scholarly journals LEM domain proteins control the efficiency of adaptation through copy number variation

2018 ◽  
Author(s):  
Paolo Colombi ◽  
Diane E. King ◽  
Jessica F. Williams ◽  
C. Patrick Lusk ◽  
Megan C. King
Keyword(s):  
Copy Number ◽  
Genome Instability ◽  
Genetic Interaction ◽  
Transcriptional Response ◽  
Genome Integrity ◽  
Changing Environment ◽  
Number Variation ◽  
Transcriptional Induction

AbstractWhile loss of genome integrity is at the basis of numerous pathologies, including cancer, genome plasticity is necessary to adapt to a changing environment and thus is essential for long-term organismal success. Here we present data supporting a targeted mechanism that promotes adaptation to environmental stress by driving site-specific genome instability tied to transcriptional induction and the formation of RNA-DNA hybrids. Using an in vitro evolution assay we observe that the inner nuclear membrane LEM domain proteins Heh1 and Heh2 play antagonistic roles in inhibiting or promoting adaptation through copy number expansion, respectively, which is also reflected in their genetic interaction networks with genes responsible for transcription-dependent genome instability. Taken together, our data suggest the existence of a LEM domain protein-mediated mechanism by which an immediate transcriptional response to a changing environment drives targeted genome instability to promote increased variation on which selection can act to support long-term adaptation.

scholarly journals Human rDNA Copy Number Is Unstable in Metastatic Breast Cancers

2019 ◽  
Author(s):  
Virginia Valori ◽  
Katalin Tus ◽  
Christina Laukaitis ◽  
David T. Harris ◽  
Lauren LeBeau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number Variation ◽  
Copy Number ◽  
Genome Instability ◽  
Gene Clusters ◽  
Genome Rearrangements ◽  
Epigenetic Silencing ◽  
Healthy Tissue ◽  
Gene Promoters ◽  
Number Variation

AbstractEpigenetic silencing, including the formation of heterochromatin, silent chromosome territories, and repressed gene promoters, acts to stabilize patterns of gene regulation and the physical structure of the genome. Reduction of epigenetic silencing can result in genome rearrangements, particularly at intrinsically unstable regions of the genome such as transposons, satellite repeats, and repetitive gene clusters including the rRNA gene clusters (rDNA). It is thus expected that mutational or environmental conditions that compromise heterochromatin function might cause genome instability, and diseases associated with decreased epigenetic stability might exhibit genome changes as part of their etiology. We find support of this hypothesis in invasive ductal breast carcinoma, in which reduced epigenetic silencing has been previously described, by using a facile method to quantify rDNA copy number in biopsied breast tumors and pair-matched healthy tissue. We found that rDNA and satellite DNA sequences had significant copy number variation – both losses and gains of copies – compared to healthy tissue, arguing that these genome rearrangements are common in developing breast cancer. Thus, any proposed etiology onset or progression of breast cancer should consider alterations to the epigenome, but must also accommodate concomitant changes to genome sequence at heterochromatic loci.Authors’ StatementOne of the common hallmarks of cancer is genome instability, including hypermutation and changes to chromosome structure. Using tumor tissues obtained from women with invasive ductal carcinoma, we find that a sensitive area of the genome – the ribosomal DNA gene repeat cluster – shows hypervariability in copy number. The patterns we observe as not consistent with an adaptive loss leading to increased tumor growth, but rather we conclude that copy number variation at repeat DNA is a general consequence of reduced heterochromatin function in cancer progression.

Abstract 4949: 18q copy number variation in primary prostate tumors as a predictor of long-term outcome

2016 ◽  
Author(s):  
Keith A. Ashcraft ◽  
Teresa L. Johnson-Pais ◽  
Jonathan A.L Gelfond ◽  
Javier Hernandez ◽  
Ian M. Thompson ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Copy Number ◽  
Prostate Tumors ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Number Variation

scholarly journals High-resolution genetic mapping reveals cis-regulatory and copy number variation in loci associated with cytochrome P450-mediated detoxification in a generalist arthropod pest

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009422
Author(s):  
Seyedeh Masoumeh Fotoukkiaii ◽  
Nicky Wybouw ◽  
Andre H. Kurlovs ◽  
Dimitra Tsakireli ◽  
Spiros A. Pergantis ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Resolution ◽  
Copy Number Variation ◽  
Genetic Mapping ◽  
Copy Number ◽  
Spider Mite ◽  
Bulked Segregant Analysis ◽  
Resistant Population ◽  
Number Variation

