal of encapsidation. Here we describe a panel of mutants with amino acid exchanges in the pores at the fivefold axes of symmetry on AAV2 capsids with reduced packaging and reduced Rep-capsid interaction. Mutation of two threonines at the rim of the fivefold pore nearly completely abolished Rep-capsid interaction and packaging. This suggests a Rep-binding site at the highly conserved amino acids at or close to the pores formed by the capsid protein pentamers. A different mutant (P. Wu, W. Xiao, T. Conlon, J. Hughes, M. Agbandje-McKenna, T. Ferkol, T. Flotte, and N. Muzyczka, J. Virol. 74:8635-8647, 2000) with an amino acid exchange at the interface of capsid protein pentamers led to a complete block of DNA encapsidation. Analysis of the capsid conformation of this mutant revealed that the pores at the fivefold axes were occupied by VP1/VP2 N termini, thereby preventing DNA introduction into the capsid. Nevertheless, the corresponding capsids had more Rep proteins bound than wild-type AAV, showing that correct Rep interaction with the capsid depends on a defined capsid conformation. Both mutant types together support the conclusion that the pores at the fivefold symmetry axes are involved in genome packaging and that capsid conformation-dependent Rep-capsid interactions play an essential role in the packaging process.
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Su, Ying-Hsiu, Xianchao Zhang, Xiaohe Wang, Nigel W. Fraser, and Timothy M. Block. "Evidence that the Immediate-Early Gene Product ICP4 Is Necessary for the Genome of the Herpes Simplex Virus Type 1 ICP4 Deletion Mutant Strain d120 To Circularize in Infected Cells." Journal of Virology 80, no. 23 (2006): 11589–97. http://dx.doi.org/10.1128/jvi.01869-06.
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ABSTRACT Following infection, the physical state of linear herpes simplex virus (HSV) genomes may change into an “endless” or circular form. In this study, using Southern blot analysis of the HSV genome, we provide evidence that immediate-early protein ICP4 is involved in the process of converting the linear HSV-1 ICP4-deleted mutant strain d120 genome into its endless form. Under conditions where de novo viral DNA synthesis was inhibited, the genome of the ICP4 deletion mutant d120 failed to assume an endless conformation following infection of Vero cells (compared with the ability of wild-type strain KOS). This defect was reversed in the Vero-derived cell line E5, which produces the ICP4 protein, suggesting that ICP4 is necessary and sufficient to complement the d120 defect. When ICP4 protein was provided by the replication-defective DNA polymerase mutant HP66, the genomes of mutant d120 could assume an endless conformation in Vero cells. Western blot analysis using antibody specific to the ICP4 protein showed that although the d120 virions contained ICP4 protein, the majority of that ICP4 protein was in a 40-kDa truncated form, with only a small fraction present as a full-length 175-kDa protein. When expression of ICP4 protein from E5 cells was inhibited by cycloheximide, the d120 virion-associated ICP4 protein was unable to mediate endless formation after infection of E5 cells. Collectively, these data suggest that ICP4 protein has an important role in mediating the endless formation of the HSV-1 genome upon infection and that this function can be provided in trans.
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Laflamme, Mark, and Robert W. Lee. "MITOCHONDRIAL GENOME CONFORMATION AMONG CW-GROUP CHLOROPHYCEAN ALGAE1." Journal of Phycology 39, no. 1 (2003): 213–20. http://dx.doi.org/10.1046/j.1529-8817.2003.02045.x.
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Laflamme, Mark, and Robert W. Lee. "MITOCHONDRIAL GENOME CONFORMATION AMONG CW-GROUP CHLOROPHYCEAN ALGAE." Journal of Phycology 39, no. 2 (2003): 462. http://dx.doi.org/10.1046/j.1529-8817.2003.392031.x.
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Yan, A. P., P. A. Salnikov, M. M. Gridina, P. S. Belokopytova, and V. S. Fishman. "Towards development of the 4c-based method detecting interactions of plasmid dna with host genome." Biohimiâ 89, no. 4 (2024): 612–22. http://dx.doi.org/10.31857/s0320972524040051.
