scholarly journals Estimation of Rearrangement Break Rates Across the Genome

2018 ◽  
Author(s):  
Christopher Hann-Soden ◽  
Ian Holmes ◽  
John W. Taylor
Keyword(s):  
Neurospora Crassa ◽  
Interval Graph ◽  
Double Strand Breaks ◽  
Genomic Rearrangements ◽  
Strand Breaks ◽  
Minimum Cover ◽  
A Genome ◽  
History Of ◽  
Cover Problem ◽  
Special Case

Genomic rearrangements provide an important source of variation, but reconstructing the history of rearrangements often has many solutions. We answer the question of where rearrangements occur by solving the simpler problem of estimating the rate of double-strand breaks at every site in a genome. This problem is a special case of the minimum cover problem for an interval graph. We implement this method as a Python program, BRAG, and use it to estimate break rates in the genome of Neurospora crassa. We find that more frequent rearrangement in the subtelomeres facilitates the evolution of novel genes.

scholarly journals Estimation of Rearrangement Break Rates Across the Genome

2018 ◽  
Author(s):  
Christopher Hann-Soden ◽  
Ian Holmes ◽  
John W. Taylor
Keyword(s):  
Interval Graph ◽  
Double Strand Breaks ◽  
Genomic Rearrangements ◽  
Strand Breaks ◽  
Graph Theoretic ◽  
Minimum Cover ◽  
A Genome ◽  
History Of ◽  
Special Case ◽  
Subtelomeric Regions

AbstractGenomic rearrangements provide an important source of novel functions by recombining genes and motifs throughout and between genomes. However, understanding how rearrangement functions to shape genomes is hard because reconstructing rearrangements is a combinatoric problem which often has many solutions. In lieu of reconstructing the history of rearrangements, we answer the question of where rearrangements are occurring in the genome by remaining agnostic to the types of rearrangement and solving the simpler problem of estimating the rate at which double-strand breaks occur at every site in a genome. We phrase this problem in graph theoretic terms and find that it is a special case of the minimum cover problem for an interval graph. We employ and modify existing algorithms for efficiently solving this problem. We implement this method as a Python program, named BRAG, and use it to estimate the break rates in the genome of the model Ascomycete mold,Neurospora crassa. We find evidence that rearrangements are more common in the subtelomeric regions of the chromosomes, which facilitates the evolution of novel genes.

TALEN-mediated genome editing: prospects and perspectives

2014 ◽  
Vol 462 (1) ◽  
pp. 15-24 ◽  
Author(s):  
David A. Wright ◽  
Ting Li ◽  
Bing Yang ◽  
Martin H. Spalding
Keyword(s):  
Genome Editing ◽  
Double Strand Breaks ◽  
Zinc Finger Nucleases ◽  
Transcription Activator ◽  
Strand Breaks ◽  
Natural Processes ◽  
Current State ◽  
A Genome ◽  
Dna Dsbs ◽  
Repair Mechanisms

Genome editing is the practice of making predetermined and precise changes to a genome by controlling the location of DNA DSBs (double-strand breaks) and manipulating the cell's repair mechanisms. This technology results from harnessing natural processes that have taken decades and multiple lines of inquiry to understand. Through many false starts and iterative technology advances, the goal of genome editing is just now falling under the control of human hands as a routine and broadly applicable method. The present review attempts to define the technique and capture the discovery process while following its evolution from meganucleases and zinc finger nucleases to the current state of the art: TALEN (transcription-activator-like effector nuclease) technology. We also discuss factors that influence success, technical challenges and future prospects of this quickly evolving area of study and application.

scholarly journals Simultaneous precise editing of multiple genes in human cells

2019 ◽  
Vol 47 (19) ◽  
pp. e116-e116 ◽  
Author(s):  
Stephan Riesenberg ◽  
Manjusha Chintalapati ◽  
Dominik Macak ◽  
Philipp Kanis ◽  
Tomislav Maricic ◽  
...  
Keyword(s):  
Genome Editing ◽  
Kinase Inhibitor ◽  
Double Strand Breaks ◽  
End Joining ◽  
Nucleotide Substitutions ◽  
Strand Breaks ◽  
Homology Directed Repair ◽  
A Genome ◽  
Dependent Protein ◽  
Non Homologous End Joining

