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Bosfield, Kerri, Jullianne Diaz, and Eyby Leon. "Pure Distal 7q Duplication: Describing a Macrocephalic Neurodevelopmental Syndrome, Case Report and Review of the Literature." Molecular Syndromology 12, no. 3 (2021): 159–68. http://dx.doi.org/10.1159/000513453.
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Pure distal duplications of 7q have rarely been described in the medical literature. The term pure refers to duplications that occur without an accompanying clinically significant deletion. Pure 7q duplications of various segments have previously been reported in the literature; however, pure distal 7q duplications have only been reported in 21 cases. Twenty of these earlier reports described patients who were identified via karyotype and 1 recently by microarray. Cases have also been reported in genomic databases such as DECIPHER and the University of California Santa Cruz genome browser. We have reviewed 7 additional cases with distal 7q duplications from these databases and compared them to 7 previously reported distal 7q duplication cases to uncover common features including global developmental delay, frontal bossing, macrocephaly, seizures, kyphoscoliosis/skeletal anomalies, and microretrognathia/palatal anomalies. In this case, we describe a 4-year-old boy with a 30.8-Mb pure duplication of 7q32.1q36.3. Newly reported features associated with this duplication include intermittent dystonic posturing, increased behavioral irritability, eosinophilic esophagitis, segmental vertebral anomalies, and segmental intermittent limb cyanosis. We highlight the importance of using publicly available databases to describe rare genetic syndromes and to better characterize the features of pure distal 7q duplications and further postulate that duplication of this region represents a recognizable macrocephalic neurodevelopmental syndrome.
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Fraser, James A., Johnny C. Huang, Read Pukkila-Worley, J. Andrew Alspaugh, Thomas G. Mitchell, and Joseph Heitman. "Chromosomal Translocation and Segmental Duplication in Cryptococcus neoformans." Eukaryotic Cell 4, no. 2 (February 2005): 401–6. http://dx.doi.org/10.1128/ec.4.2.401-406.2005.
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ABSTRACT Large chromosomal events such as translocations and segmental duplications enable rapid adaptation to new environments. Here we marshal genomic, genetic, meiotic mapping, and physical evidence to demonstrate that a chromosomal translocation and segmental duplication occurred during construction of a congenic strain pair in the fungal human pathogen Cryptococcus neoformans. Two chromosomes underwent telomere-telomere fusion, generating a dicentric chromosome that broke to produce a chromosomal translocation, forming two novel chromosomes sharing a large segmental duplication. The duplication spans 62,872 identical nucleotides and generated a second copy of 22 predicted genes, and we hypothesize that this event may have occurred during meiosis. Gene disruption studies of one embedded gene (SMG1) corroborate that this region is duplicated in an otherwise haploid genome. These findings resolve a genome project assembly anomaly and illustrate an example of rapid genome evolution in a fungal genome rich in repetitive elements.
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Emanuel, Beverly S., and Tamim H. Shaikh. "Segmental duplications: an 'expanding' role in genomic instability and disease." Nature Reviews Genetics 2, no. 10 (October 2001): 791–800. http://dx.doi.org/10.1038/35093500.
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Soylev, Arda, Thong Minh Le, Hajar Amini, Can Alkan, and Fereydoun Hormozdiari. "Discovery of tandem and interspersed segmental duplications using high-throughput sequencing." Bioinformatics 35, no. 20 (April 1, 2019): 3923–30. http://dx.doi.org/10.1093/bioinformatics/btz237.
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Abstract Motivation Several algorithms have been developed that use high-throughput sequencing technology to characterize structural variations (SVs). Most of the existing approaches focus on detecting relatively simple types of SVs such as insertions, deletions and short inversions. In fact, complex SVs are of crucial importance and several have been associated with genomic disorders. To better understand the contribution of complex SVs to human disease, we need new algorithms to accurately discover and genotype such variants. Additionally, due to similar sequencing signatures, inverted duplications or gene conversion events that include inverted segmental duplications are often characterized as simple inversions, likewise, duplications and gene conversions in direct orientation may be called as simple deletions. Therefore, there is still a need for accurate algorithms to fully characterize complex SVs and thus improve calling accuracy of more simple variants. Results We developed novel algorithms to accurately characterize tandem, direct and inverted interspersed segmental duplications using short read whole genome sequencing datasets. We integrated these methods to our TARDIS tool, which is now capable of detecting various types of SVs using multiple sequence signatures such as read pair, read depth and split read. We evaluated the prediction performance of our algorithms through several experiments using both simulated and real datasets. In the simulation experiments, using a 30× coverage TARDIS achieved 96% sensitivity with only 4% false discovery rate. For experiments that involve real data, we used two haploid genomes (CHM1 and CHM13) and one human genome (NA12878) from the Illumina Platinum Genomes set. Comparison of our results with orthogonal PacBio call sets from the same genomes revealed higher accuracy for TARDIS than state-of-the-art methods. Furthermore, we showed a surprisingly low false discovery rate of our approach for discovery of tandem, direct and inverted interspersed segmental duplications prediction on CHM1 (<5% for the top 50 predictions). Availability and implementation TARDIS source code is available at https://github.com/BilkentCompGen/tardis, and a corresponding Docker image is available at https://hub.docker.com/r/alkanlab/tardis/. Supplementary information Supplementary data are available at Bioinformatics online.
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Nicholas, Thomas J., Ze Cheng, Katrina L. Mealey, Evan E. Eichler, and Joshua M. Akey. "The genomic architecture of segmental duplications and copy number variants in dogs." Journal of Veterinary Behavior 4, no. 2 (March 2009): 71–72. http://dx.doi.org/10.1016/j.jveb.2008.09.037.
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Dang, Vinh T., Karin S. Kassahn, Andrés Esteban Marcos, and Mark A. Ragan. "Identification of human haploinsufficient genes and their genomic proximity to segmental duplications." European Journal of Human Genetics 16, no. 11 (June 4, 2008): 1350–57. http://dx.doi.org/10.1038/ejhg.2008.111.
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Costantino, Lorenzo, Sotirios K. Sotiriou, Juha K. Rantala, Simon Magin, Emil Mladenov, Thomas Helleday, James E. Haber, George Iliakis, Olli P. Kallioniemi, and Thanos D. Halazonetis. "Break-Induced Replication Repair of Damaged Forks Induces Genomic Duplications in Human Cells." Science 343, no. 6166 (December 5, 2013): 88–91. http://dx.doi.org/10.1126/science.1243211.
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In budding yeast, one-ended DNA double-strand breaks (DSBs) and damaged replication forks are repaired by break-induced replication (BIR), a homologous recombination pathway that requires the Pol32 subunit of DNA polymerase delta. DNA replication stress is prevalent in cancer, but BIR has not been characterized in mammals. In a cyclin E overexpression model of DNA replication stress, POLD3, the human ortholog of POL32, was required for cell cycle progression and processive DNA synthesis. Segmental genomic duplications induced by cyclin E overexpression were also dependent on POLD3, as were BIR-mediated recombination events captured with a specialized DSB repair assay. We propose that BIR repairs damaged replication forks in mammals, accounting for the high frequency of genomic duplications in human cancers.
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Nicholas, T. J., Z. Cheng, M. Ventura, K. Mealey, E. E. Eichler, and J. M. Akey. "The genomic architecture of segmental duplications and associated copy number variants in dogs." Genome Research 19, no. 3 (December 22, 2008): 491–99. http://dx.doi.org/10.1101/gr.084715.108.
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Yoshimoto, Maisa, Olga Ludkovski, Dave DeGrace, Julia L. Williams, Andrew Evans, Kanishka Sircar, Tarek A. Bismar, Paulo Nuin, and Jeremy A. Squire. "PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications." Genes, Chromosomes and Cancer 51, no. 2 (November 1, 2011): 149–60. http://dx.doi.org/10.1002/gcc.20939.
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Nuttle, Xander, Andy Itsara, Jay Shendure, and Evan E. Eichler. "Resolving genomic disorder–associated breakpoints within segmental DNA duplications using massively parallel sequencing." Nature Protocols 9, no. 6 (May 29, 2014): 1496–513. http://dx.doi.org/10.1038/nprot.2014.096.
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McLure, Craig A., Peter Hinchliffe, Susan Lester, Joseph F. Williamson, John A. Millman, Peter J. Keating, Brent J. Stewart, and Roger L. Dawkins. "Genomic evolution and polymorphism: Segmental duplications and haplotypes at 108 regions on 21 chromosomes." Genomics 102, no. 1 (July 2013): 15–26. http://dx.doi.org/10.1016/j.ygeno.2013.02.011.
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Albano, Francesco, Luisa Anelli, Antonella Zagaria, Nicoletta Coccaro, Pietro D'Addabbo, Vincenzo Liso, Mariano Rocchi, and Giorgina Specchia. "Genomic Segmental Duplications at the Basis of t(9;22) Rearrangement in Chronic Myeloid Leukemia." Blood 114, no. 22 (November 20, 2009): 3261. http://dx.doi.org/10.1182/blood.v114.22.3261.3261.