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Chromosome conformation capture techniques have revolutionized our understanding of chromatin architecture and dynamics at the genome-wide scale. In recent years, these methods have been applied to a diverse array of species, revealing fundamental principles of chromosomal organization. However, structural organization of the extrachromosomal entities, like viral genomes or plasmids, and their interactions with the host genome, remain relatively underexplored. In this work, we introduce an enhanced 4C-protocol tailored for probing plasmid DNA interactions. We design specific plasmid vector and optimize protocol to allow high detection rate of contacts between the plasmid and host DNA.
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Yost, Kathryn E., Yanding Zhao, King L. Hung, et al. "Three-dimensional genome landscape of primary human cancers." Nature Genetics 57, no. 5 (2025): 1189–200. https://doi.org/10.1038/s41588-025-02188-0.
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Abstract Genome conformation underlies transcriptional regulation by distal enhancers, and genomic rearrangements in cancer can alter critical regulatory interactions. Here we profiled the three-dimensional genome architecture and enhancer connectome of 69 tumor samples spanning 15 primary human cancer types from The Cancer Genome Atlas. We discovered the following three archetypes of enhancer usage for over 100 oncogenes across human cancers: static, selective gain or dynamic rewiring. Integrative analyses revealed the enhancer landscape of noncancer cells in the tumor microenvironment for genes related to immune escape. Deep whole-genome sequencing and enhancer connectome mapping provided accurate detection and validation of diverse structural variants across cancer genomes and revealed distinct enhancer rewiring consequences from noncoding point mutations, genomic inversions, translocations and focal amplifications. Extrachromosomal DNA promoted more extensive enhancer rewiring among several types of focal amplification mechanisms. These results suggest a systematic approach to understanding genome topology in cancer etiology and therapy.
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Ren, Zhongqing, Constantin N. Takacs, Hugo B. Brandão, Christine Jacobs-Wagner, and Xindan Wang. "Organization and replicon interactions within the highly segmented genome of Borrelia burgdorferi." PLOS Genetics 19, no. 7 (2023): e1010857. http://dx.doi.org/10.1371/journal.pgen.1010857.
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Borrelia burgdorferi, a causative agent of Lyme disease, contains the most segmented bacterial genome known to date, with one linear chromosome and over twenty plasmids. How this unusually complex genome is organized, and whether and how the different replicons interact are unclear. We recently demonstrated that B. burgdorferi is polyploid and that the copies of the chromosome and plasmids are regularly spaced in each cell, which is critical for faithful segregation of the genome to daughter cells. Regular spacing of the chromosome is controlled by two separate partitioning systems that involve the protein pairs ParA/ParZ and ParB/Smc. Here, using chromosome conformation capture (Hi-C), we characterized the organization of the B. burgdorferi genome and the interactions between the replicons. We uncovered that although the linear chromosome lacks contacts between the two replication arms, the two telomeres are in frequent contact. Moreover, several plasmids specifically interact with the chromosome oriC region, and a subset of plasmids interact with each other more than with others. We found that Smc and the Smc-like MksB protein mediate long-range interactions on the chromosome, but they minimally affect plasmid-chromosome or plasmid-plasmid interactions. Finally, we found that disruption of the two partition systems leads to chromosome restructuring, correlating with the mis-positioning of chromosome oriC. Altogether, this study revealed the conformation of a complex genome and analyzed the contribution of the partition systems and SMC family proteins to this organization. This work expands the understanding of the organization and maintenance of multipartite bacterial genomes.
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Deschepper, Pablo, Sam Vanbergen, Lore Esselens, et al. "A new genome sequence resource for five invasive fruit flies of agricultural concern: Ceratitis capitata, C. quilicii, C. rosa, Zeugodacus cucurbitae and Bactrocera zonata (Diptera, Tephritidae)." F1000Research 13 (December 6, 2024): 1492. https://doi.org/10.12688/f1000research.157946.1.
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Here, we present novel high quality genome assemblies for five invasive tephritid species of agricultural concern: Ceratitis capitata, C. quilicii, C. rosa, Zeugodacus cucurbitae and Bactrocera zonata (read depths between 65 and 78x). Three assemblies (C. capitata, C. quilicii and Z. cucurbitae) were scaffolded with chromosome conformation data and annotated using RNAseq reads. For some species this is the first reference genome available (B. zonata, C. quilicii and C. rosa), for others we have published improved annotated genomes (C. capitata and Z. cucurbitae). Together, the new references provide an important resource to advance research on genetic techniques for population control, develop rapid species identification methods, and explore eco-evolutionary studies.
