scholarly journals Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 342
Author(s):  
Laura J. Jilderda ◽  
Lin Zhou ◽  
Floris Foijer
Keyword(s):  
Cancer Cells ◽  
Chromosomal Instability ◽  
Large Scale ◽  
Small Scale ◽  
Genetic Screens ◽  
Driver Genes ◽  
Cancer Driver ◽  
The Past ◽  
Cancer Models ◽  
Genome Wide

Chromosomal instability is the process of mis-segregation for ongoing chromosomes, which leads to cells with an abnormal number of chromosomes, also known as an aneuploid state. Induced aneuploidy is detrimental during development and in primary cells but aneuploidy is also a hallmark of cancer cells. It is therefore believed that premalignant cells need to overcome aneuploidy-imposed stresses to become tumorigenic. Over the past decade, some aneuploidy-tolerating pathways have been identified through small-scale screens, which suggest that aneuploidy tolerance pathways can potentially be therapeutically exploited. However, to better understand the processes that lead to aneuploidy tolerance in cancer cells, large-scale and unbiased genetic screens are needed, both in euploid and aneuploid cancer models. In this review, we describe some of the currently known aneuploidy-tolerating hits, how large-scale genome-wide screens can broaden our knowledge on aneuploidy specific cancer driver genes, and how we can exploit the outcomes of these screens to improve future cancer therapy.

scholarly journals Unsupervised correction of gene-independent cell responses to CRISPR-Cas9 targeting

2017 ◽  
Author(s):  
Francesco Iorio ◽  
Fiona M Behan ◽  
Emanuel Gonçalves ◽  
Shriram G Bhosle ◽  
Elisabeth Chen ◽  
...  
Keyword(s):  
Copy Number ◽  
Large Scale ◽  
False Positive Rate ◽  
Essential Genes ◽  
Driver Genes ◽  
Cancer Driver ◽  
Guide Rna ◽  
Genome Wide ◽  
Positive Rate ◽  
Downstream Analysis

AbstractBackground: Genome editing by CRISPR-Cas9 technology allows large-scale screening of gene essentiality in cancer. A confounding factor when interpreting CRISPR-Cas9 screens is the high false-positive rate in detecting essential genes within copy number amplified regions of the genome. We have developed the computational tool CRISPRcleanR which is capable of identifying and correcting gene-independent responses to CRISPR-Cas9 targeting. CRISPRcleanR uses an unsupervised approach based on the segmentation of single-guide RNA fold change values across the genome, without making any assumption about the copy number status of the targeted genes.Results Applying our method to existing and newly generated genome-wide essentiality profiles from 15 cancer cell lines, we demonstrate that CRISPRcleanR reduces false positives when calling essential genes, correcting biases within and outside of amplified regions, while maintaining true positive rates. Established cancer dependencies and essentiality signals of amplified cancer driver genes are detectable post-correction. CRISPRcleanR reports sgRNA fold changes and normalised read counts, is therefore compatible with downstream analysis tools, and works with multiple sgRNA libraries.Conclusions CRISPRcleanR is a versatile open-source tool for the analysis of CRISPR-Cas9 knockout screens to identify essential genes.

scholarly journals A systems genomics approach to uncover the molecular properties of cancer genes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Felix Grassmann ◽  
Yudi Pawitan ◽  
Kamila Czene
Keyword(s):  
Cancer Survival ◽  
Association Studies ◽  
Gc Content ◽  
Molecular Properties ◽  
Molecular Profile ◽  
Genome Wide Association Studies ◽  
Cancer Genes ◽  
Driver Genes ◽  
Cancer Driver ◽  
Genome Wide

Abstract Genes involved in cancer are under constant evolutionary pressure, potentially resulting in diverse molecular properties. In this study, we explore 23 omic features from publicly available databases to define the molecular profile of different classes of cancer genes. Cancer genes were grouped according to mutational landscape (germline and somatically mutated genes), role in cancer initiation (cancer driver genes) or cancer survival (survival genes), as well as being implicated by genome-wide association studies (GWAS genes). For each gene, we also computed feature scores based on all omic features, effectively summarizing how closely a gene resembles cancer genes of the respective class. In general, cancer genes are longer, have a lower GC content, have more isoforms with shorter exons, are expressed in more tissues and have more transcription factor binding sites than non-cancer genes. We found that germline genes more closely resemble single tissue GWAS genes while somatic genes are more similar to pleiotropic cancer GWAS genes. As a proof-of-principle, we utilized aggregated feature scores to prioritize genes in breast cancer GWAS loci and found that top ranking genes were enriched in cancer related pathways. In conclusion, we have identified multiple omic features associated with different classes of cancer genes, which can assist prioritization of genes in cancer gene discovery.