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Abstract Abstract 3261 Poster Board III-1 A crucial role of segmental duplications (SDs) of the human genome has been demonstrated in chromosomal rearrangements associated with several genomic disorders. Limited knowledge is yet available on the molecular processes resulting in chromosomal rearrangements in tumors. The t(9;22)(q34;q11) causing the 5'BCR/3'ABL gene formation has been detected in more than 90% of chronic myeloid leukemia (CML) cases. Some years ago, a 76-kb duplicon was reported, closely located to both ABL and BCR genes which are involved in the t(9;22)(q34;q11) translocation associated with CML. However, the exact role of this duplicon in mediating the t(9;22) rearrangement remained mostly speculative. In 10–18% of CML patients genomic deletions were detected on der(9) chromosome next to translocation breakpoints. The molecular mechanism triggering the t(9;22) and deletions on der(9) is still unknown. Our study presents an experimental evidence of the involvement of SDs in the genesis of the t(9;22) translocation in CML and in the occurrence of genomic deletions on der(9) chromosome. We identified 71 (17%) cases with der(9) deletions by FISH screening of 416 CML patients at diagnosis. Fine-mapping of deletions was performed using appropriate bacterial and Phage P1-derived artificial chromosome clones. The deletions sizes were heterogeneous, ranging from 230 Kb to 12.9 Mb on chromosome 22 and from 260 Kb to 41.8 Mb on chromosome 9. The mapping of all breakpoints revealed an evident breakpoints clustering, on both chromosomes 9 and 22, in two regions of about 2 Mb in size. Indeed, these regions contained the breakpoints detected in 54 out of 60 (90%) patients bearing chromosome 9 deletions and in all patients with chromosome 22 sequences loss. Bioinformatic analysis of chromosome 9 and chromosome 22 genomic regions involved in the deletions was performed to search for features that could correlate with the breakpoints clustering. To this aim, the breakpoint regions were subdivided into 250 Kb intervals. The most striking result was the fact that both clusters contain the above reported 76-kb duplicon, shared by chromosome 9 and 22 (SD_9/22). The SD_9/22 is the only duplication located inside the breakpoints clustering region on chromosome 9, whereas the chromosome 22 clustering region harbors several duplications. A remarkable feature of the chromosome 9 clustering region was the high frequency of Alu repeats. The mean Alu frequency overall on chromosome 9 is 10.8%, whereas the average Alu content on this cluster is 31.3%. Accordingly, as expected, the content in LINE sequences of the region was relatively low (average overall on chromosome 9: 21.2%, as opposed to 8.7% on the cluster region). Gene distribution analysis of chromosome 9 and 22 showed that both SD_9/22 map inside gene-poor regions, of about 460 Kb and 250 Kb in size, respectively. To corroborate the observations on the distribution of SDs and Alu/LINE repeats, the chromosome 9 and 22 regions surrounding the SD_9/22 were once more divided into 250 Kb segments, positioning the SD_9 and SD_22 as landmarks. A statistically significant negative association was observed between the number of breaks and the distance from SD_9/22, on both chromosomes 9 (p=0.01) and 22 (p=0.006), respectively. The relationship between the breaks and the interspersed repeats revealed, on chromosome 9, a positive linear regression with Alu repeats (p=0.04), and a negative one with LINEs (p=0.04). Very similar conclusions were obtained by comparing the distance from the SD_9 and the Alu (p= 0.03, positive) and LINE distribution (p=0.02, negative). No statistically significant relationship was observed on chromosome 22. In our study the involvement of SDs was proposed to explain the recurrent t(9;22) translocation in CML and the genomic deletions that could accompany the rearrangement. Although the chromosomes 9 and 22 breakpoints clustering regions are quite large, the strong non-randomness of SD_9/22 location and the genomic features identified in our work suggest that the chromosomal segments near the ABL and BCR genes are brought together by an active process, facilitating recombination. At the light of these findings, the analysis of secondary non-recurrent events could represent a new methodological approach able to identify architectural elements involved in the occurrence of recurrent primary rearrangements in human neoplasia. Disclosures: No relevant conflicts of interest to declare.
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Sawyer, Jeffrey R., Guido Tricot, Janet L. Lukacs, Regina Lichti Binz, Erming Tian, Bart Barlogie, and John Shaughnessy. "Genomic instability in multiple myeloma: Evidence for jumping segmental duplications of chromosome arm 1q." Genes, Chromosomes and Cancer 42, no. 1 (2004): 95–106. http://dx.doi.org/10.1002/gcc.20109.
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Caputo, Sandrine, Dominique Telly, Adrien Briaux, Julie Sesen, Maurizio Ceppi, Françoise Bonnet, Violaine Bourdon, et al. "5′ Region Large Genomic Rearrangements in the BRCA1 Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints." Cancers 13, no. 13 (June 25, 2021): 3171. http://dx.doi.org/10.3390/cancers13133171.
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Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5′ region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families. Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing. Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1, fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin. Conclusions: Taken together, our results firmly establish that the BRCA1 5′ region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious.
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Maurin, Marie-Laure, Chloé Arfeuille, Pascale Sonigo, Sophie Rondeau, Michel Vekemans, Catherine Turleau, Yves Ville, and Valérie Malan. "Large Duplications Can Be Benign Copy Number Variants: A Case of a 3.6-Mb Xq21.33 Duplication." Cytogenetic and Genome Research 151, no. 3 (2017): 115–18. http://dx.doi.org/10.1159/000460278.
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Segmental aneusomies are usually associated with clinical consequences, but an increasing number of nonpathogenic cytogenetically visible as well as large cryptic chromosomal imbalances have been reported. Here, we report a 3.6-Mb Xq21.33 microduplication detected prenatally on a female fetus which was inherited from a phenotypically normal mother and grandfather. It is assumed that male patients harboring Xq or Xp duplication present with syndromic intellectual disability because of functional disomy of the corresponding genes. Female carriers are generally asymptomatic because of preferential inactivation of the abnormal X. In the present case, the 3.6-Mb-duplicated segment encompasses only 2 genes, DIAPH2 and RPL4A. Since the asymptomatic grandfather carries the duplication, we hypothesize that these genes are not dosage sensitive and/or involved in cognitive function. Our observation further illustrates that large copy number variants can be associated with a normal phenotype, especially where gene density is low. Reporting rare cases of large genomic imbalances without a phenotypic effect can be very helpful, especially for genetic counseling in the prenatal setting.
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Albano, F., L. Anelli, A. Zagaria, N. Coccaro, P. D'Addabbo, V. Liso, M. Rocchi, and G. Specchia. "Genomic segmental duplications on the basis of the t(9;22) rearrangement in chronic myeloid leukemia." Oncogene 29, no. 17 (January 25, 2010): 2509–16. http://dx.doi.org/10.1038/onc.2009.524.
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Khan, Nadeem, Fizza Fatima, Muhammad Salman Haider, Hamna Shazadee, Zhongjie Liu, Ting Zheng, and Jinggui Fang. "Genome-Wide Identification and Expression Profiling of the Polygalacturonase (PG) and Pectin Methylesterase (PME) Genes in Grapevine (Vitis vinifera L.)." International Journal of Molecular Sciences 20, no. 13 (June 28, 2019): 3180. http://dx.doi.org/10.3390/ijms20133180.
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In pectin regulation, polygalacturonases (PGs) and pectin methylesterases (PMEs) are critical components in the transformation, disassembly network, and remodeling of plant primary cell walls. In the current study, we identified 36 PG and 47 PME genes using the available genomic resources of grapevine. Herein, we provide a comprehensive overview of PGs and PMEs, including phylogenetic and collinearity relationships, motif and gene structure compositions, gene duplications, principal component analysis, and expression profiling during developmental stages. Phylogenetic analysis of PGs and PMEs revealed similar domain composition patterns with Arabidopsis. The collinearity analysis showed high conservation and gene duplications with purifying selection. The type of duplications also varied in terms of gene numbers in PGs (10 dispersed, 1 proximal, 12 tandem, and 13 segmental, respectively) and PMEs (23 dispersed, 1 proximal, 16 tandem, and 7 segmental, respectively). The tissue-specific response of PG and PME genes based on the reported transcriptomic data exhibited diverged expression patterns in various organs during different developmental stages. Among PGs, VvPG8, VvPG10, VvPG13, VvPG17, VvPG18, VvPG19, VvPG20, VvPG22, and VvPG23 showed tissue- or organ-specific expression in majority of the tissues during development. Similarly, in PMEs, VvPME3, VvPME4, VvPME5, VvPME6, VvPME19, VvPME21, VvPME23, VvPME29, VvPME31, and VvPME32 suggested high tissue-specific response. The gene ontology (GO), Kyoto Encyclopedia of Genes and Genomics (KEGG) enrichment, and cis-elements prediction analysis also suggested the putative functions of PGs and PMEs in plant development, such as pectin and carbohydrate metabolism, and stress activities. Moreover, qRT-PCR validation of 32 PG and PME genes revealed their role in various organs of grapevines (i.e., root, stem, tendril, inflorescence, flesh, skins, and leaves). Therefore, these findings will lead to novel insights and encourage cutting-edge research on functional characterization of PGs and PMEs in fruit crop species.
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Chaux-Jukic, Frédéric, Samuel O’Donnell, Rory J. Craig, Stephan Eberhard, Olivier Vallon, and Zhou Xu. "Architecture and evolution of subtelomeres in the unicellular green alga Chlamydomonas reinhardtii." Nucleic Acids Research 49, no. 13 (June 24, 2021): 7571–87. http://dx.doi.org/10.1093/nar/gkab534.
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Abstract In most eukaryotes, subtelomeres are dynamic genomic regions populated by multi-copy sequences of different origins, which can promote segmental duplications and chromosomal rearrangements. However, their repetitive nature has complicated the efforts to sequence them, analyse their structure and infer how they evolved. Here, we use recent genome assemblies of Chlamydomonas reinhardtii based on long-read sequencing to comprehensively describe the subtelomere architecture of the 17 chromosomes of this model unicellular green alga. We identify three main repeated elements present at subtelomeres, which we call Sultan, Subtile and Suber, alongside three chromosome extremities with ribosomal DNA as the only identified component of their subtelomeres. The most common architecture, present in 27 out of 34 subtelomeres, is a heterochromatic array of Sultan elements adjacent to the telomere, followed by a transcribed Spacer sequence, a G-rich microsatellite and transposable elements. Sequence similarity analyses suggest that Sultan elements underwent segmental duplications within each subtelomere and rearranged between subtelomeres at a much lower frequency. Analysis of other green algae reveals species-specific repeated elements that are shared across subtelomeres, with an overall organization similar to C. reinhardtii. This work uncovers the complexity and evolution of subtelomere architecture in green algae.
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Theofanopoulou, Constantina, Gregory Gedman, James A. Cahill, Cedric Boeckx, and Erich D. Jarvis. "Universal nomenclature for oxytocin–vasotocin ligand and receptor families." Nature 592, no. 7856 (April 28, 2021): 747–55. http://dx.doi.org/10.1038/s41586-020-03040-7.