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Herbert, Alan. "Training your genome." Open Access Government 46, no. 1 (2025): 110–11. https://doi.org/10.56367/oag-046-11483.
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Training your genome Founder and President of InsideOutBio, Alan Herbert, explores the evolving understanding of genome information storage, and the significance of repetitive sequences called flipons in genome training. These flipons can alter their shape without breaking DNA and are vital in cell biology, especially in responding to environmental stress. Our view of how genomes store information has rapidly changed. In the classical view, codons contain the important content. Each codon consists of three DNA bases uniquely mapped to an amino acid. The order of codons gives the position of amino acids in the protein product that determines its function. Mutations that change codons or their expression then cause disease. In this view, the repetitive sequences that comprise over 50% of the human genome are just a nuisance. They cause genomic instability by frequently breaking and disrupting DNA repair. However, some repeats are useful. For example, telomeric repeats help protect chromosome ends and prevent senescence, while those at centromeres play a role in cell division. Otherwise, most repeat sequences are confined by nucleosomal proteins to limit the harm that they can cause. Recently, a more nuanced understanding of how genomes work has emerged. With this new focus, repeats that dynamically change their conformation in a programmable manner play important roles in cell biology. This class of repeats is called flipons. They enable genomes to learn and optimize cell responses to environmental stressors.
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Long, Mingxue, Bo Wang, Zhangping Yang, and Xubin Lu. "Genome-Wide Association Study as an Efficacious Approach to Discover Candidate Genes Associated with Body Linear Type Traits in Dairy Cattle." Animals 14, no. 15 (2024): 2181. http://dx.doi.org/10.3390/ani14152181.
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Body shape traits are very important and play a crucial role in the economic development of dairy farming. By improving the accuracy of selection for body size traits, we can enhance economic returns across the dairy industry and on farms, contributing to the future profitability of the dairy sector. Registered body conformation traits are reliable and cost-effective tools for use in national cattle breeding selection programs. These traits are significantly related to the production, longevity, mobility, health, fertility, and environmental adaptation of dairy cows. Therefore, they can be considered indirect indicators of economically important traits in dairy cows. Utilizing efficacious genetic methods, such as genome-wide association studies (GWASs), allows for a deeper understanding of the genetic architecture of complex traits through the identification and application of genetic markers. In the current review, we summarize information on candidate genes and genomic regions associated with body conformation traits in dairy cattle worldwide. The manuscript also reviews the importance of body conformation, the relationship between body conformation traits and other traits, heritability, influencing factors, and the genetics of body conformation traits. The information on candidate genes related to body conformation traits provided in this review may be helpful in selecting potential genetic markers for the genetic improvement of body conformation traits in dairy cattle.
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Deng, Shaoxiong, Yibin Qiu, Zhanwei Zhuang, et al. "Genome-Wide Association Study of Body Conformation Traits in a Three-Way Crossbred Commercial Pig Population." Animals 13, no. 15 (2023): 2414. http://dx.doi.org/10.3390/ani13152414.
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Body conformation is the most direct production index, which can fully reflect pig growth status and is closely related to critical economic traits. In this study, we conducted a genome-wide association study (GWAS) on body conformation traits in a population of 1518 Duroc × (Landrace × Yorkshire) commercial pigs. These traits included body length (BL), body height (BH), chest circumference (CC), abdominal circumference (AC), and waist circumference (WC). Both the mixed linear model (MLM) and fixed and random model circulating probability unification (FarmCPU) approaches were employed for the analysis. Our findings revealed 60 significant single nucleotide polymorphisms (SNPs) associated with these body conformation traits in the crossbred pig population. Specifically, sixteen SNPs were significantly associated with BL, three SNPs with BH, thirteen SNPs with CC, twelve SNPs with AC, and sixteen SNPs with WC. Moreover, we identified several promising candidate genes located within the genomic regions associated with body conformation traits. These candidate genes include INTS10, KIRREL3, SOX21, BMP2, MAP4K3, SOD3, FAM160B1, ATL2, SPRED2, SEC16B, and RASAL2. Furthermore, our analysis revealed a novel significant quantitative trait locus (QTL) on SSC7 specifically associated with waist circumference, spanning an 84 kb interval. Overall, the identification of these significant SNPs and potential candidate genes in crossbred commercial pigs enhances our understanding of the genetic basis underlying body conformation traits. Additionally, these findings provide valuable genetic resources for pig breeding programs.