Chemical control strategies are driving the evolution of pesticide resistance in pest populations. Understanding the genetic mechanisms of these evolutionary processes is of crucial importance to develop sustainable resistance management strategies. The acaricide pyflubumide is one of the most recently developed mitochondrial complex II inhibitors with a new mode of action that specifically targets spider mite pests. In this study, we characterize the molecular basis of pyflubumide resistance in a highly resistant population of the spider mite Tetranychus urticae. Classical genetic crosses indicated that pyflubumide resistance was incompletely recessive and controlled by more than one gene. To identify resistance loci, we crossed the resistant population to a highly susceptible T. urticae inbred strain and propagated resulting populations with and without pyflubumide exposure for multiple generations in an experimental evolution set-up. High-resolution genetic mapping by a bulked segregant analysis approach led to the identification of three quantitative trait loci (QTL) linked to pyflubumide resistance. Two QTLs were found on the first chromosome and centered on the cytochrome P450 CYP392A16 and a cluster of CYP392E6-8 genes. Comparative transcriptomics revealed a consistent overexpression of CYP392A16 and CYP392E8 in the experimental populations that were selected for pyflubumide resistance. We further corroborated the involvement of CYP392A16 in resistance by in vitro functional expression and metabolism studies. Collectively, these experiments uncovered that CYP392A16 N-demethylates the toxic carboxamide form of pyflubumide to a non-toxic compound. A third QTL coincided with cytochrome P450 reductase (CPR), a vital component of cytochrome P450 metabolism. We show here that the resistant population harbors three gene copies of CPR and that this copy number variation is associated with higher mRNA abundance. Together, we provide evidence for detoxification of pyflubumide by cytochrome P450s that is likely synergized by gene amplification of CPR.

175 Testis-Specific Protein Y Encoded Copy Number Variation in In Vitro-Produced Bovine Early Embryos

2018 ◽  
Vol 30 (1) ◽  
pp. 227
Author(s):  
N.Y. Rho ◽  
L. A. Favetta ◽  
T. Mogas ◽  
W. A. King
Keyword(s):  
Copy Number Variation ◽  
Copy Number ◽  
Specific Protein ◽  
Development Rate ◽  
Male Reproduction ◽  
Cell Stage ◽  
Early Embryos ◽  
Number Variation ◽  
Developmental Rates

Testis-specific protein Y (TSPY) is one of the genes located in the male-specific region of the Y chromosome involved in male reproduction, particularly in spermatogenesis. It has been shown to have different copy number (CN) in different species, in different individuals within a species and in the same family (i.e. among brothers from the same father). Previous studies from our laboratory in the bovine species showed that different TSPY CN was correlated with fertility, as bulls with higher CN showed higher fertility rate. In this study, we investigated development rate in in vitro-produced (IVP) bovine early embryos produced by sex-sorted semen (X and Y) from 3 bulls (1, 2, and 3) and TSPY copy number variation (CNV) in the male blastocysts. The IVP embryos by the 3 different types of semen (sub-divided: 1X, 1Y, 2X, 2Y, 3X, 3Y) and parthenotes (PART) for the negative control were assessed for developmental rates (shown in Table 1 below) and individually collected at each cell stage from zygote to blastocyst to extract DNA for TSPY CN analysis. The DNA from individual blastocysts was treated with a restriction enzyme for relative quantification of TSPY CN using digital droplet PCR (ddPCR) with SRY, known to have only one copy in bovine, as a reference gene. Developmental data showed that Y-carrying semen had higher rates both in cleavage and blastocyst compared with X-carrying semen from the same bull. Particularly, bull 3 (both 3X and 3Y) had the highest developmental rates compared with the other 2 types of bulls. TSPY was detected in male blastocyst, where both parthenotes and female embryos were negative. Relative CN of TSPY versus SRY from blastocysts produced from bulls 1, 2, and 3 averaged to 87.5, 55, and 20, respectively. Interestingly, the CN among brother blastocysts showed a variation of less than 7.5, where bull-to-bull variation was approximately from 20 to 60 copies. Our results show that TSPY CN in the embryo varies according to the sire and among brother blastocysts. Moreover, TSPY CNV among brother blastocysts allows us to speculate that individually different recombination events occurred in meiosis during spermatogenesis. Table 1.Embryo development rate by semen type This research was funded by the Canada Research Chair’s program, Natural Sciences and Engineering Research Council of Canada and the Ontario Veterinary College.

scholarly journals Wss1 Is a SUMO-Dependent Isopeptidase That Interacts Genetically with the Slx5-Slx8 SUMO-Targeted Ubiquitin Ligase