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AbstractOxytocin (OXT; hereafter OT) and arginine vasopressin or vasotocin (AVP or VT; hereafter VT) are neurotransmitter ligands that function through specific receptors to control diverse functions1,2. Here we performed genomic analyses on 35 species that span all major vertebrate lineages, including newly generated high-contiguity assemblies from the Vertebrate Genomes Project3,4. Our findings support the claim5 that OT (also known as OXT) and VT (also known as AVP) are adjacent paralogous genes that have resulted from a local duplication, which we infer was through DNA transposable elements near the origin of vertebrates and in which VT retained more of the parental sequence. We identified six major oxytocin–vasotocin receptors among vertebrates. We propose that all six of these receptors arose from a single receptor that was shared with the common ancestor of invertebrates, through a combination of whole-genome and large segmental duplications. We propose a universal nomenclature based on evolutionary relationships for the genes that encode these receptors, in which the genes are given the same orthologous names across vertebrates and paralogous names relative to each other. This nomenclature avoids confusion due to differential naming in the pre-genomic era and incomplete genome assemblies, furthers our understanding of the evolution of these genes, aids in the translation of findings across species and serves as a model for other gene families.
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Cao, Liru, Xiaomin Lu, Pengyu Zhang, Guorui Wang, Li Wei, and Tongchao Wang. "Systematic Analysis of Differentially Expressed Maize ZmbZIP Genes between Drought and Rewatering Transcriptome Reveals bZIP Family Members Involved in Abiotic Stress Responses." International Journal of Molecular Sciences 20, no. 17 (August 22, 2019): 4103. http://dx.doi.org/10.3390/ijms20174103.
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The basic leucine zipper (bZIP) family of transcription factors (TFs) regulate diverse phenomena during plant growth and development and are involved in stress responses and hormone signaling. However, only a few bZIPs have been functionally characterized. In this paper, 54 maize bZIP genes were screened from previously published drought and rewatering transcriptomes. These genes were divided into nine groups in a phylogenetic analysis, supported by motif and intron/exon analyses. The 54 genes were unevenly distributed on 10 chromosomes and contained 18 segmental duplications, suggesting that segmental duplication events have contributed to the expansion of the maize bZIP family. Spatio-temporal expression analyses showed that bZIP genes are widely expressed during maize development. We identified 10 core ZmbZIPs involved in protein transport, transcriptional regulation, and cellular metabolism by principal component analysis, gene co-expression network analysis, and Gene Ontology enrichment analysis. In addition, 15 potential stress-responsive ZmbZIPs were identified by expression analyses. Localization analyses showed that ZmbZIP17, -33, -42, and -45 are nuclear proteins. These results provide the basis for future functional genomic studies on bZIP TFs in maize and identify candidate genes with potential applications in breeding/genetic engineering for increased stress resistance. These data represent a high-quality molecular resource for selecting resistant breeding materials.
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García-Pascual, Carmen M., Luis Navarro-Sánchez, Roser Navarro, Lucía Martínez, Jorge Jiménez, Lorena Rodrigo, Carlos Simón, and Carmen Rubio. "Optimized NGS Approach for Detection of Aneuploidies and Mosaicism in PGT-A and Imbalances in PGT-SR." Genes 11, no. 7 (June 29, 2020): 724. http://dx.doi.org/10.3390/genes11070724.
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The detection of chromosomal aneuploidies and mosaicism degree in preimplantation embryos may be essential for achieving pregnancy. The aim of this study was to determine the robustness of diagnosing homogenous and mosaic aneuploidies using a validated algorithm and the minimal resolution for de novo and inherited deletions and duplications (Del/Dup). Two workflows were developed and validated: (a,b) preimplantation genetic testing for uniform whole and segmental aneuploidies, plus mixtures of euploid/aneuploid genomic DNA to develop an algorithm for detecting mosaicism; and (c) preimplantation genetic testing for structural rearrangements for detecting Del/Dup ≥ 6 Mb. Next-generation sequencing (NGS) was performed with automatic library preparation and multiplexing up to 24–96 samples. Specificity and sensitivity for PGT-A were both 100% for whole chromosomes and segmentals. The thresholds stablished for mosaicism were: euploid embryos (<30% aneuploidy), low mosaic (from 30% to <50%), high mosaic (50–70%) or aneuploid (>70%). In the PGT-SR protocol, changes were made to increase the detection level to ≥6 Mb. This is the first study reporting an accurate assessment of semiautomated-NGS protocols using Reproseq on pools of cells. Both protocols allow for the analysis of homogeneous and segmental aneuploidies, different degrees of mosaicism, and small Del/Dup with high sensitivity and specificity.
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Haag, Karen L., Jean-François Pombert, Yukun Sun, Nathalia Rammé M. de Albuquerque, Brendan Batliner, Peter Fields, Tiago Falcon Lopes, and Dieter Ebert. "Microsporidia with Vertical Transmission Were Likely Shaped by Nonadaptive Processes." Genome Biology and Evolution 12, no. 1 (December 11, 2019): 3599–614. http://dx.doi.org/10.1093/gbe/evz270.
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Abstract Microsporidia have the leanest genomes among eukaryotes, and their physiological and genomic simplicity has been attributed to their intracellular, obligate parasitic life-style. However, not all microsporidia genomes are small or lean, with the largest dwarfing the smallest ones by at least an order of magnitude. To better understand the evolutionary mechanisms behind this genomic diversification, we explore here two clades of microsporidia with distinct life histories, Ordospora and Hamiltosporidium, parasitizing the same host species, Daphnia magna. Based on seven newly assembled genomes, we show that mixed-mode transmission (the combination of horizontal and vertical transmission), which occurs in Hamiltosporidium, is found to be associated with larger and AT-biased genomes, more genes, and longer intergenic regions, as compared with the exclusively horizontally transmitted Ordospora. Furthermore, the Hamiltosporidium genome assemblies contain a variety of repetitive elements and long segmental duplications. We show that there is an excess of nonsynonymous substitutions in the microsporidia with mixed-mode transmission, which cannot be solely attributed to the lack of recombination, suggesting that bursts of genome size in these microsporidia result primarily from genetic drift. Overall, these findings suggest that the switch from a horizontal-only to a mixed mode of transmission likely produces population bottlenecks in Hamiltosporidium species, therefore reducing the effectiveness of natural selection, and allowing their genomic features to be largely shaped by nonadaptive processes.
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Beà, Sílvia, Itziar Salaverria, Lluís Armengol, Magda Pinyol, Verónica Fernández, Elena M. Hartmann, Pedro Jares, et al. "Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling." Blood 113, no. 13 (March 26, 2009): 3059–69. http://dx.doi.org/10.1182/blood-2008-07-170183.
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Abstract Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. However, only a limited number of target genes have been identified. We have studied 10 MCL cell lines and 28 primary tumors with a combination of a high-density single-nucleotide polymorphism array and gene expression profiling. We detected highly altered genomes in the majority of the samples with a high number of partial uniparental disomies (UPDs). The UPD at 17p was one of the most common, and it was associated with TP53 gene inactivation. Homozygous deletions targeted 4 known tumor suppressor genes (CDKN2C, BCL2L11, CDKN2A, and RB1) and 6 new genes (FAF1, MAP2, SP100, MOBKL2B, ZNF280A, and PRAME). Gene amplification coupled with overexpression was identified in 35 different regions. The most recurrent amplified regions were 11q13.3-q13.5, 13q31.3, and 18q21.33, which targeted CCND1, C13orf25, and BCL2, respectively. Interestingly, the breakpoints flanking all the genomic alterations, including UPDs, were significantly associated with genomic regions enriched in copy number variants and segmental duplications, suggesting that the recombination at these regions may play a role in the genomic instability of MCL. This integrative genomic analysis has revealed target genes that may be potentially relevant in MCL pathogenesis.
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Gounot, Jean-Sébastien, Cécile Neuvéglise, Kelle C. Freel, Hugo Devillers, Jure Piškur, Anne Friedrich, and Joseph Schacherer. "High Complexity and Degree of Genetic Variation in Brettanomyces bruxellensis Population." Genome Biology and Evolution 12, no. 6 (April 22, 2020): 795–807. http://dx.doi.org/10.1093/gbe/evaa077.
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Abstract Genome-wide characterization of genetic variants of a large population of individuals within the same species is essential to have a deeper insight into its evolutionary history as well as the genotype–phenotype relationship. Population genomic surveys have been performed in multiple yeast species, including the two model organisms, Saccharomyces cerevisiae and Schizosaccharomyces pombe. In this context, we sought to characterize at the population level the Brettanomyces bruxellensis yeast species, which is a major cause of wine spoilage and can contribute to the specific flavor profile of some Belgium beers. We have completely sequenced the genome of 53 B. bruxellensis strains isolated worldwide. The annotation of the reference genome allowed us to define the gene content of this species. As previously suggested, our genomic data clearly highlighted that genetic diversity variation is related to ploidy level, which is variable in the B. bruxellensis species. Genomes are punctuated by multiple loss-of-heterozygosity regions, whereas aneuploidies as well as segmental duplications are uncommon. Interestingly, triploid genomes are more prone to gene copy number variation than diploids. Finally, the pangenome of the species was reconstructed and was found to be small with few accessory genes compared with S. cerevisiae. The pangenome is composed of 5,409 ORFs (open reading frames) among which 5,106 core ORFs and 303 ORFs that are variable within the population. All these results highlight the different trajectories of species evolution and consequently the interest of establishing population genomic surveys in more populations.
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Daga, Aditi, Afzal Ansari, Rakesh Rawal, and Valentina Umrania. "Characterization of Chromosomal Translocation Breakpoint Sequences in Solid Tumours: “An In Silico Analysis”." Open Medical Informatics Journal 9, no. 1 (April 30, 2015): 1–8. http://dx.doi.org/10.2174/1874431101509010001.