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Silva, Emanueli F. P., Rita C. Gaia, Henrique A. Mulim, et al. "Genome-Wide Association Study of Conformation Traits in Brazilian Holstein Cattle." Animals 14, no. 17 (2024): 2472. http://dx.doi.org/10.3390/ani14172472.
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The linear conformation of animals exerts an influence on health, reproduction, production, and welfare, in addition to longevity, which directly affects the profitability of milk-producing farms. The objectives of this study were (1) to perform genome-wide association studies (GWASs) of conformation traits, namely the Rump, Feet and Legs, Mammary System, Dairy Strength, and Final Classification traits, and (2) to identify genes and related pathways involved in physiological processes associated with conformation traits in Brazilian Holstein cattle. Phenotypic and genotypic data from 2339 Holstein animals distributed across the states of Rio Grande do Sul, Paraná, São Paulo, and Minas Gerais were used. The genotypic data were obtained with a 100 K SNP marker panel. The single-step genome-wide association study (ssGWAS) method was employed in the analyses. Genes close to a significant SNP were identified in an interval of 100 kb up- and downstream using the Ensembl database available in the BioMart tool. The DAVID database was used to identify the main metabolic pathways and the STRING program was employed to create the gene regulatory network. In total, 36 significant SNPs were found on 15 chromosomes; 27 of these SNPs were linked to genes that may influence the traits studied. Fourteen genes most closely related to the studied traits were identified, as well as four genes that showed interactions in important metabolic pathways such as myogenesis, adipogenesis, and angiogenesis. Among the total genes, four were associated with myogenesis (TMOD2, TMOD3, CCND2, and CTBP2), three with angiogenesis (FGF23, FGF1, and SCG3), and four with adipogenesis and body size and development (C5H12orf4, CCND2, EMILIN1, and FGF6). These results contribute to a better understanding of the biological mechanisms underlying phenotypic variability in conformation traits in Brazilian Holstein cattle.
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Mitter, Michael, Catherina Gasser, Zsuzsanna Takacs, et al. "Conformation of sister chromatids in the replicated human genome." Nature 586, no. 7827 (2020): 139–44. http://dx.doi.org/10.1038/s41586-020-2744-4.
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Nazarov, Leonid I., Mikhail V. Tamm, Vladik A. Avetisov, and Sergei K. Nechaev. "A statistical model of intra-chromosome contact maps." Soft Matter 11, no. 5 (2015): 1019–25. http://dx.doi.org/10.1039/c4sm02519a.
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Zhang, Rong, Jian-Jun Jin, Michael J. Moore, and Ting-Shuang Yi. "Assembly and comparative analyses of the mitochondrial genome of Castanospermum australe (Papilionoideae, Leguminosae)." Australian Systematic Botany, 2019. http://dx.doi.org/10.1071/sb19014.
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Plant mitochondrial genomes are often difficult to assemble because of frequent recombination mediated by repeats. Only a few mitochondrial genomes have been characterised in subfamily Papilionoideae of Leguminosae. Here, we report the complete mitochondrial genome of Castanospermum australe A.Cunn. & C.Fraser, an important medicinal and ornamental species in the Aldinoid clade of Papilionoideae. By mapping paired-end reads, seven hypothetical subgenomic conformations were rejected and two hypothetical complete isometric mitochondrial genome conformations that differed by a 64-kb inversion were strongly supported. Quantitative assessment of repeat-spanning read pairs showed a major conformation (MC1) and a minor conformation (MC2). The complete mitochondrial genome of C. australe was, thus, generated as 542079bp in length, with a high depth of coverage (~389.7×). Annotation of this mitochondrial genome yielded 58 genes encoding 37 proteins, 18 tRNAs and three rRNAs, as well as 17 introns and three medium-sized repeats (133, 119 and 114bp). Comparison of 10 mitochondrial genomes from Papilionoideae demonstrated significant variation in genome size, structure, gene content and RNA editing sites. In addition, mitochondrial genes were shown to be potentially useful in resolving the deep relationships of Papilionoideae.
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Organtini, Lindsey J., Kristin L. Shingler, Robert E. Ashley, et al. "Honey Bee Deformed Wing Virus Structures Reveal that Conformational Changes Accompany Genome Release." Journal of Virology 91, no. 2 (2016). http://dx.doi.org/10.1128/jvi.01795-16.