Comparison of 200 Liter and 40 Milliliter Leach Tests

1982 ◽  
Vol 15 ◽  
Author(s):  
J. H. Westsik ◽  
C. O. Harvey ◽  
F. P. Roberts ◽  
W. A. Ross ◽  
R. E. Thornhill
Keyword(s):  
Large Scale ◽  
Deionized Water ◽  
Waste Form ◽  
Small Scale ◽  
Matrix Elements ◽  
Elemental Concentrations ◽  
The Past ◽  
Leach Test ◽  
The Matrix ◽  
Scale Test

ABSTRACTDuring the past year we have conducted a modified MCC-1 leach test on a 145 kg block of a cast cement waste form. The leach vessel was a 200 liter Teflon®-lined drum and contained 97.5 liters of deionized water. The results of this large-scale leach test were compared with the results of standard MCC-1 tests (40 ml) on smaller samples of the same waste form. The ratio of leachate volumes between the large and small scale tests was 2500 and the ratio of sample masses was 150,000. The cast cement samples for both tests contained plutonium-doped incinerator ash.The leachates from these tests were analyzed for both plutonium and the matrix elements. Evaluation of plutonium plateout in the large-scale test indicated that the majority of the plutonium leached from the samples deposits onto vessel walls and little (<3 × 10−12M) remains in solution. Comparison of elemental concentrations in the leachates indicates some differences up to 5X in the concentration in the large- and small-scale tests. The differences are attributed to differences in the solubilities of Ca, Si, and Fe at pH ˜11.5 and at pH ˜12.5. The higher pH observed for the large-scale test is a result of the larger quantities of sodium in the large block of cement.

scholarly journals N-Ethyl-N-Nitrosourea Mutagenesis: Boarding the Mouse Mutant Express

2005 ◽  
Vol 69 (3) ◽  
pp. 426-439 ◽  
Author(s):  
Sabine P. Cordes
Keyword(s):  
Genetic Mapping ◽  
Large Scale ◽  
Random Mutagenesis ◽  
Small Scale ◽  
Mouse Mutant ◽  
Genetic Screens ◽  
Screen Design ◽  
Mouse Mutants ◽  
Balancer Chromosomes ◽  
Forward Mutagenesis

SUMMARY In the mouse, random mutagenesis with N-ethyl-N-nitrosourea (ENU) has been used since the 1970s in forward mutagenesis screens. However, only in the last decade has ENU mutagenesis been harnessed to generate a myriad of new mouse mutations in large-scale genetic screens and focused, smaller efforts. The development of additional genetic tools, such as balancer chromosomes, refinements in genetic mapping strategies, and evolution of specialized assays, has allowed these screens to achieve new levels of sophistication. The impressive productivity of these screens has led to a deluge of mouse mutants that wait to be harnessed. Here the basic large- and small-scale strategies are described, as are the basics of screen design. Finally, and importantly, this review describes the mechanisms by which such mutants may be accessed now and in the future. Thus, this review should serve both as an overview of the power of forward mutagenesis in the mouse and as a resource for those interested in developing their own screens, adding onto existing efforts, or obtaining specific mouse mutants that have already been generated.