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Chromosomal translocations that results in formation and activation of fusion oncogenes are observed in numerous solid malignancies since years back. Expression of fusion kinases in these cancers drives the initiation & progression that ultimately leads to tumour development and thus comes out to be clinically imperative in terms of diagnosis and treatment of cancer. Nonetheless, molecular mechanisms beneath these translocations remained unexplored consequently limiting our knowledge of carcinogenesis and hence is the current field where further research is required. The issue of prime focus is the precision with which the chromosomes breaks and reunites within genome. Characterization of Genomic sequences located at Breakpoint region may direct us towards the thorough understanding of mechanism leading to chromosomal rearrangement. A unique computational multi-parametric analysis was performed for characterization of genomic sequence within and around breakpoint region. This study turns out to be novel as it reveals the occurrence of Segmental Duplications flanking the breakpoints of all translocation. Breakpoint Islands were also investigated for the presence of other intricate genomic architecture and various physico-chemical parameters. Our study particularly highlights the probable role of SDs and specific genomic features in precise chromosomal breakage. Additionally, it pinpoints the potential features that may be significant for double-strand breaks leading to chromosomal rearrangements.
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Marques-Bonet, Tomàs, Ze Cheng, Xinwei She, Evan E. Eichler, and Arcadi Navarro. "The genomic distribution of intraspecific and interspecific sequence divergence of human segmental duplications relative to human/chimpanzee chromosomal rearrangements." BMC Genomics 9, no. 1 (2008): 384. http://dx.doi.org/10.1186/1471-2164-9-384.
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Tollis, Marc, Jooke Robbins, Andrew E. Webb, Lukas F. K. Kuderna, Aleah F. Caulin, Jacinda D. Garcia, Martine Bèrubè, et al. "Return to the Sea, Get Huge, Beat Cancer: An Analysis of Cetacean Genomes Including an Assembly for the Humpback Whale (Megaptera novaeangliae)." Molecular Biology and Evolution 36, no. 8 (May 9, 2019): 1746–63. http://dx.doi.org/10.1093/molbev/msz099.
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Abstract Cetaceans are a clade of highly specialized aquatic mammals that include the largest animals that have ever lived. The largest whales can have ∼1,000× more cells than a human, with long lifespans, leaving them theoretically susceptible to cancer. However, large-bodied and long-lived animals do not suffer higher risks of cancer mortality than humans—an observation known as Peto’s Paradox. To investigate the genomic bases of gigantism and other cetacean adaptations, we generated a de novo genome assembly for the humpback whale (Megaptera novaeangliae) and incorporated the genomes of ten cetacean species in a comparative analysis. We found further evidence that rorquals (family Balaenopteridae) radiated during the Miocene or earlier, and inferred that perturbations in abundance and/or the interocean connectivity of North Atlantic humpback whale populations likely occurred throughout the Pleistocene. Our comparative genomic results suggest that the evolution of cetacean gigantism was accompanied by strong selection on pathways that are directly linked to cancer. Large segmental duplications in whale genomes contained genes controlling the apoptotic pathway, and genes inferred to be under accelerated evolution and positive selection in cetaceans were enriched for biological processes such as cell cycle checkpoint, cell signaling, and proliferation. We also inferred positive selection on genes controlling the mammalian appendicular and cranial skeletal elements in the cetacean lineage, which are relevant to extensive anatomical changes during cetacean evolution. Genomic analyses shed light on the molecular mechanisms underlying cetacean traits, including gigantism, and will contribute to the development of future targets for human cancer therapies.
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Parida, Swarup K., Devendra K. Yadava, and Trilochan Mohapatra. "Microsatellites in Brassica unigenes: relative abundance, marker design, and use in comparative physical mapping and genome analysis." Genome 53, no. 1 (January 2010): 55–67. http://dx.doi.org/10.1139/g09-084.
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Microsatellites present in the transcribed regions of the genome have the potential to reveal functional diversity. Unigene sequence databases are the sources of such genic microsatellites with unique flanking sequences and genomic locations even in complex polyploids. The present study was designed to assay the unigenes of Brassica napus and B. rapa for various microsatellite repeats, and to design markers and use them in comparative genome analysis and study of evolution. The average frequency of microsatellites in Brassica unigenes was one in every 7.25 kb of sequence, as compared with one in every 8.57 kb of sequence in Arabidopsis thaliana . Trinucleotide motifs coding for serine and the dinucleotide motif GA were most abundant. We designed 2374 and 347 unigene-based microsatellite (UGMS) markers including 541 and 58 class I types in B. napus and B. rapa, respectively, and evaluated their use across diverse species and genera. Most of these markers (93.3%) gave successful amplification of target microsatellite motifs, which was confirmed by sequencing. Interspecific polymorphism between B. napus and B. rapa detected in silico for the UGMS markers was 4.16 times higher in 5′ untranslated regions than in coding sequences. Physical anchoring of Brassica UGMS markers on the A. thaliana genome indicated their significance in studying the evolutionary history of A. thaliana genomic duplications in relation to speciation. Comparative physical mapping identified 85% of Brassica unigenes as single copy and gave clues for the presence of conserved primordial gene order. Complex chromosomal rearrangements such as inversions, tandem and segmental duplications, and insertions/deletions were evident between A. thaliana and B. rapa genomes. The results obtained have encouraging implications for the use of UGMS markers in comparative genome analysis and for understanding evolutionary complexities in the family Brassicaceae.
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Czyż, Katarzyna B., Michał Książkiewicz, Grzegorz Koczyk, Anna Szczepaniak, Jan Podkowiński, and Barbara Naganowska. "A Tale of Two Families: Whole Genome and Segmental Duplications Underlie Glutamine Synthetase and Phosphoenolpyruvate Carboxylase Diversity in Narrow-Leafed Lupin (Lupinus angustifolius L.)." International Journal of Molecular Sciences 21, no. 7 (April 8, 2020): 2580. http://dx.doi.org/10.3390/ijms21072580.
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Narrow-leafed lupin (Lupinus angustifolius L.) has recently been supplied with advanced genomic resources and, as such, has become a well-known model for molecular evolutionary studies within the legume family—a group of plants able to fix nitrogen from the atmosphere. The phylogenetic position of lupins in Papilionoideae and their evolutionary distance to other higher plants facilitates the use of this model species to improve our knowledge on genes involved in nitrogen assimilation and primary metabolism, providing novel contributions to our understanding of the evolutionary history of legumes. In this study, we present a complex characterization of two narrow-leafed lupin gene families—glutamine synthetase (GS) and phosphoenolpyruvate carboxylase (PEPC). We combine a comparative analysis of gene structures and a synteny-based approach with phylogenetic reconstruction and reconciliation of the gene family and species history in order to examine events underlying the extant diversity of both families. Employing the available evidence, we show the impact of duplications on the initial complement of the analyzed gene families within the genistoid clade and posit that the function of duplicates has been largely retained. In terms of a broader perspective, our results concerning GS and PEPC gene families corroborate earlier findings pointing to key whole genome duplication/triplication event(s) affecting the genistoid lineage.
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Francis, Nigel J., Bairbre McNicholas, Atif Awan, Mary Waldron, Donal Reddan, Denise Sadlier, David Kavanagh, et al. "A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome." Blood 119, no. 2 (January 12, 2012): 591–601. http://dx.doi.org/10.1182/blood-2011-03-339903.
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Abstract Genomic disorders affecting the genes encoding factor H (fH) and the 5 factor H related proteins have been described in association with atypical hemolytic uremic syndrome. These include deletions of CFHR3, CFHR1, and CFHR4 in association with fH autoantibodies and the formation of a hybrid CFH/CFHR1 gene. These occur through nonallelic homologous recombination secondary to the presence of large segmental duplications (macrohomology) in this region. Using multiplex ligation-dependent probe amplification to screen for such genomic disorders, we have identified a large atypical hemolytic uremic syndrome family where a deletion has occurred through microhomology-mediated end joining rather than nonallelic homologous recombination. In the 3 affected persons of this family, we have shown that the deletion results in formation of a CFH/CFHR3 gene. We have shown that the protein product of this is a 24 SCR protein that is secreted with normal fluid-phase activity but marked loss of complement regulation at cell surfaces despite increased heparin binding. In this study, we have therefore shown that microhomology in this area of chromosome 1 predisposes to disease associated genomic disorders and that the complement regulatory function of fH at the cell surface is critically dependent on the structural integrity of the whole molecule.
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Redaelli, Serena, Silvia Maitz, Francesca Crosti, Elena Sala, Nicoletta Villa, Luigina Spaccini, Angelo Selicorni, et al. "Refining the Phenotype of Recurrent Rearrangements of Chromosome 16." International Journal of Molecular Sciences 20, no. 5 (March 4, 2019): 1095. http://dx.doi.org/10.3390/ijms20051095.
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Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.
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O'Keefe, Christine, Bartlomiej P. Przychodzen, Azim M. Mohamedali, Ghulam J. Mufti, Michael McDevitt, and Jaroslaw P. Maciejewski. "Inborn Genomic Variation as Predisposing Factors to Myeloid Malignancies." Blood 114, no. 22 (November 20, 2009): 1590. http://dx.doi.org/10.1182/blood.v114.22.1590.1590.