Abstract When double-strand breaks are introduced in a genome by CRISPR they are repaired either by non-homologous end joining (NHEJ), which often results in insertions or deletions (indels), or by homology-directed repair (HDR), which allows precise nucleotide substitutions to be introduced if a donor oligonucleotide is provided. Because NHEJ is more efficient than HDR, the frequency with which precise genome editing can be achieved is so low that simultaneous editing of more than one gene has hitherto not been possible. Here, we introduced a mutation in the human PRKDC gene that eliminates the kinase activity of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). This results in an increase in HDR irrespective of cell type and CRISPR enzyme used, sometimes allowing 87% of chromosomes in a population of cells to be precisely edited. It also allows for precise editing of up to four genes simultaneously (8 chromosomes) in the same cell. Transient inhibition of DNA-PKcs by the kinase inhibitor M3814 is similarly able to enhance precise genome editing.

scholarly journals Genomic Instability and Cancer Risk Associated with Erroneous DNA Repair

2021 ◽  
Vol 22 (22) ◽  
pp. 12254
Author(s):  
Ken-ichi Yoshioka ◽  
Rika Kusumoto-Matsuo ◽  
Yusuke Matsuno ◽  
Masamichi Ishiai
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Risk ◽  
Genomic Instability ◽  
Double Strand Breaks ◽  
Genomic Rearrangements ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Brca1 And Brca2 ◽  
Strand Breaks

Many cancers develop as a consequence of genomic instability, which induces genomic rearrangements and nucleotide mutations. Failure to correct DNA damage in DNA repair defective cells, such as in BRCA1 and BRCA2 mutated backgrounds, is directly associated with increased cancer risk. Genomic rearrangement is generally a consequence of erroneous repair of DNA double-strand breaks (DSBs), though paradoxically, many cancers develop in the absence of DNA repair defects. DNA repair systems are essential for cell survival, and in cancers deficient in one repair pathway, other pathways can become upregulated. In this review, we examine the current literature on genomic alterations in cancer cells and the association between these alterations and DNA repair pathway inactivation and upregulation.

scholarly journals Meiotic Crossover Patterning

2021 ◽  
Vol 9 ◽  
Author(s):  
Nila M. Pazhayam ◽  
Carolyn A. Turcotte ◽  
Jeff Sekelsky
Keyword(s):  
Chromosome Segregation ◽  
Chromosome Pair ◽  
Double Strand Breaks ◽  
Current Understanding ◽  
Genetic Studies ◽  
Strand Breaks ◽  
Proper Number ◽  
Key Players ◽  
Meiotic Crossover ◽  
History Of

Proper number and placement of meiotic crossovers is vital to chromosome segregation, with failures in normal crossover distribution often resulting in aneuploidy and infertility. Meiotic crossovers are formed via homologous repair of programmed double-strand breaks (DSBs). Although DSBs occur throughout the genome, crossover placement is intricately patterned, as observed first in early genetic studies by Muller and Sturtevant. Three types of patterning events have been identified. Interference, first described by Sturtevant in 1915, is a phenomenon in which crossovers on the same chromosome do not occur near one another. Assurance, initially identified by Owen in 1949, describes the phenomenon in which a minimum of one crossover is formed per chromosome pair. Suppression, first observed by Beadle in 1932, dictates that crossovers do not occur in regions surrounding the centromere and telomeres. The mechanisms behind crossover patterning remain largely unknown, and key players appear to act at all scales, from the DNA level to inter-chromosome interactions. There is also considerable overlap between the known players that drive each patterning phenomenon. In this review we discuss the history of studies of crossover patterning, developments in methods used in the field, and our current understanding of the interplay between patterning phenomena.

scholarly journals Genomic rearrangements induced by unscheduled DNA double strand breaks in somatic mammalian cells