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ABSTRACT The picornavirus-like deformed wing virus (DWV) has been directly linked to colony collapse; however, little is known about the mechanisms of host attachment or entry for DWV or its molecular and structural details. Here we report the three-dimensional (3-D) structures of DWV capsids isolated from infected honey bees, including the immature procapsid, the genome-filled virion, the putative entry intermediate (A-particle), and the empty capsid that remains after genome release. The capsids are decorated by large spikes around the 5-fold vertices. The 5-fold spikes had an open flower-like conformation for the procapsid and genome-filled capsids, whereas the putative A-particle and empty capsids that had released the genome had a closed tube-like spike conformation. Between the two conformations, the spikes undergo a significant hinge-like movement that we predicted using a Robetta model of the structure comprising the spike. We conclude that the spike structures likely serve a function during host entry, changing conformation to release the genome, and that the genome may escape from a 5-fold vertex to initiate infection. Finally, the structures illustrate that, similarly to picornaviruses, DWV forms alternate particle conformations implicated in assembly, host attachment, and RNA release. IMPORTANCE Honey bees are critical for global agriculture, but dramatic losses of entire hives have been reported in numerous countries since 2006. Deformed wing virus (DWV) and infestation with the ectoparasitic mite Varroa destructor have been linked to colony collapse disorder. DWV was purified from infected adult worker bees to pursue biochemical and structural studies that allowed the first glimpse into the conformational changes that may be required during transmission and genome release for DWV.
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Qiu, Yueqi, Delong Feng, Wenjuan Jiang, Tingting Zhang, Qianjin Lu, and Ming Zhao. "3D genome organization and epigenetic regulation in autoimmune diseases." Frontiers in Immunology 14 (June 6, 2023). http://dx.doi.org/10.3389/fimmu.2023.1196123.
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Three-dimensional (3D) genomics is an emerging field of research that investigates the relationship between gene regulatory function and the spatial structure of chromatin. Chromatin folding can be studied using chromosome conformation capture (3C) technology and 3C-based derivative sequencing technologies, including chromosome conformation capture-on-chip (4C), chromosome conformation capture carbon copy (5C), and high-throughput chromosome conformation capture (Hi-C), which allow scientists to capture 3D conformations from a single site to the entire genome. A comprehensive analysis of the relationships between various regulatory components and gene function also requires the integration of multi-omics data such as genomics, transcriptomics, and epigenomics. 3D genome folding is involved in immune cell differentiation, activation, and dysfunction and participates in a wide range of diseases, including autoimmune diseases. We describe hierarchical 3D chromatin organization in this review and conclude with characteristics of C-techniques and multi-omics applications of the 3D genome. In addition, we describe the relationship between 3D genome structure and the differentiation and maturation of immune cells and address how changes in chromosome folding contribute to autoimmune diseases.
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Yang, Xin, Yong Liu, Wen Cui, Mengmeng Liu, and Wei Wang. "Distinct Gag interaction properties of HIV-1 RNA 5′ leader conformers reveal a mechanism for dimeric genome selection." RNA, November 16, 2022, rna.079347.122. http://dx.doi.org/10.1261/rna.079347.122.
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During HIV-1 assembly, two copies of viral genomic RNAs (gRNA) are selectively packaged into new viral particles. This process is mediated by specific interactions between HIV-1 Gag and the packaging signals at 5′ RNA leader (5′L). 5′L is able to adopt different conformations, which promotes either gRNA dimerization and packaging or Gag translation. Dimerization and packaging are coupled. Whether the selective packaging of gRNA dimer is due to favorable interactions between Gag and 5′L in packaging conformation is not known. Here, using RNAs mimicking the two 5′L conformers, we show that 5′L conformation dramatically affects Gag-RNA interactions. Compare to the RNA in translation conformation (5′LT), the one in packaging conformation (5′LP) is able to bind more Gag molecules. Gag associates with 5′LPfaster than it binds to 5′LT; Gag dissociates from 5′LPmuch slower. The Gag-5′LPcomplex is more stable at high salt. The NC-SP2-p6 region of Gag likely accounts for the faster association and slower dissociation kinetics for the Gag-5′LPinteraction and for the higher stability.In summary, our data suggests that conformational changes play an important role in the selection of dimeric genomes, probably by affecting the dissociation kinetics and stability of the Gag-5′L complex.