Experience and Plans for Rationalization of Small-Scale Fisheries in India

1973 ◽  
Vol 30 (12) ◽  
pp. 2172-2177
Author(s):  
P. C. George
Keyword(s):  
Large Scale ◽  
Training Programs ◽  
Pilot Scale ◽  
Small Scale ◽  
Fishing Industry ◽  
Small Scale Fisheries ◽  
The Past ◽  
The World ◽  
Fishing Capacity ◽  
Small Craft

Small-scale fisheries have traditionally been the backbone of the fishing industry all over the world. Although large-scale mechanized fishing has come into the limelight recently, even such countries as have developed substantial capability in this direction still have a large fleet of small boats in coastal areas. The landings of this sector of the industry are always substantial, and in many countries they still dominate the picture. In India, small-scale fisheries landed almost 1.15 million tons in 1971. This figure has been increasing as motor-powered small craft have increased in numbers, although 70% of marine fish is still caught from nonpowered boats. Measures taken to increase fishing capacity, landings, and net fishermen’s income over the past 10 years include various kinds of loans and subsidies for the purchase of boats, motors, and nets; assistance for the construction of ponds in inland areas; organization of cooperatives; training programs for fishermen and supporting personnel, especially motor repairmen (with the cooperation of Norway); and gear and vessel research including pilot-scale demonstrations with new types of vessels and equipment.

scholarly journals Tenacity in Performance of Small and Mid-cap Mutual Funds in Indian Scenario- In support to Investors Decision

2020 ◽  
Vol 9 (1) ◽  
pp. 1088-1091
Keyword(s):  
Decision Making ◽  
Comparative Analysis ◽  
Mutual Funds ◽  
Crucial Role ◽  
Large Scale ◽  
Small Scale ◽  
The Past ◽  
Market Risks ◽  
Support Decision Making ◽  
Indian Scenario

Mutual funds play a crucial role in financial sector for small-scale and large-scale investors. Within the Indian scenario, there is a need to define criteria to guide the investors in selection between small-caps and mid-caps mutual funds. Although small-caps provide there is always a question of higher market risks compared to mid-caps. So, the work emphasizes on analysis performances of Small caps in comparison with mid-caps that would certainly support decision-making. In the present work a comprehensive assessment of existing mutual funds that involves small and mid-cap with respect to Indian scenario is presented and their performance in the market for the past ten years is analyzed. The study analyses the fund’s performance by considering parameters like market risk, momentum, expenses, size and value. The persistence and decision-making of the investor are discussed with respect to the small and mid-cap funds. In this regard, we have considered the best and worst-performing small and mid-cap funds according to their returns in a overall span of more than 3 years. A comparative analysis between the decision making parameters that are performing and underperforming during this period are considered. In this study, small-caps funds like HDFC small-cap fund, Kotak, DSP small Cap fund and Franklin India Small MF and in parallel, mid-cap funds including Kota Emerging equity, DSP Midcap and Axis Midcap and Franklin India are considered

scholarly journals Architecting a distributed bioinformatics platform with iRODS and iPlant Agave API

2015 ◽  
Author(s):  
Liya Wang ◽  
Peter Van Buren ◽  
Doreen Ware
Keyword(s):  
Large Scale ◽  
Genome Wide Association Study ◽  
Data Transfer ◽  
Genomic Analysis ◽  
The Past ◽  
Large Scale Data ◽  
Genome Wide ◽  
A Genome ◽  
Bioinformatics Workflow ◽  
Scale Data

Over the past few years, cloud-based platforms have been proposed to address storage, management, and computation of large-scale data, especially in the field of genomics. However, for collaboration efforts involving multiple institutes, data transfer and management, interoperability and standardization among different platforms have imposed new challenges. This paper proposes a distributed bioinformatics platform that can leverage local clusters with remote computational clusters for genomic analysis using the unified bioinformatics workflow. The platform is built with a data server configured with iRODS, a computation cluster authenticated with iPlant Agave system, and web server to interact with the platform. A Genome-Wide Association Study workflow is integrated to validate the feasibility of the proposed approach.

scholarly journals Efficient strategies for screening large-scale genetic interaction networks

2017 ◽  
Author(s):  
Raamesh Deshpande ◽  
Justin Nelson ◽  
Scott W. Simpkins ◽  
Michael Costanzo ◽  
Jeff S. Piotrowski ◽  
...  
Keyword(s):  
Large Scale ◽  
Optimal Algorithm ◽  
Genetic Interaction ◽  
Genetic Screens ◽  
Chemical Genetic ◽  
Genome Wide ◽  
Powerful Approach ◽  
Interaction Screening ◽  
Genetic Interaction Data

