scholarly journals Unscrambling cancer genomes via integrated analysis of structural variation and copy number

2020 ◽  
Author(s):  
Charles Shale ◽  
Jonathan Baber ◽  
Daniel L. Cameron ◽  
Marie Wong ◽  
Mark J. Cowley ◽  
...  
Keyword(s):  
Copy Number ◽  
Structural Variation ◽  
Mobile Element ◽  
Integrated Analysis ◽  
Derivative Chromosome ◽  
Diverse Range ◽  
Structural Variant ◽  
Wide Range ◽  
Cancer Genomes ◽  
Intragenic Deletions

AbstractComplex somatic genomic rearrangement and copy number alterations (CNA) are hallmarks of nearly all cancers. Whilst whole genome sequencing (WGS) in principle allows comprehensive profiling of these events, biological and clinical interpretation remains challenging. We have developed LINX, a novel algorithm which allows interpretation of short-read paired-end WGS derived structural variant and CNA data by clustering raw structural variant calls into distinct events, predicting their impact on the local structure of the derivative chromosome, and annotating their functional impact on affected genes. Novel visualisations facilitate further investigation of complex genomic rearrangements. We show that LINX provides insights into a diverse range of structural variation events including single and double break-junction events, mobile element insertions, complex shattering and high amplification events. We demonstrate that LINX can reliably detect a wide range of pathogenic rearrangements including gene fusions, immunoglobulin enhancer rearrangements, intragenic deletions and duplications. Uniquely, LINX also predicts chained fusions which we demonstrate account for 13% of clinically relevant oncogenic fusions. LINX also reports a class of inactivation events we term homozygous disruptions which may be a driver mutation in up to 8.8% of tumors including frequently affecting PTEN, TP53 and RB1, and are likely missed by many standard WGS analysis pipelines.

scholarly journals GRIDSS, PURPLE, LINX: Unscrambling the tumor genome via integrated analysis of structural variation and copy number

2019 ◽  
Author(s):  
Daniel L. Cameron ◽  
Jonathan Baber ◽  
Charles Shale ◽  
Anthony T. Papenfuss ◽  
Jose Espejo Valle-Inclan ◽  
...  
Keyword(s):  
Copy Number ◽  
Variant Calling ◽  
Genomic Rearrangements ◽  
Whole Genome Sequencing Data ◽  
Integrated Analysis ◽  
Derivative Chromosome ◽  
Structural Variants ◽  
Sequencing Data ◽  
Structural Variant ◽  
Complex Events

AbstractWe have developed a novel, integrated and comprehensive purity, ploidy, structural variant and copy number somatic analysis toolkit for whole genome sequencing data of paired tumor/normal samples. We show that the combination of using GRIDSS for somatic structural variant calling and PURPLE for somatic copy number alteration calling allows highly sensitive, precise and consistent copy number and structural variant determination, as well as providing novel insights for short structural variants and regions of complex local topology. LINX, an interpretation tool, leverages the integrated structural variant and copy number calling to cluster individual structural variants into higher order events and chains them together to predict local derivative chromosome structure. LINX classifies and extensively annotates genomic rearrangements including simple and reciprocal breaks, LINE, viral and pseudogene insertions, and complex events such as chromothripsis. LINX also comprehensively calls genic fusions including chained fusions. Finally, our toolkit provides novel visualisation methods providing insight into complex genomic rearrangements.

scholarly journals GRIDSS2: comprehensive characterisation of somatic structural variation using single breakend variants and structural variant phasing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. Cameron ◽  
Jonathan Baber ◽  
Charles Shale ◽  
Jose Espejo Valle-Inclan ◽  
Nicolle Besselink ◽  
...  
Keyword(s):  
Copy Number ◽  
Structural Variation ◽  
False Negative ◽  
False Negative Rate ◽  
Structural Variants ◽  
Structural Variant ◽  
Complex Rearrangement ◽  
False Discovery ◽  
Copy Number Changes ◽  
Paired End Sequencing