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Kozlovskii, Igor, and Petr Popov. "Spatiotemporal identification of druggable binding sites using deep learning." Communications Biology 3, no. 1 (2020). http://dx.doi.org/10.1038/s42003-020-01350-0.
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Abstract Identification of novel protein binding sites expands druggable genome and opens new opportunities for drug discovery. Generally, presence or absence of a binding site depends on the three-dimensional conformation of a protein, making binding site identification resemble the object detection problem in computer vision. Here we introduce a computational approach for the large-scale detection of protein binding sites, that considers protein conformations as 3D-images, binding sites as objects on these images to detect, and conformational ensembles of proteins as 3D-videos to analyze. BiteNet is suitable for spatiotemporal detection of hard-to-spot allosteric binding sites, as we showed for conformation-specific binding site of the epidermal growth factor receptor, oligomer-specific binding site of the ion channel, and binding site in G protein-coupled receptor. BiteNet outperforms state-of-the-art methods both in terms of accuracy and speed, taking about 1.5 minutes to analyze 1000 conformations of a protein with ~2000 atoms.
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Chen, Mengjie, Xingyu Liu, Qingyou Liu, Deshun Shi, and Hui Li. "3D genomics and its applications in precision medicine." Cellular & Molecular Biology Letters 28, no. 1 (2023). http://dx.doi.org/10.1186/s11658-023-00428-x.
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AbstractThree-dimensional (3D) genomics is an emerging discipline that studies the three-dimensional structure of chromatin and the three-dimensional and functions of genomes. It mainly studies the three-dimensional conformation and functional regulation of intranuclear genomes, such as DNA replication, DNA recombination, genome folding, gene expression regulation, transcription factor regulation mechanism, and the maintenance of three-dimensional conformation of genomes. Self-chromosomal conformation capture (3C) technology has been developed, and 3D genomics and related fields have developed rapidly. In addition, chromatin interaction analysis techniques developed by 3C technologies, such as paired-end tag sequencing (ChIA-PET) and whole-genome chromosome conformation capture (Hi-C), enable scientists to further study the relationship between chromatin conformation and gene regulation in different species. Thus, the spatial conformation of plant, animal, and microbial genomes, transcriptional regulation mechanisms, interaction patterns of chromosomes, and the formation mechanism of spatiotemporal specificity of genomes are revealed. With the help of new experimental technologies, the identification of key genes and signal pathways related to life activities and diseases is sustaining the rapid development of life science, agriculture, and medicine. In this paper, the concept and development of 3D genomics and its application in agricultural science, life science, and medicine are introduced, which provides a theoretical basis for the study of biological life processes.
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Qin, Nannan, Shanjie Yang, Yunan Wang, et al. "The de novo assembly and characterization of the complete mitochondrial genome of bottle gourd (Lagenaria siceraria) reveals the presence of homologous conformations produced by repeat-mediated recombination." Frontiers in Plant Science 15 (August 12, 2024). http://dx.doi.org/10.3389/fpls.2024.1416913.
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IntroductionBottle gourd is an annual herbaceous plant that not only has high nutritional value and many medicinal applications but is also used as a rootstock for the grafting of cucurbit crops such as watermelon, cucumber and melon. Organellar genomes provide valuable resources for genetic breeding.MethodsA hybrid strategy with Illumina and Oxford Nanopore Technology sequencing data was used to assemble bottle gourd mitochondrial and chloroplast genomes.ResultsThe length of the bottle gourd mitochondrial genome was 357547 bp, and that of the chloroplast genome was 157121 bp. These genomes had 27 homologous fragments, accounting for 6.50% of the total length of the bottle gourd mitochondrial genome. In the mitochondrial genome, 101 simple sequence repeats (SSRs) and 10 tandem repeats were identified. Moreover, 1 pair of repeats was shown to mediate homologous recombination into 1 major conformation and 1 minor conformation. The existence of these conformations was verified via PCR amplification and Sanger sequencing. Evolutionary analysis revealed that the mitochondrial genome sequence of bottle gourd was highly conserved. Furthermore, collinearity analysis revealed many rearrangements between the homologous fragments of Cucurbita and its relatives. The Ka/Ks values for most genes were between 0.3~0.9, which means that most of the genes in the bottle gourd mitochondrial genome are under purifying selection. We also identified a total of 589 potential RNA editing sites on 38 mitochondrial protein-coding genes (PCGs) on the basis of long noncoding RNA (lncRNA)-seq data. The RNA editing sites of nad1-2, nad4L-2, atp6-718, atp9-223 and rps10-391 were successfully verified via PCR amplification and Sanger sequencing.ConclusionIn conclusion, we assembled and annotated bottle gourd mitochondrial and chloroplast genomes to provide a theoretical basis for similar organelle genomic studies.