Large-scale genetic interaction screening is a powerful approach for unbiased characterization of gene function and understanding systems-level cellular organization. While genome-wide screens are desirable as they provide the most comprehensive interaction profiles, they are resource and time-intensive and sometimes infeasible, depending on the species and experimental platform. For these scenarios, optimal methods for more efficient screening while still producing the maximal amount of information from the resulting profiles are of interest.To address this problem, we developed an optimal algorithm, called COMPRESS-GI, which selects a small but informative set of genes that captures most of the functional information contained within genome-wide genetic interaction profiles. The utility of this algorithm is demonstrated through an application of the approach to define a diagnostic mutant set for large-scale chemical genetic screens, where more than 13,000 compound screens were achieved through the increased throughput enabled by the approach. COMPRESS-GI can be broadly applied for directing genetic interaction screens in other contexts, including in species with little or no prior genetic-interaction data.

scholarly journals Recessive effects in cancer predisposition exposed by genome-wide and proteome-wide association studies

2020 ◽  
Author(s):  
Nadav Brandes ◽  
Nathan Linial ◽  
Michal Linial
Keyword(s):  
Cancer Risk ◽  
Large Scale ◽  
Association Studies ◽  
Cancer Predisposition ◽  
Small Scale ◽  
Cancer Type ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Cancer Types ◽  
Genomic Regions

AbstractThe characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Current attempts to detect cancer predisposition genomic regions are typically based on small-scale familial studies or genome-wide association studies (GWAS) over dedicated case-control cohorts. In this study, we utilized the UK Biobank as a large-scale prospective cohort to conduct a comprehensive analysis of cancer predisposition using both GWAS and proteome-wide association study (PWAS), a method that highlights genetic associations mediated by functional alterations to protein-coding genes. We discovered 137 unique genomic loci implicated with cancer risk in the white British population across nine cancer types and pan-cancer. While most of these genomic regions are supported by external evidence, our results highlight novel loci as well. We performed a comparative analysis of cancer predisposition between cancer types, finding that most of the implicated regions are cancer-type specific. We further analyzed the role of recessive genetic effects in cancer predisposition. We found that 30 of the 137 cancer regions were recovered only by a recessive model, highlighting the importance of recessive inheritance outside of familial studies. Finally, we show that many of the cancer associations exert substantial cancer risk in the studied cohort, suggesting their clinical relevance.

scholarly journals ATAC-seq identifies thousands of extrachromosomal circular DNA in cancer and cell lines

2020 ◽  
Vol 6 (20) ◽  
pp. eaba2489 ◽  
Author(s):  
Pankaj Kumar ◽  
Shashi Kiran ◽  
Shekhar Saha ◽  
Zhangli Su ◽  
Teressa Paulsen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Inverse Pcr ◽  
Driver Genes ◽  
Circular Dna ◽  
Cancer Driver ◽  
Genome Wide ◽  
Number Variation ◽  
Circular Dnas ◽  
Tumor Types ◽  
Pan Cancer

Extrachromosomal circular DNAs (eccDNAs) are somatically mosaic and contribute to intercellular heterogeneity in normal and tumor cells. Because short eccDNAs are poorly chromatinized, we hypothesized that they are sequenced by tagmentation in ATAC-seq experiments without any enrichment of circular DNA. Indeed, ATAC-seq identified thousands of eccDNAs in cell lines that were validated by inverse PCR and by metaphase FISH. ATAC-seq in gliomas and glioblastomas identify hundreds of eccDNAs, including one containing the well-known EGFR gene amplicon from chr7. More than 18,000 eccDNAs, many carrying known cancer driver genes, are identified in a pan-cancer analysis of ATAC-seq libraries from 23 tumor types. Somatically mosaic eccDNAs are identified by ATAC-seq even before amplification is recognized by genome-wide copy number variation measurements. Thus, ATAC-seq is a sensitive method to detect eccDNA present in a tumor at the pre-amplification stage and can be used to predict resistance to therapy.

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