AbstractGRIDSS2 is the first structural variant caller to explicitly report single breakends—breakpoints in which only one side can be unambiguously determined. By treating single breakends as a fundamental genomic rearrangement signal on par with breakpoints, GRIDSS2 can explain 47% of somatic centromere copy number changes using single breakends to non-centromere sequence. On a cohort of 3782 deeply sequenced metastatic cancers, GRIDSS2 achieves an unprecedented 3.1% false negative rate and 3.3% false discovery rate and identifies a novel 32–100 bp duplication signature. GRIDSS2 simplifies complex rearrangement interpretation through phasing of structural variants with 16% of somatic calls phasable using paired-end sequencing.

scholarly journals Patterns of structural variation in human cancer

2017 ◽  
Author(s):  
Yilong Li ◽  
Nicola D Roberts ◽  
Joachim Weischenfeldt ◽  
Jeremiah A Wala ◽  
Ofer Shapira ◽  
...  
Keyword(s):  
Size Distribution ◽  
Copy Number ◽  
Structural Variation ◽  
Human Cancer ◽  
Structural Variants ◽  
Oncogenic Potential ◽  
Cancer Genomes ◽  
Rearrangement Processes ◽  
Tandem Duplications ◽  
Mutational Process

ABSTRACTA key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments ranging in size from kilobases to whole chromosomes. We developed methods to group, classify and describe structural variants, applied to >2,500 cancer genomes. Nine signatures of structural variation emerged. Deletions have trimodal size distribution; assort unevenly across tumour types and patients; enrich in late-replicating regions; and correlate with inversions. Tandem duplications also have trimodal size distribution, but enrich in early-replicating regions, as do unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy number gains and frequent inverted rearrangements. One prominent structure consists of 1-7 templates copied from distinct regions of the genome strung together within one locus. Such ‘cycles of templated insertions’ correlate with tandem duplications, frequently activating the telomerase gene, TERT, in liver cancer. Cancers access many rearrangement processes, flexibly sculpting the genome to maximise oncogenic potential.

scholarly journals Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Science ◽  
2021 ◽  
Vol 372 (6537) ◽  
pp. eabf7117 ◽  
Author(s):  
Peter Ebert ◽  
Peter A. Audano ◽  
Qihui Zhu ◽  
Bernardo Rodriguez-Martin ◽  
David Porubsky ◽  
...  
Keyword(s):  
Structural Variation ◽  
De Novo ◽  
Mobile Element ◽  
Integrated Analysis ◽  
Base Pairs ◽  
Adaptive Selection ◽  
Short Read Sequencing ◽  
Sequencing Technologies ◽  
Human Genomes ◽  
Long Read

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.

scholarly journals De novo assembly of 64 haplotype-resolved human genomes of diverse ancestry and integrated analysis of structural variation

2020 ◽  
Author(s):  
Peter Ebert ◽  
Peter A. Audano ◽  
Qihui Zhu ◽  
Bernardo Rodriguez-Martin ◽  
David Porubsky ◽  
...  
Keyword(s):  
Structural Variation ◽  
De Novo ◽  
Mobile Element ◽  
Integrated Analysis ◽  
Adaptive Selection ◽  
Short Read Sequencing ◽  
Sequencing Technologies ◽  
Histocompatibility Complex ◽  
Human Genomes ◽  
Long Read

AbstractLong-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent–child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average contig N50: 26 Mbp) integrate all forms of genetic variation across even complex loci such as the major histocompatibility complex. We focus on 107,590 structural variants (SVs), of which 68% are inaccessible by short-read sequencing. We identify new SV hotspots (spanning megabases of gene-rich sequence), characterize 130 of the most active mobile element source elements, and find that 63% of all SVs arise by homology-mediated mechanisms—a twofold increase from previous studies. Our resource now enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1,525 expression quantitative trait loci (SV-eQTLs) as well as SV candidates for adaptive selection within the human population.