FEBS Journal ◽  
2017 ◽  
Vol 284 (15) ◽  
pp. 2324-2344 ◽  
Author(s):  
Ayeong So ◽  
Tangui Le Guen ◽  
Bernard S. Lopez ◽  
Josée Guirouilh-Barbat
Keyword(s):  
Mammalian Cells ◽  
Double Strand Breaks ◽  
Genomic Rearrangements ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

scholarly journals Evolutionary and Comparative Analysis of Bacterial Nonhomologous End Joining Repair

2020 ◽  
Vol 12 (12) ◽  
pp. 2450-2466
Author(s):  
Mohak Sharda ◽  
Anjana Badrinarayanan ◽  
Aswin Sai Narain Seshasayee
Keyword(s):  
Genome Stability ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Ancestral Reconstruction ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Domains Of Life ◽  
History Of ◽  
Two Kingdoms

Abstract DNA double-strand breaks (DSBs) are a threat to genome stability. In all domains of life, DSBs are faithfully fixed via homologous recombination. Recombination requires the presence of an uncut copy of duplex DNA which is used as a template for repair. Alternatively, in the absence of a template, cells utilize error-prone nonhomologous end joining (NHEJ). Although ubiquitously found in eukaryotes, NHEJ is not universally present in bacteria. It is unclear as to why many prokaryotes lack this pathway. Toward understanding what could have led to the current distribution of bacterial NHEJ, we carried out comparative genomics and phylogenetic analysis across ∼6,000 genomes. Our results show that this pathway is sporadically distributed across the phylogeny. Ancestral reconstruction further suggests that NHEJ was absent in the eubacterial ancestor and can be acquired via specific routes. Integrating NHEJ occurrence data for archaea, we also find evidence for extensive horizontal exchange of NHEJ genes between the two kingdoms as well as across bacterial clades. The pattern of occurrence in bacteria is consistent with correlated evolution of NHEJ with key genome characteristics of genome size and growth rate; NHEJ presence is associated with large genome sizes and/or slow growth rates, with the former being the dominant correlate. Given the central role these traits play in determining the ability to carry out recombination, it is possible that the evolutionary history of bacterial NHEJ may have been shaped by requirement for efficient DSB repair.

scholarly journals Selections that isolate recombinant mitochondrial genomes in animals

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Hansong Ma ◽  
Patrick H O'Farrell
Keyword(s):  
Mitochondrial Dna ◽  
Homologous Recombination ◽  
Mitochondrial Genome ◽  
Double Strand Breaks ◽  
Mitochondrial Genomes ◽  
Strand Breaks ◽  
Somatic Recombination ◽  
Functional Benefit ◽  
A Genome ◽  
Drosophila Yakuba

Homologous recombination is widespread and catalyzes evolution. Nonetheless, its existence in animal mitochondrial DNA is questioned. We designed selections for recombination between co-resident mitochondrial genomes in various heteroplasmic Drosophila lines. In four experimental settings, recombinant genomes became the sole or dominant genome in the progeny. Thus, selection uncovers occurrence of homologous recombination in Drosophila mtDNA and documents its functional benefit. Double-strand breaks enhanced recombination in the germline and revealed somatic recombination. When the recombination partner was a diverged Drosophila melanogaster genome or a genome from a different species such as Drosophila yakuba, sequencing revealed long continuous stretches of exchange. In addition, the distribution of sequence polymorphisms in recombinants allowed us to map a selected trait to a particular region in the Drosophila mitochondrial genome. Thus, recombination can be harnessed to dissect function and evolution of mitochondrial genome.

scholarly journals MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription–replication conflicts

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Emily Yun-Chia Chang ◽  
Shuhe Tsai ◽  
Maria J. Aristizabal ◽  
James P. Wells ◽  
Yan Coulombe ◽  
...  
Keyword(s):  
Dna Replication ◽  
Fanconi Anemia ◽  
Genome Instability ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Mrn Complex ◽  
Genome Wide ◽  
A Genome ◽  
Dna Replication Stress

Abstract Ectopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors including the MRE11-RAD50-NBS1 (MRN) complex. While MRN has been shown to promote R-loops at DNA double-strand breaks, we show that it suppresses R-loops and associated DNA damage at transcription–replication conflicts. This occurs through a non-nucleolytic function of MRE11 that is important for R-loop suppression by the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms at transcription–replication conflicts.

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