2010 ◽  
Vol 30 (15) ◽  
pp. 3737-3748 ◽  
Author(s):  
Janet R. Mullen ◽  
Chi-Fu Chen ◽  
Steven J. Brill
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Fusion Protein ◽  
Ubiquitin Ligase ◽  
Copy Number ◽  
Dna Helicase ◽  
Genome Integrity ◽  
Growth Defect ◽  
Sumo Fusion ◽  
Isopeptidase Activity

ABSTRACT Protein sumoylation plays an important but poorly understood role in controlling genome integrity. In Saccharomyces cerevisiae, the Slx5-Slx8 SUMO-targeted Ub ligase appears to be needed to ubiquitinate sumoylated proteins that arise in the absence of the Sgs1 DNA helicase. WSS1, a high-copy-number suppressor of a mutant SUMO, was implicated in this pathway because it shares phenotypes with SLX5-SLX8 mutants, including a wss1Δ sgs1Δ synthetic-fitness defect. Here we show that Wss1, a putative metalloprotease, physically binds SUMO and displays in vitro isopeptidase activity on poly-SUMO chains. Like that of SLX5, overexpression of WSS1 suppresses sgs1Δ slx5Δ lethality and the ulp1ts growth defect. Interestingly, although Wss1 is relatively inactive on ubiquitinated substrates and poly-Ub chains, it efficiently deubiquitinates a Ub-SUMO isopeptide conjugate and a Ub-SUMO fusion protein. Wss1 was further implicated in Ub metabolism on the basis of its physical association with proteasomal subunits. The results suggest that Wss1 is a SUMO-dependent isopeptidase that acts on sumoylated substrates as they undergo proteasomal degradation.

scholarly journals MODL-23. DNA METHYLATION AND COPY NUMBER VARIATION PROFILE FOR CHARACTERIZATION OF PEDIATRIC BRAIN TUMOR PRIMARY CELL LINES

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii415-iii415
Author(s):  
Lucia Pedace ◽  
Maria Vinci ◽  
Simone Pizzi ◽  
Giulia Pericoli ◽  
Giuseppina Catanzaro ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Tumor ◽  
Cell Lines ◽  
Copy Number ◽  
In Vitro Models ◽  
Primary Cell ◽  
Primary Cell Lines ◽  
Number Variation ◽  
Pediatric Brain

Abstract BACKGROUND In vitro models of pediatric brain tumors (pBT) are instrumental for both understanding the oncogenic molecular mechanisms and identifying/testing new therapeutic strategies. DNA methylation (DM) is a stable epigenetic modification recently used to classify tumors. We aim to apply DM and Copy Number Variation (CNV) profiling to characterize pBT primary cell lines and tumors. METHODS We included 36 pBT tissues from different histology (13 LGG, 9 DIPG, 9 HGG, 3 MB, and 2 Ependymomas), paired to their derived primary cultures. Cultures were established in two-dimensional (2D) or three-dimensional (3D) condition, as stem-cell or in serum-supplemented medium. For 9 cultures, both early (P2-P3) and long-term passages (>P4) were considered. Samples were analyzed for DM and CNV profiles using Illumina EPIC arrays and data compared with those of the brain tumor classifier. RESULTS At early passages all cells retained the same DM and genetic patterns of original tumors, with no differences related to 2D/3D methods or presence of serum in media. Primary cell lines analyzed at > P4 and cultured in serum diverged from the primary tumor. CONCLUSIONS DM profiles and CNV are useful tools to detect the recapitulation of pBT-derived primary cell-lines from the original tumor. Whatever subgroups tested, results suggest that in vitro models should be passaged as little as possible to retain the epigenetic and genetic alterations of the tumors and thus to be considered relevant for basic and translational biology. Ongoing experiments are aimed to determine how stable DM and CNV are in other conditions/tumor subgroups.

scholarly journals Horizontally Acquired nrDNAs Persist in Low Amounts in Host Hordeum Genomes and Evolve Independently of Native nrDNA

2021 ◽  
Vol 12 ◽  
Author(s):  
Karol Krak ◽  
Petra Caklová ◽  
David Kopecký ◽  
Frank R. Blattner ◽  
Václav Mahelka
Keyword(s):  
Horizontal Transfer ◽  
Copy Number ◽  
Nuclear Ribosomal Dna ◽  
Evolutionary Significance ◽  
Phylogenetic Groups ◽  
Copy Numbers ◽  
Dead End ◽  
As Species ◽  
Number Variation