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Li, Tianhao, Mingdong Liu, Zhanxi Gu, et al. "Structures of the mumps virus polymerase complex via cryo-electron microscopy." Nature Communications 15, no. 1 (2024). http://dx.doi.org/10.1038/s41467-024-48389-9.
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AbstractThe viral polymerase complex, comprising the large protein (L) and phosphoprotein (P), is crucial for both genome replication and transcription in non-segmented negative-strand RNA viruses (nsNSVs), while structures corresponding to these activities remain obscure. Here, we resolved two L–P complex conformations from the mumps virus (MuV), a typical member of nsNSVs, via cryogenic-electron microscopy. One conformation presents all five domains of L forming a continuous RNA tunnel to the methyltransferase domain (MTase), preferably as a transcription state. The other conformation has the appendage averaged out, which is inaccessible to MTase. In both conformations, parallel P tetramers are revealed around MuV L, which, together with structures of other nsNSVs, demonstrates the diverse origins of the L-binding X domain of P. Our study links varying structures of nsNSV polymerase complexes with genome replication and transcription and points to a sliding model for polymerase complexes to advance along the RNA templates.
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Li, Bingbing, Dan Lin, Xiaoqiao Zhai, et al. "Conformational changes in three-dimensional chromatin structure in Paulownia fortunei after phytoplasma infection." Phytopathology®, June 14, 2021. http://dx.doi.org/10.1094/phyto-01-21-0030-r.
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Abstract Higher-order chromatin structures play important roles in regulating multiple biological processes, growth and development, biotic and abiotic stress response. However, little is known about three-dimensional chromatin structures in Paulownia, or about whole-genome chromatin conformational changes that occur in response to Paulownia witches’ broom (PaWB) disease. We used high-throughput chromosome conformation capture (Hi-C) to obtain genome-wide profiles of chromatin conformation in healthy and phytoplasma-infected Paulownia fortunei genome. The heatmap results indicated that the strongest interactions between chromosomes were in the telomeres. We confirmed the main structural characteristics, such as A/B compartments, topologically associated domains, and chromatin loops were prominent in Paulownia genome and clearly altered in phytoplasma-infected plants. By combining chromatin Immunoprecipitation sequencing, Hi-C signals, and RNA sequencing data, we inferred that the chromatin structure changed and the modification levels of three histones (H3K4me3/K9ac/K36me3) increased in phytoplasma-infected P. fortunei, which was associated with changes of transcriptional activity. We concluded that epigenetic modifications, transcriptional activity might function in combination to shape chromatin packing in healthy and phytoplasm-infected Paulownia. Finally, 11 genes (such as RPN6, Sec61 subunit alpha), commonly located at specific TAD boundaries, A/B compartment switching, specific loops, and associated with histone marks, were identified and considered as closely related to PaWB stress. Our results provide new insights into the nexus between gene regulation and chromatin conformational alterations in non-model plants upon phytopathogen infection and plant disease resistance. Key words: Paulownia witches’ broom; chromatin conformation; histone modification; transcription regulation
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Bista, Basanta, Laura González-Rodelas, Lucía Álvarez-González, et al. "De novo genome assemblies of two cryptodiran turtles with ZZ/ZW and XX/XY sex chromosomes provide insights into patterns of genome reshuffling and uncover novel 3D genome folding in amniotes." Genome Research, October 16, 2024. http://dx.doi.org/10.1101/gr.279443.124.