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Abstract Abstract 1590 Poster Board I-616 Single nucleotide polymorphism arrays (SNP-A) are increasingly accepted as a karyotyping tool, but with systematic application of this technology to study clonal somatic chromosomal lesion came a realization as to how widespread are copy number variations (CNV) and copy-number neutral runs of homozygosity (ROH) through the human genome. Recognition of recurrent CNVs and ROH is of importance for distinction of truly somatic lesions but clearly both ROH and CNVs themselves could constitute risk factors for development of MDS and AML prediction as sites frequently affected by these changes could constitute fragile sites for chromosomal breaks and recombination events. Alternatively these inherited genomic variants could affect expression of corresponding genes and alter regulatory elements. They can physically disrupt a gene, potentially creating new isoforms and can have a subtle effect on gene expression, either through variable penetrance of gene dosage effects or through interaction between the CNV/ROH and the genetic background. As all ROH is unlikely to be explained by autozygosity, meiotic errors or early embryonic mitotic events could be responsible. The role of CNVs in disease, in particular immune-related disorders, has become increasingly apparent, while acquired ROH is well-recognized as playing a role in carcinogenesis and malignant evolution. However, CNVs and inborn ROH as predisposing factors in myeloid malignancies has not been explored in depth. SNP-A (for example Affymetrix 6.0 arrays) offer an opportunity to systematically investigate not only somatic unbalanced translocations but also copy neutral loss of heterozygosity (CN-LOH), including ROH. To determine how CNVs and inborn ROH may affect predisposition to myeloid malignancies, we first studied an large cohort of control individuals (N=995) from internal and publicly-available sources. We identified 261 CNVs distributed across the entire genome; 15 were unique to our cohort and had not been previously reported. The remaining CNVs were verified against the Database of Genomic Variants (http://projects.tcag.ca/variation/) and their frequency was established. We also identified 153 non-clonal regions of ROH in the normal cohort (9.8%), distributed across all chromosomes and mapped frequently occurring ROH. No correlation was found between chromosome size and size of ROH on that chromosome. ROH could be divided into two groups: interstitial (N=147) and telomeric (N=6). Interstitial ROH ranged in size from 0.29-64.9Mb with a median of 7.2Mb; the rare telomeric germline ROH was 2.5-13.2Mb with a median of 5.8Mb. There were 30 recurrent regions of ROH; the most frequent (at 0.4%) were at 4q13.1-q13.3 and 5q15-q21.1. We concluded that interstitial ROH<24.5Mb and telomeric ROH<13.2Mb most likely reflected a germline event. Using this information as a reference we next investigated a large cohort of patients with MDS, MDS/MPN (N=395) and secondary AML (N=130). We identified several CNVs significantly overrepresented in each cohort. For MDS, gains at 3q26.1 (p<.0001), 4q13.2 (p<.0001), 12p11.1 (p<.0001), 15q11.2 (p=.015) 22q11.22 (p=.0008) and losses at 14q11.2 (p<.0001) and 1q21 (p<.0001) were significantly more frequent. In sAML, gain at 22q11.22 (p<.0001) and loss of 4q13.2, 7q34, 8p11.23 and 14q11.2 (all p<.0001) were more frequent than in normal controls. Regions of genomic structural instability, such as fragile sites or segmental duplications, are commonly associated with CNVs. The genomic architecture of each region was investigated with the UCSC Genome Browser (http://www.genome.ucsc.edu/cgi-bin/hgGateway). Overrepresented CNV were associated with regions harboring segmental duplications (1q21, 4q13.2, 12p11.1, 15q11.2, 22q11.22) or repetitive gene families (T cell receptor loci; 7p14.1, 7q34, 14q11.2). We also identified germline ROH in the patient cohorts. ROH at 11q14.1-q14.2 was more frequent in patients with MDS and sAML (6% MDS; 12% AML vs 0%, p=.02); these patients had high-risk disease and a normal karyotype or one chromosomal abnormality. In sAML, several regions were enriched in patients including 1q25.2-q25.3, 13q11q12.13 and 21q21.1 (all N=2; p=0.01). We conclude, genomic variations once thought to be pathologically silent is now recognized as potential predisposing pathogenic factor in disease; we have demonstrate that specific CNVs and ROH can be associated with myeloid malignancies. It is possible that the presence of CNV or LOH predisposes to somatic chromosomal aberrations and points towards fragile sites. Disclosures Maciejewski: Taligen: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Celgene: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees.
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Makunin, Alexey, Svetlana Romanenko, Violetta Beklemisheva, Polina Perelman, Anna Druzhkova, Kristina Petrova, Dmitry Prokopov, et al. "Sequencing of Supernumerary Chromosomes of Red Fox and Raccoon Dog Confirms a Non-Random Gene Acquisition by B Chromosomes." Genes 9, no. 8 (August 10, 2018): 405. http://dx.doi.org/10.3390/genes9080405.
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B chromosomes (Bs) represent a variable addition to the main karyotype in some lineages of animals and plants. Bs accumulate through non-Mendelian inheritance and become widespread in populations. Despite the presence of multiple genes, most Bs lack specific phenotypic effects, although their influence on host genome epigenetic status and gene expression are recorded. Previously, using sequencing of isolated Bs of ruminants and rodents, we demonstrated that Bs originate as segmental duplications of specific genomic regions, and subsequently experience pseudogenization and repeat accumulation. Here, we used a similar approach to characterize Bs of the red fox (Vulpes vulpes L.) and the Chinese raccoon dog (Nyctereutes procyonoides procyonoides Gray). We confirm the previous findings of the KIT gene on Bs of both species, but demostrate an independent origin of Bs in these species, with two reused regions. Comparison of gene ensembles in Bs of canids, ruminants, and rodents once again indicates enrichment with cell-cycle genes, development-related genes, and genes functioning in the neuron synapse. The presence of B-chromosomal copies of genes involved in cell-cycle regulation and tissue differentiation may indicate importance of these genes for B chromosome establishment.
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Pan, Xinghua, Alexander Eckehart Urban, Dean Palejev, Vincent Schulz, Fabian Grubert, Yiping Hu, Michael Snyder, and Sherman M. Weissman. "A procedure for highly specific, sensitive, and unbiased whole-genome amplification." Proceedings of the National Academy of Sciences 105, no. 40 (October 1, 2008): 15499–504. http://dx.doi.org/10.1073/pnas.0808028105.
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Highly specific amplification of complex DNA pools without bias or template-independent products (TIPs) remains a challenge. We have developed a method using phi29 DNA polymerase and trehalose and optimized control of amplification to create micrograms of specific amplicons without TIPs from down to subfemtograms of DNA. With an input of as little as 0.5–2.5 ng of human gDNA or a few cells, the product could be close to native DNA in locus representation. The amplicons from 5 and 0.5 ng of DNA faithfully demonstrated all previously known heterozygous segmental duplications and deletions (3 Mb to 18 kb) located on chromosome 22 and even a homozygous deletion smaller than 1 kb with high-resolution chromosome-wide comparative genomic hybridization. With 550k Infinium BeadChip SNP typing, the >99.7% accuracy was compared favorably with results on unamplified DNA. Importantly, underrepresentation of chromosome termini that occurred with GenomiPhi v2 was greatly rescued with the present procedure, and the call rate and accuracy of SNP typing were also improved for the amplicons with a 0.5-ng, partially degraded DNA input. In addition, the amplification proceeded logarithmically in terms of total yield before saturation; the intact cells was amplified >50 times more efficiently than an equivalent amount of extracted DNA; and the locus imbalance for amplicons with 0.1 ng or lower input of DNA was variable, whereas for higher input it was largely reproducible. This procedure facilitates genomic analysis with single cells or other traces of DNA, and generates products suitable for analysis by massively parallel sequencing as well as microarray hybridization.
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Dai, Yi, Pidong Li, Zhiqiang Wang, Fan Liang, Fan Yang, Li Fang, Yu Huang, et al. "Single-molecule optical mapping enables quantitative measurement of D4Z4 repeats in facioscapulohumeral muscular dystrophy (FSHD)." Journal of Medical Genetics 57, no. 2 (September 10, 2019): 109–20. http://dx.doi.org/10.1136/jmedgenet-2019-106078.
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PurposeFacioscapulohumeral muscular dystrophy (FSHD) is a common adult muscular dystrophy. Over 95% of FSHD cases are associated with contraction of the D4Z4 tandem repeat (~3.3 kb per unit) at 4q35 with a specific genomic configuration (haplotype) called 4qA. Molecular diagnosis of FSHD typically requires pulsed-field gel electrophoresis with Southern blotting. We aim to develop novel genomic and computational methods for characterising D4Z4 repeat numbers in FSHD.MethodsWe leveraged a single-molecule optical mapping platform that maps locations of restriction enzyme sites on high molecular weight (>150 kb) DNA molecules. We developed bioinformatics methods to address several challenges, including the differentiation of 4qA with 4qB alleles, the differentiation of 4q35 and 10q26 segmental duplications, the quantification of repeat numbers with different enzymes that may or may not have recognition sites within D4Z4 repeats. We evaluated the method on 25 human subjects (13 patients, 3 individual control subjects, 9 control subjects from 3 families) labelled by the Nb.BssSI and/or Nt.BspQI enzymes.ResultsWe demonstrated that the method gave a direct quantitative measurement of repeat numbers on D4Z4 repeats with 4qA allelic configuration and the levels of postzygotic mosaicism. Our method had high concordance with Southern blots from several cohorts on two platforms (Bionano Saphyr and Bionano Irys), but with improved quantification of repeat numbers.ConclusionWhile the study is limited by small sample size, our results demonstrated that single-molecule optical mapping is a viable approach for more refined analysis on genotype-phenotype relationships in FSHD, especially when postzygotic mosaicism is present.
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Zhu, Lin, Jisen Zhang, Youqiang Chen, Hongyu Pan, and Ray Ming. "Identification and genes expression analysis of ATP-dependent phosphofructokinase family members among three Saccharum species." Functional Plant Biology 40, no. 4 (2013): 369. http://dx.doi.org/10.1071/fp12182.