Nuclear ribosomal DNA (nrDNA) has displayed extraordinary dynamics during the evolution of plant species. However, the patterns and evolutionary significance of nrDNA array expansion or contraction are still relatively unknown. Moreover, only little is known of the fate of minority nrDNA copies acquired between species via horizontal transfer. The barley genus Hordeum (Poaceae) represents a good model for such a study, as species of section Stenostachys acquired nrDNA via horizontal transfer from at least five different panicoid genera, causing long-term co-existence of native (Hordeum-like) and non-native (panicoid) nrDNAs. Using quantitative PCR, we investigated copy number variation (CNV) of nrDNA in the diploid representatives of the genus Hordeum. We estimated the copy number of the foreign, as well as of the native ITS types (ribotypes), and followed the pattern of their CNV in relation to the genus’ phylogeny, species’ genomes size and the number of nrDNA loci. For the native ribotype, we encountered an almost 19-fold variation in the mean copy number among the taxa analysed, ranging from 1689 copies (per 2C content) in H. patagonicum subsp. mustersii to 31342 copies in H. murinum subsp. glaucum. The copy numbers did not correlate with any of the genus’ phylogeny, the species’ genome size or the number of nrDNA loci. The CNV was high within the recognised groups (up to 13.2 × in the American I-genome species) as well as between accessions of the same species (up to 4×). Foreign ribotypes represent only a small fraction of the total number of nrDNA copies. Their copy numbers ranged from single units to tens and rarely hundreds of copies. They amounted, on average, to between 0.1% (Setaria ribotype) and 1.9% (Euclasta ribotype) of total nrDNA. None of the foreign ribotypes showed significant differences with respect to phylogenetic groups recognised within the sect. Stenostachys. Overall, no correlation was found between copy numbers of native and foreign nrDNAs suggesting the sequestration and independent evolution of native and non-native nrDNA arrays. Therefore, foreign nrDNA in Hordeum likely poses a dead-end by-product of horizontal gene transfer events.

scholarly journals The Role of Human Satellite III (1q12) Copy Number Variation in the Adaptive Response during Aging, Stress, and Pathology: A Pendulum Model

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1524
Author(s):  
Lev N. Porokhovnik ◽  
Natalia N. Veiko ◽  
Elizaveta S. Ershova ◽  
Svetlana V. Kostyuk
Keyword(s):  
Stress Response ◽  
Copy Number Variation ◽  
Copy Number ◽  
Tandem Repeats ◽  
Genotoxic Stress ◽  
Close Link ◽  
Copy Numbers ◽  
Number Variation

The pericentric satellite III (SatIII or Sat3) and II tandem repeats recently appeared to be transcribed under stress conditions, and the transcripts were shown to play an essential role in the universal stress response. In this paper, we review the role of human-specific SatIII copy number variation (CNV) in normal stress response, aging and pathology, with a focus on 1q12 loci. We postulate a close link between transcription of SatII/III repeats and their CNV. The accrued body of data suggests a hypothetical universal mechanism, which provides for SatIII copy gain during the stress response, alongside with another, more hypothetical reverse mechanism that might reduce the mean SatIII copy number, likely via the selection of cells with excessively large 1q12 loci. Both mechanisms, working alternatively like swings of the pendulum, may ensure the balance of SatIII copy numbers and optimum stress resistance. This model is verified on the most recent data on SatIII CNV in pathology and therapy, aging, senescence and response to genotoxic stress in vitro.

scholarly journals Impact of G-Quadruplexes on the Regulation of Genome Integrity, DNA Damage and Repair

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1284
Author(s):  
Anzhela V. Pavlova ◽  
Elena A. Kubareva ◽  
Mayya V. Monakhova ◽  
Maria I. Zvereva ◽  
Nina G. Dolinnaya
Keyword(s):  
Dna Damage ◽  
Genome Instability ◽  
Critical Role ◽  
Dna Lesions ◽  
Genome Integrity ◽  
Dna Breaks ◽  
Dna Damage And Repair ◽  
Repair Processes

DNA G-quadruplexes (G4s) are known to be an integral part of the complex regulatory systems in both normal and pathological cells. At the same time, the ability of G4s to impede DNA replication plays a critical role in genome integrity. This review summarizes the results of recent studies of G4-mediated genomic and epigenomic instability, together with associated DNA damage and repair processes. Although the underlying mechanisms remain to be elucidated, it is known that, among the proteins that recognize G4 structures, many are linked to DNA repair. We analyzed the possible role of G4s in promoting double-strand DNA breaks, one of the most deleterious DNA lesions, and their repair via error-prone mechanisms. The patterns of G4 damage, with a focus on the introduction of oxidative guanine lesions, as well as their removal from G4 structures by canonical repair pathways, were also discussed together with the effects of G4s on the repair machinery. According to recent findings, there must be a delicate balance between G4-induced genome instability and G4-promoted repair processes. A broad overview of the factors that modulate the stability of G4 structures in vitro and in vivo is also provided here.

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