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Understanding the evolution of chromatin conformation among species is fundamental to elucidate the architecture and plasticity of genomes. Nonrandom interactions of linearly distant loci regulate gene function in species-specific patterns, affecting genome function, evolution, and, ultimately, speciation. Yet, data from nonmodel organisms are scarce. To capture the macroevolutionary diversity of vertebrate chromatin conformation, here we generate de novo genome assemblies for two cryptodiran (hidden-neck) turtles via Illumina sequencing, chromosome conformation capture, and RNA-seq:Apalone spinifera(ZZ/ZW, 2n= 66) andStaurotypus triporcatus(XX/XY, 2n= 54). We detected differences in the three-dimensional (3D) chromatin structure in turtles compared to other amniotes beyond the fusion/fission events detected in the linear genomes. Namely, whole-genome comparisons revealed distinct trends of chromosome rearrangements in turtles: (1) a low rate of genome reshuffling inApalone(Trionychidae) whose karyotype is highly conserved when compared to chicken (likely ancestral for turtles), and (2) a moderate rate of fusions/fissions inStaurotypus(Kinosternidae) andTrachemys scripta(Emydidae). Furthermore, we identified a chromosome folding pattern that enables “centromere–telomere interactions” previously undetected in turtles. The combined turtle pattern of “centromere–telomere interactions” (discovered here) plus “centromere clustering” (previously reported in sauropsids) is novel for amniotes and it counters previous hypotheses about amniote 3D chromatin structure. We hypothesize that the divergent pattern found in turtles originated from an amniote ancestral state defined by a nuclear configuration with extensive associations among microchromosomes that were preserved upon the reshuffling of the linear genome.
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Markowski, Julia, Rieke Kempfer, Alexander Kukalev, et al. "GAMIBHEAR: whole-genome haplotype reconstruction from Genome Architecture Mapping data." Bioinformatics, April 8, 2021. http://dx.doi.org/10.1093/bioinformatics/btab238.
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Abstract Motivation Genome Architecture Mapping (GAM) was recently introduced as a digestion- and ligation-free method to detect chromatin conformation. Orthogonal to existing approaches based on chromatin conformation capture (3C), GAM’s ability to capture both inter- and intra-chromosomal contacts from low amounts of input data makes it particularly well suited for allele-specific analyses in a clinical setting. Allele-specific analyses are powerful tools to investigate the effects of genetic variants on many cellular phenotypes including chromatin conformation, but require the haplotypes of the individuals under study to be known a priori. So far, however, no algorithm exists for haplotype reconstruction and phasing of genetic variants from GAM data, hindering the allele-specific analysis of chromatin contact points in non-model organisms or individuals with unknown haplotypes. Results We present GAMIBHEAR, a tool for accurate haplotype reconstruction from GAM data. GAMIBHEAR aggregates allelic co-observation frequencies from GAM data and employs a GAM-specific probabilistic model of haplotype capture to optimize phasing accuracy. Using a hybrid mouse embryonic stem cell line with known haplotype structure as a benchmark dataset, we assess correctness and completeness of the reconstructed haplotypes, and demonstrate the power of GAMIBHEAR to infer accurate genome-wide haplotypes from GAM data. Availability and implementation GAMIBHEAR is available as an R package under the open-source GPL-2 license at https://bitbucket.org/schwarzlab/gamibhear. Supplementary information Supplementary data are available at Bioinformatics online.
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Zhang, Xinxin, and Tianzuo Wang. "Plant 3-D Chromatin Organization: Important Insights from Chromosome Conformation Capture Analyses of the Last 10 Years." Plant and Cell Physiology, September 6, 2021. http://dx.doi.org/10.1093/pcp/pcab134.
Full textAbstract:
Abstract Over the past few decades, eukaryotic linear genomes and epigenomes have been widely and extensively studied for understanding gene expression regulation. More recently, the three-dimensional (3-D) chromatin organization was found to be important for determining genome functionality, finely tuning physiological processes for appropriate cellular responses. With the development of visualization techniques and chromatin conformation capture (3C)-based techniques, increasing evidence indicates that chromosomal architecture characteristics and chromatin domains with different epigenetic modification in the nucleus are correlated to transcriptional activities. Subsequent studies have further explored the intricate interplay between 3-D genome organization and the function of interacting regions. In this review, we summarize spatial distribution patterns of chromatin, including chromatin positioning, configurations and domains, with a particular focus on the effect of a unique form of interaction between a variety of factors that shapes the 3-D genome conformation in plants. We further discuss the methods, advantages and limitations of various chromatin conformation capture (3C)-based techniques, highlighting the applications of these technologies in plants to identify chromatin domains, and address their dynamic changes and functional implications in evolution, and adaptation to development and changing environmental conditions. Moreover, the future implications and emerging research directions of 3-D genome organization are discussed.