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Sugarcane contributes ~80% of sugar production in the world and is an established biofuel crop. In working towards understanding the molecular basis of high sucrose accumulation, we have annotated and analysed the ATP-dependent phosphofructokinase (PFK) gene family that catalyses the phosphorylation of D-fructose 6-phosphate to D-fructose 1,6-bisphosphate. PFKs play an essential role in sucrose metabolism in plants and their expression patterns are unknown in sugarcane. In this study, based on the sorghum genome and sugarcane EST database, 10 PFK gene members were annotated and further verified by PCR using sugarcane genomic DNA. An unrooted phylogenetic tree was constructed with the deduced protein sequences of PFKs that were from the assembly of cDNA library of sugarcane and other plants. The results showed that gene duplication events and the retention rate after genome wide or segmental duplications occurred in higher frequency in monocots than in dicots and the genes in subgroup II of group III were likely originated from recent duplication events. Quantitative RT–PCR was performed to investigate the gene expression of 10 PFK genes in five tissues of three Saccharum species, including two developmental stages in leaves and three in culms. Of the PFK family members in sugarcane, ScPFK6, 7 and 8 appeared to be the primary isoforms based on the highly abundant expression of these three genes. ScPFK7 showed high expression level in the leaves, suggesting a potential role in sucrose metabolism. ScPFK8 had lower expression level in Saccharum officinarum L. than in the other two species, suggesting negative regulation of sucrose metabolism, which might have contributed to the high sugar content of S. officinarum. The genes in monocot specific subgroup II of group III, PFK7, 8 and 9, showed variation among the three Saccharum species, suggesting potential functional redundancy. Our results provide detailed annotation and analysis of the PFK gene family in sugarcane. Further elucidation of the role of ScPFK8 in the domestication process of sugarcane would be useful.
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Wang, Jian, Tsz-Kwong Man, Kwong Kwok Wong, Pulivarthi H. Rao, Hon-Chiu Eastwood Leung, Rudy Guerra, and Ching C. Lau. "Genome-Wide Analysis of Copy Number Variations in Normal Population Identified by SNP Arrays." Open Biology Journal 2, no. 1 (July 8, 2009): 54–65. http://dx.doi.org/10.2174/1874196700902010054.
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Gene copy number change is an essential characteristic of many types of cancer. However, it is important to distinguish copy number variation (CNV) in the human genome of normal individuals from bona fide abnormal copy number changes of genes specific to cancers. Based on Affymetrix 50K single nucleotide polymorphism (SNP) array data, we identified genome-wide copy number variations among 104 normal subjects from three ethnic groups that were used in the HapMap project. Our analysis revealed 155 CNV regions, of which 37% were gains and 63% were losses. About 21% (30) of the CNV regions are concordant with earlier reports. These 155 CNV regions are located on more than 100 cytobands across all 23 chromosomes. The CNVs range from 68bp to 18 Mb in length, with a median length of 86 Kb. Eight CNV regions were selected for validation by quantitative PCR. Analysis of genomic sequences within and adjacent to CNVs suggests that repetitive sequences such as long interspersed nuclear elements (LINEs) and long terminal repeats (LTRs) may play a role in the origin of CNVs by facilitating non-allelic homologous recombination. Thirty-two percent of the CNVs identified in this study are associated with segmental duplications. CNVs were not preferentially enriched in gene-encoding regions. Among the 364 genes that are completely encompassed by these 155 CNVs, genes related to olfactory sensory, chemical stimulus, and other physiological responses are significantly enriched. A statistical analysis of CNVs by ethnic group revealed distinct patterns regarding the CNV location and gain-to-loss ratio. The CNVs reported here will help build a more comprehensive map of genomic variations in the human genome and facilitate the differentiation between copy number variation and somatic changes in cancers. The potential roles of certain repeat elements in CNV formation, as corroborated by other studies, shed light on the origin of CNVs and will improve our understanding of the mechanisms of genomic rearrangements in the human genome.
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Kean, Adam C., Benjamin M. Helm, Matteo Vatta, Mark D. Ayers, John J. Parent, and Robert K. Darragh. "Clinical characterisation of a novel SCN5A variant associated with progressive malignant arrhythmia and dilated cardiomyopathy." Cardiology in the Young 29, no. 10 (September 3, 2019): 1257–63. http://dx.doi.org/10.1017/s1047951119001860.
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AbstractIntroduction:The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest.Methods:A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing.Results:All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination.Conclusions:There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.
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Ishii, Kotaro, Ryuji Sugiyama, Megumi Onuki, Yusuke Kazama, Sachihiro Matsunaga, and Shigeyuki Kawano. "The Y chromosome-specific STS marker MS2 and its peripheral regions on the Y chromosome of the dioecious plant Silene latifolia." Genome 51, no. 4 (April 2008): 251–60. http://dx.doi.org/10.1139/g08-005.
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Sex determination in Silene latifolia uses the XX/XY system. The recent evolution of dioecy in S. latifolia provides a unique opportunity to study the early stages of Y chromosome evolution. However, the current Y chromosome map still contains many large gaps with no available markers. In this study, a sequence tagged site (STS) marker, MS2, was isolated and mapped to the same locus as L8 on the Y chromosome. To investigate the peripheral regions of MS2, a bacterial artificial chromosome (BAC) library was constructed from a male plant, and the BAC clone containing MS2 (MS2-9d12F) was isolated from 32 640 clones with an average insert size of 115 kb. A 109-kb insert of the BAC clone was analyzed. BLASTX analysis showed 11 sequences similar to some known proteins, most of which are retrotransposon-like elements. The ORF Finder predicted 9 ORFs within MS2-9d12F. RT-PCR analyses revealed that only 4 of the 9 predicted ORFs are expressed in both male and female plants. These 4 ORFs are candidates for genes having counterparts on both the X and Y chromosomes. Dot-matrix plot analysis and a BLASTN search revealed LTR-like sequences close to the retrotransposon-like elements and high similarity to 3 known genomic sequences of S. latifolia. These results suggest an accumulation of retrotransposons and segmental duplications in peripheral regions of MS2 during the early stage of sex chromosome evolution.
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Hargreaves, Chantal, Chisako Iriyama, Matthew JJ Rose-Zerilli, Charlotte Lee, Kathleen Potter, Rosalind Ganderton, Khiyam Hussain, et al. "Genomic Dissection of the Fcγ Receptor Region in the Context of Monoclonal Antibody Therapy." Blood 124, no. 21 (December 6, 2014): 2996. http://dx.doi.org/10.1182/blood.v124.21.2996.2996.
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Abstract Development of the anti-CD20 antibody, rituximab, heralded the start of monoclonal antibody (mAb) therapy as an effective means of treating cancer. Despite its undoubted impact, clinical responses remain variable and cures are rarely achieved. Evidence from pre-clinical models and human trials indicates that mAbs primarily act through engaging low-affinity Fc gamma receptor (FcγR)-expressing effector immune cells. The low-affinity FcγR genes, FCGR2A, FCGR2B, FCGR2C, FCGR3A and FCGR3B, are located within a highly homologous 200 kb region at 1q23, which is the result of an ancestral segmental duplication event (Figure 1). The locus also contains numerous single nucleotide polymorphisms (SNPs), many of which can affect receptor affinity and/or function and are associated with differential responses following mAb immunotherapy. Moreover, the region contains extensive copy number variation (CNV) that also can affect the expression and function of these receptors, but its impact on mAb immunotherapy remains unknown. To investigate the full impact of SNPs and CNV in the FcγR locus, we have optimised a number of sensitive and specific assays which are amenable to formalin fixed paraffin embedded (FFPE) material in order to apply them to clinical trial samples in a high-throughput manner. Initially we assessed the accuracy of established TaqMan and novel allele-specific (KASP) genotyping assays for FCGR2A-131H/R (rs1801274), FCGR3A-158F/V (rs396991) and FCGR2B-232I/T (rs1050501) SNPs by analysing 2085 DNA samples derived from peripheral blood lymphocytes (PBL) from a large, multi-centre cohort. Our data showed that although clear discrimination was possible at the FCGR2A-131H/R SNP, we needed additional selective Sanger sequencing to discriminate the FF/FV and IT/TT genotypes for the FCGR3A-158F/V and FCGR2B-232I/T SNPs, respectively. This difficulty in genotype discrimination in the cases of FCGR3A and FCGR2B is likely due to sequence homology with other genes and CNV in the gene regions which complicate assay design and interpretation of certain genotypes. Secondly, we applied a combined KASP genotyping and Sanger sequencing approach to matched PBL DNA and FFPE-extracted DNA from follicular lymphoma (FL) patients [n=14] and showed that while FFPE material was more likely to fail genotyping, successfully genotyped cases were concordant with the matched genomic DNA samples. FFPE samples which failed to amplify PCR products of at least 100 bp using the BIOMED-2 multiplex PCR protocol were more likely to fail genotyping assays. Finally, we assessed the ability of a multiplex ligation-dependent probe amplification (MLPA) assay to concurrently determine SNP genotype and CNV in the low-affinity FCGR locus in a cohort of 155 normal donors and DNA from seven matched PBL-/FFPE-derived FL cases. We employed a paralog ratio test (PRT) assay for FCGR3A and FCGR3B CNV confirmation. In our normal donors, MLPA and PRT results were concordant. 16% of normal donors harboured a deletion [n=15] or duplication [n=10] affecting the FCGR2C locus (A summary of regions of CNV is shown in Figure 1). CNV of FCGR3B was associated with variation at FCGR2C and no CNV was observed in FCGR2A and FCGR2B. CNV affecting FCGR3A was observed in 5% of donors with deletions and duplications in 4 and 5 donors, respectively. In the FFPE-derived DNA samples, we observed elevated variability in data quality that was most noticeable in probes targeting HSPA6, FCGR2C exon 4 and HSPA7. Poor quality data correlated with samples that failed to amplify at least the 100 bp PCR product using the BIOMED-2 multiplex PCR protocol. As such, the preclusion of HSPA6, FCGR2C exon 4 and HSPA7 probes and FFPE samples that failed to amplify any BIOMED-2 PCR product from the analysis permitted the production of high-quality MLPA data. Finally, we designed, and are currently optimising, a targeted re-sequencing platform (Haloplex, Agilent) to interrogate informative regions of the FcγR region, which includes those with unique sequence identify for CNV analysis, and those that include known SNPs. In conclusion, we have evaluated a suite of assays for the genomic analysis of the FcγR locus that are scalable for application in large clinical trials of antibody therapy. This work will ultimately provide a detailed architecture of the region and establish the importance of FcγR genetics in predicting response to antibody therapeutics. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Julca, Irene, Marina Marcet-Houben, Fernando Cruz, Carlos Vargas-Chavez, John Spencer Johnston, Jèssica Gómez-Garrido, Leonor Frias, et al. "Phylogenomics Identifies an Ancestral Burst of Gene Duplications Predating the Diversification of Aphidomorpha." Molecular Biology and Evolution 37, no. 3 (November 8, 2019): 730–56. http://dx.doi.org/10.1093/molbev/msz261.
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Abstract Aphids (Aphidoidea) are a diverse group of hemipteran insects that feed on plant phloem sap. A common finding in studies of aphid genomes is the presence of a large number of duplicated genes. However, when these duplications occurred remains unclear, partly due to the high relatedness of sequenced species. To better understand the origin of aphid duplications we sequenced and assembled the genome of Cinara cedri, an early branching lineage (Lachninae) of the Aphididae family. We performed a phylogenomic comparison of this genome with 20 other sequenced genomes, including the available genomes of five other aphids, along with the transcriptomes of two species belonging to Adelgidae (a closely related clade to the aphids) and Coccoidea. We found that gene duplication has been pervasive throughout the evolution of aphids, including many parallel waves of recent, species-specific duplications. Most notably, we identified a consistent set of very ancestral duplications, originating from a large-scale gene duplication predating the diversification of Aphidomorpha (comprising aphids, phylloxerids, and adelgids). Genes duplicated in this ancestral wave are enriched in functions related to traits shared by Aphidomorpha, such as association with endosymbionts, and adaptation to plant defenses and phloem-sap-based diet. The ancestral nature of this duplication wave (106–227 Ma) and the lack of sufficiently conserved synteny make it difficult to conclude whether it originated from a whole-genome duplication event or, alternatively, from a burst of large-scale segmental duplications. Genome sequencing of other aphid species belonging to different Aphidomorpha and related lineages may clarify these findings.
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Wang, Chutian, Farhat Abbas, Yiwei Zhou, Yanguo Ke, Xinyue Li, Yuechong Yue, Yunyi Yu, Rangcai Yu, and Yanping Fan. "Genome-wide identification and expression pattern of SnRK gene family under several hormone treatments and its role in floral scent emission in Hedychium coronarium." PeerJ 9 (March 10, 2021): e10883. http://dx.doi.org/10.7717/peerj.10883.
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The SnRK (Snf1-Related protein Kinase) gene family plays crucial roles in various plant signaling pathways and stress-adaptive responses including biotic and abiotic stresses via activating protein phosphorylation pathways. However, there is no information available on the role of the SnRK gene family in Hedychium coronarium. H. coronarium is an important crop widely cultivated as an ornamental plant, herb, spice, or condiment. In this study, 60 HcSnRK genes were identified from the H. coronarium genomic and transcriptome data. Phylogenetic and gene structure analysis showed that the HcSnRK genes were divided into three groups (HcSnRK1, HcSnRK2 and HcSnRK3) and among them HcSnRK3 subfamily was further subdivided into two clades according to the number of introns. Chromosome localization analysis showed that HcSnRK genes were unevenly mapped onto all chromosomes, and the Ka/Ks ratio of 24 paralogues includes four tandems and 20 segmental duplications indicated that the HcSnRK gene family underwent a purifying selection. Cis-regulatory elements analysis suggested that the HcSnRK genes respond to multiple hormones and other stresses. The responsiveness of HcSnRK genes to several hormones was analyzed by quantitative real-time PCR. Based on the different transcriptome data, two candidates HcSnRK genes (HcSnRK2.2 and HcSnRK2.9) were screened out for further characterization . The subcellular localization experiment revealed that both genes were located in the nucleus and cytoplasm. Moreover, virus-induced gene silencing (VIGS) of HcSnRK2.2 and HcSnRK2.9 significantly reduced the floral volatile contents by suppressing the expression of terpene synthase genes (HcTPS1, HcTPS3, and HcTPS5), indicating that HcSnRK2.2 and HcSnRK2.9 genes play an important role in the regulatory mechanism of floral aroma. These results will provide novel insights into the functional dissection of H. coronarium SnRK gene family.
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Konrad, Anke, Stephane Flibotte, Jon Taylor, Robert H. Waterston, Donald G. Moerman, Ulfar Bergthorsson, and Vaishali Katju. "Mutational and transcriptional landscape of spontaneous gene duplications and deletions in Caenorhabditis elegans." Proceedings of the National Academy of Sciences 115, no. 28 (June 25, 2018): 7386–91. http://dx.doi.org/10.1073/pnas.1801930115.
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Gene duplication and deletion are pivotal processes shaping the structural and functional repertoire of genomes, with implications for disease, adaptation, and evolution. We employed a mutation accumulation (MA) framework partnered with high-throughput genomics to assess the molecular and transcriptional characteristics of newly arisen gene copy-number variants (CNVs) in Caenorhabditis elegans populations subjected to varying intensity of selection. Here, we report a direct spontaneous genome-wide rate of gene duplication of 2.9 × 10−5/gene per generation in C. elegans, the highest for any species to date. The rate of gene deletion is sixfold lower (5 × 10−6/gene per generation). Deletions of highly expressed genes are particularly deleterious, given their paucity in even the N = 1 lines with minimal efficacy of selection. The increase in average transcript abundance of new duplicates arising under minimal selection is significantly greater than twofold compared with single copies of the same gene, suggesting that genes in segmental duplications are frequently overactive at inception. The average increase in transcriptional activity of gene duplicates is greater in the N = 1 MA lines than in MA lines with larger population bottlenecks. There is an inverse relationship between the ancestral transcription levels of new gene duplicates and population size, with duplicate copies of highly expressed genes less likely to accumulate in larger populations. Our results demonstrate a fitness cost of increased transcription following duplication, which results in purifying selection against new gene duplicates. However, on average, duplications also provide a significant increase in gene expression that can facilitate adaptation to novel environmental challenges.
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Gondek, Lukasz P., Andrew J. Dunbar, Michael A. McDevitt, Hadrian Szpurka, Mikkael A. Sekeres, and Jaroslaw P. Maciejewski. "Detection of Recurrent Uniparental Disomy and Cryptic Chromosomal Abnormalities in MDS/MPD-U and MDS/MPD-Derived Secondary AML." Blood 110, no. 11 (November 16, 2007): 1542. http://dx.doi.org/10.1182/blood.v110.11.1542.1542.
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Abstract The WHO classification distinguishes MDS/MPD as a distinct entity. The JAK2 V617F mutation is present in a minority of these patients (pts). UPD9p characterizes pts homozygous for the V617F mutation. Other chromosomal abnormalities can also be detected in pts with typical MPD and MDS/MPD, and it is likely that cytogenetic methods with higher resolution could detect additional defects. We applied 250K SNP-arrays to examine genomic composition and identify previously cryptic defects and molecular abnormalities in pts with MDS/MPD-U and secondary AML (sAML) arising from MDS/MPD-U both in pts wild-type for V617F and those with the mutation. Any deletions, duplications, and/or UPD found by SNP-A in 76 controls or on available internet databases were considered copy number variants (CNV) and non-pathogenic. First, we used pts with typical MPD to assess the ability of SNP-A to detect UPD. All pts homozygous for V617F showed UPD9p by SNP-A. In pts with MDS/MPD, several additional cryptic lesions were detected, including segmental micro-deletions on chr 1, 5, 9, and 12. UPD was common, occurring on chromosomes other than 9 in 9/28 patients (32%, i.e. on chr 1,11,12). Shared/overlapping lesions (in >2 pts) included small segmental lesions on chr 7 (N=3), and a small cytoband (q14.1) of chr 11 (N=3). Overall, clonal lesions including segmental UPD were found in 23/28 (82%) pts by SNP-A in comparison to 17/28 (61%) by metaphase cytogenetics (MC). Pts with a history of MDS/MPD-U with (N=14) and without the JAK2 V617F mutation (N=14) were also analyzed. MC revealed chr aberrations in 10/14 (71%) of V617F+ pts, including common lesions such as +8 and del5q. With SNP-A, 1 additional pt with normal MC was found to have an abnormal karyotype (UPD 7 and 9), and 9/10 pts with abnormal MC had additional lesions previously undetected, including UPD on chrs other than 9 in 3/14 pts (21%). Examples of deleted regions include segmental losses within chrs 2, 7, 8 and 13, and UPD on chrs 1p, 7q, and 11. Likewise, additional lesions were identified in MDS/MPD-U pts negative for V617F. 8/14 pts (57%) showed abnormal MC; however SNP-A showed lesions in 12/14. In addition, 6/8 pts with abnormal MC had lesions in addition to those detected by MC. UPD was also common in V617F- pts, occurring in 6/14 (43%), predominantly on chr 11 (in 3/6 pts). No significant difference was found between the number or type of lesions found in pts with and without V617F mutation. SNP-A can also be used to identify lesions acquired during AML evolution. In 1 MPD pt at diagnosis, SNP-A showed UPD9p as a sole abnormality consistent with a homozygous V617F mutation. Upon transformation, repeated SNP-A showed a V617F- leukemic clone (normal chr 9) possessing microdeletions on chr 4 and 19. Similar evolution of a V617 negative leukemic clone was also observed in an MDS/MPD pt in whom a new UPD6 was detected. However, in 3 other MDS/MPD patients, SNP-A showed the presence of a V617+ leukemic clone (showing UPD9) in AML blasts. In summary, SNP-A-based karyotyping complements MC and allows for precise definition of chr aberrations in pts with MDS/MPD, including copy-neutral LOH. UPD is common in both JAK2 V617F+ and V617F- disorders, and is not restricted only to chr 9p, indicating other potential causative genes.
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Baumgarten, Andrew, Steven Cannon, Russ Spangler, and Georgiana May. "Genome-Level Evolution of Resistance Genes in Arabidopsis thaliana." Genetics 165, no. 1 (September 1, 2003): 309–19. http://dx.doi.org/10.1093/genetics/165.1.309.
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Abstract Pathogen resistance genes represent some of the most abundant and diverse gene families found within plant genomes. However, evolutionary mechanisms generating resistance gene diversity at the genome level are not well understood. We used the complete Arabidopsis thaliana genome sequence to show that most duplication of individual NBS-LRR sequences occurs at close physical proximity to the parent sequence and generates clusters of closely related NBS-LRR sequences. Deploying the statistical strength of phylogeographic approaches and using chromosomal location as a proxy for spatial location, we show that apparent duplication of NBS-LRR genes to ectopic chromosomal locations is largely the consequence of segmental chromosome duplication and rearrangement, rather than the independent duplication of individual sequences. Although accounting for a smaller fraction of NBS-LRR gene duplications, segmental chromosome duplication and rearrangement events have a large impact on the evolution of this multi-gene family. Intergenic exchange is dramatically lower between NBS-LRR sequences located in different chromosome regions as compared to exchange between sequences within the same chromosome region. Consequently, once translocated to new chromosome locations, NBS-LRR gene copies have a greater likelihood of escaping intergenic exchange and adopting new functions than do gene copies located within the same chromosomal region. We propose an evolutionary model that relates processes of genome evolution to mechanisms of evolution for the large, diverse, NBS-LRR gene family.
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Chuang, Trees-Juen, Shian-Zu Wu, and Yao-Ting Huang. "A Novel Framework for the Identification and Analysis of Duplicons between Human and Chimpanzee." BioMed Research International 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/264532.
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Human and other primate genomes consist of many segmental duplications (SDs) due to fixation of copy number variations (CNVs). Structure of these duplications within the human genome has been shown to be a complex mosaic composed of juxtaposed subunits (called duplicons). These duplicons are difficult to be uncovered from the mosaic repeat structure. In addition, the distribution and evolution of duplicons among primates are still poorly investigated. In this paper, we develop a statistical framework for discovering duplicons via integration of a Hidden Markov Model (HMM) and a permutation test. Our comparative analysis indicates that the mosaic structure of duplicons is common in CNV/SD regions of both human and chimpanzee genomes, and a subset of core duplicons is shared by the majority of CNVs/SDs. Phylogenetic analyses using duplicons suggested that most CNVs/SDs share common duplication ancestry. Many human/chimpanzee duplicons flank both ends of CNVs, which may be hotspots of nonallelic homologous recombination.
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Shao, Mingfu, and Bernard M. E. Moret. "Comparing genomes with rearrangements and segmental duplications." Bioinformatics 31, no. 12 (June 13, 2015): i329—i338. http://dx.doi.org/10.1093/bioinformatics/btv229.
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TANAKA, KENTARO M., K. RYO TAKAHASI, and TOSHIYUKI TAKANO-SHIMIZU. "Enhanced fixation and preservation of a newly arisen duplicate gene by masking deleterious loss-of-function mutations." Genetics Research 91, no. 4 (July 30, 2009): 267–80. http://dx.doi.org/10.1017/s0016672309000196.
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SummarySegmental duplications are enriched within many eukaryote genomes, and their potential consequence is gene duplication. While previous theoretical studies of gene duplication have mainly focused on the gene silencing process after fixation, the process leading to fixation is even more important for segmental duplications, because the majority of duplications would be lost before reaching a significant frequency in a population. Here, by a series of computer simulations, we show that purifying selection against loss-of-function mutations increases the fixation probability of a new duplicate gene, especially when the gene is haplo-insufficient. Theoretically, the probability of simultaneous preservation of both duplicate genes becomes twice the loss-of-function mutation rate (uc) when the population size (N), the degree of dominance of mutations (h) and the recombination rate between the duplicate genes (c) are all sufficiently large (Nuc>1, h>0·1 and c>uc). The preservation probability declines rapidly with h and becomes 0 when h=0 (haplo-sufficiency). We infer that masking deleterious loss-of-function mutations give duplicate genes an immediate selective advantage and, together with effects of increased gene dosage, would predominantly determine the fates of the duplicate genes in the early phase of their evolution.
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Sawyer, Jeffery R., Erming Tian, Brian A. Walker, Christopher P. Wardell, Joshua Epstein, Janet L. Lukacs, Gael M. Sammartino, et al. "An Acquired High-Risk Chromosome Instability Phenotype in Multiple Myeloma: Jumping 1q Syndrome." Blood 132, Supplement 1 (November 29, 2018): 4489. http://dx.doi.org/10.1182/blood-2018-99-115090.
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Abstract Introduction Chromosome instability (CIN) is a driver of copy number aberrations (CNAs) in cancer, and is a major factor leading to tumor heterogeneity and resistance to therapy. By definition, CIN is an increased rate or ongoing acquisition and accumulation of CNAs and not simply the existence of structurally and numerically abnormal aneuploid clones. In multiple myeloma (MM), the most common whole-chromosome CNAs involve either hyperdiploid or non-hyperdiploid clones. Secondary segmental CNAs are associated with high-risk (HR) in MM and involve gains of 1q21 and deletions of 17p (del17p). These types of intra-chromosomal segmental CNAs are also found in the CIN phenotypes of the autosomal recessive (AR) chromosome instability syndromes. These syndromes include Fanconi anemia, Bloom's syndrome, and ICF syndrome (Immunodeficiency, Centromeric instability and Facial anomalies). These chromosome instability syndromes display a spectrum of aberrations characterized by higher rates of chromosomal breaks, chromatid exchanges, quadriradials, and pericentromeric aberrations. In particular, patients with ICF syndrome show a marked increase of 1q12 pericentromeric instability including 1q12 decondensation, triradials, multibranched chromosomes 1q, and 1q micronuclei. ICF patients also show transient 1q aberrations including isochromosome 1q (iso1q) and unbalanced translocations of 1q to 9q and 16q. In MM, we have previously reported increasing pericentromeric instability during tumor progression resulting in increasing CNAs of 1q21 by unbalanced jumping translocations of 1q12 (JT1q12). Strikingly, in a subset of MM patients with 1q21 CNAs of ≥ 5 a distinct cytogenetic phenotype emerges which demonstrates transient 1q12 aberrations including 1q12 decondensation, triradials, and multibranched chromosomes 1q morphologically identical to those seen in ICF patients. In MM this chromosome instability leads to a cascade of increasing clonal 1q21 duplications, iso 1qs, and unbalanced 1q translocations with 16q and 17p, resulting in losses in these receptor chromosomes (RC) and massive intra-clonal CNA heterogeneity. Methods To investigate the cytogenetic impact and progression of high CNAs of 1q21, we performed a comprehensive metaphase analysis of 50 patients showing segmental aneuploidies with 4 or more copies of 1q by G-banding. Locus specific FISH and spectral karyotyping were used to identify the key transient unstable and clonal structural aberrations of 1q12 resulting in segmental aneuploidies in the derivative RCs. Probe for 1q12 (Vysis) was used according to the manufacturer's protocol. Locus specific BAC clones for 1q21 (CKS1B) and 17p (TP53) were prepared and analyzed as previously described (Sawyer et al., Blood 123: 2014). IGH translocations were investigated with IGH break apart probes (Vysis). Results Data for 50 patients including CNAs of 1q21 of ≥ 4, IGH translocations, del(17p), derivative RCs, are presented. The t(4;14) was found in 15 patients, del(17p) in 23, and both aberrations were found in 8 patients. All patients showed unbalanced gains of 1q and deletions of RCs, the most frequent being 7 patients with der(1;16) and 6 with iso1q. In four of the 23 patients with del(17p), the deletion was due to a JT1q12 to 17p. Seven patients with 1q21 CNAs of ≥ 5 showed profound instability involving the 1q12 satellite DNA, demonstrating both transient and clonal aberrations driving the 1q21 CNAs. These aberrations included unstable 1q21 triplications, JT1q12s, iso1q formation with intra-arm 1q12 CNAs, and region specific breakage-fusion-bridge cycle amplifications. Conclusions Among patients with ≥ 5 CNAs of 1q21, a subset develop an acquired HR chromosome instability phenotype with an elevated rate of 1q12 pericentromeric instability characterized by concomitant deletions in 16q, iso1q, del(17p), and intra-arm segmental instability. These patients show pronounced instability in the 1q12 satellite DNA, morphologically identical to ICF syndrome, suggesting hypomethylation of this region as a driver of both 1q21 CNAs and deletions in RCs. We hypothesize that region specific hypomethylation of 1q12 provides the genomic background for the onset of an acquired 1q12 chromosome instability phenotype in MM similar to that found in ICF syndrome. For myeloma patients demonstrating this 1q12 chromosome instability phenotype we propose the term "jumping 1q syndrome." Disclosures Epstein: University of Arkansas for Medical Sciences: Employment. Davies:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Honoraria; Abbvie: Consultancy; TRM Oncology: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; Janssen: Consultancy, Honoraria. Morgan:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria.
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Philippsen, Gisele Strieder. "Transposable Elements in the Genome of Human Parasite Schistosoma mansoni: A Review." Tropical Medicine and Infectious Disease 6, no. 3 (July 9, 2021): 126. http://dx.doi.org/10.3390/tropicalmed6030126.
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Transposable elements (TEs) are DNA sequences able to transpose within the host genome and, consequently, influence the dynamics of evolution in the species. Among the possible effects, TEs insertions may alter the expression and coding patterns of genes, leading to genomic innovations. Gene-duplication events, resulting from DNA segmental duplication induced by TEs transposition, constitute another important mechanism that contributes to the plasticity of genomes. This review aims to cover the current knowledge regarding TEs in the genome of the parasite Schistosoma mansoni, an agent of schistosomiasis—a neglected tropical disease affecting at least 250 million people worldwide. In this context, the literature concerning TEs description and TEs impact on the genomic architecture for S. mansoni was revisited, displaying evidence of TEs influence on schistosome speciation—mediated by bursts of transposition—and in gene-duplication events related to schistosome–host coevolution processes, as well several instances of TEs contribution into the coding sequences of genes. These findings indicate the relevant role of TEs in the evolution of the S. mansoni genome.