Nine Centuries of Man

2017 ◽  
Keyword(s):  
Twentieth Century ◽  
Diverse Range ◽  
Gender Expectations ◽  
Court Records ◽  
The Past ◽  
Wide Range ◽  
Police Reports ◽  
Late Twentieth ◽  
Scottish History ◽  
Late Twentieth Century

What did it mean to be a man in Scotland over the past nine centuries? Scotland, with its stereotypes of the kilted warrior and the industrial ‘hard man’, has long been characterised in masculine terms, but there has been little historical exploration of masculinity in a wider context. This interdisciplinary collection examines a diverse range of the multiple and changing forms of masculinities from the late eleventh to the late twentieth century, exploring the ways in which Scottish society through the ages defined expectations for men and their behaviour. How men reacted to those expectations is examined through sources such as documentary materials, medieval seals, romances, poetry, begging letters, police reports and court records, charity records, oral histories and personal correspondence. Focusing upon the wide range of activities and roles undertaken by men – work, fatherhood and play, violence and war, sex and commerce – the book also illustrates the range of masculinities that affected or were internalised by men. Together, the chapters illustrate some of the ways Scotland’s gender expectations have changed over the centuries and how, more generally, masculinities have informed the path of Scottish history

Diversity and Integration in Private International Law

2019 ◽  
Keyword(s):  
South America ◽  
International Law ◽  
Value Systems ◽  
Private International Law ◽  
Diverse Range ◽  
Cross Border ◽  
Wide Range ◽  
Depth Analysis ◽  
And Shifts ◽  
Substantive Law

This book opens a cross-regional dialogue and shifts the Eurocentric discussion on diversity and integration to a more inclusive engagement with South America in private international law issues. It promotes a contemporary vision of private international law as a discipline enabling legal interconnectivity, with the potential to transcend its disciplinary boundaries to further promote the reality of cross-border integration, with its focus on the ever-increasing cross-border mobility of individuals. Private international law embraces legal diversity and pluralism. Different legal traditions continue to meet, interact and integrate in different forms, at the national, regional and international levels. Different systems of substantive law couple with divergent systems of private international law (designed to accommodate the former in cross-border situations). This complex legal landscape impacts individuals and families in cross-border scenarios, and international commerce broadly conceived. Private international law methodologies and techniques offer means for the coordination of this constellation of legal orders and value systems in cross-border situations. Bringing together world-renowned academics and experienced private international lawyers from a wide range of jurisdictions in Europe and South America, this edited collection focuses on the connective capabilities of private international law in bridging and balancing legal diversity as a corollary for the development of integration. The book provides in-depth analysis of the role of private international law in dealing with legal diversity across a diverse range of topics and jurisdictions.

Understanding Schizophrenia: Genetic Causes and Treatment

2019 ◽  
Vol 1 (1) ◽  
pp. 6-12
Author(s):  
Fatima Javeria ◽  
Shazma Altaf ◽  
Alishah Zair ◽  
Rana Khalid Iqbal
Keyword(s):  
Copy Number ◽  
Drug Targets ◽  
Disease Risk ◽  
Mental Disease ◽  
Copy Number Variants ◽  
Aminobutyric Acid ◽  
Epigenetic Mechanisms ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

Cultural Accommodation of Internet-Based Interventions for Substance Use and Related Disorders: A Proposed Comprehensive Framework (Preprint)

2019 ◽  
Author(s):  
Keren Gueta ◽  
Yossi Harel-Fisch ◽  
Sophie D. Walsh
Keyword(s):  
Substance Use ◽  
Ecological Validity ◽  
Limited Attention ◽  
Diverse Range ◽  
Four Dimensions ◽  
Service Engagement ◽  
Wide Range ◽  
Cultural Accommodation ◽  
Abuse Treatment ◽  
Comprehensive Framework

BACKGROUND Despite the low utilization rates of substance use and related disorders services, and the ability of internet-based interventions for substance use and related disorders (IBIS) to address challenges related to service engagement, limited attention has been placed on the processes for the accommodation of these interventions to diverse cultural settings. OBJECTIVE The purpose of this study was to develop a conceptual framework for the cultural accommodation of IBIS across populations, settings, and countries. METHODS A pilot study of cultural accommodation of an existing internet intervention for alcohol use (Down Your Drink (DYD)), focus groups and daily online surveys of prospective consumers (N=24) and interviews with experts (N=7) in the substance abuse treatment field were conducted. RESULTS Thematic analysis revealed a wide range of themes identified as needing to be addressed in the process of DYD accommodation. It also emphasized that accommodation needs to incorporate both technical and contents themes, shaped by both the general Israeli cultural as well as by the specific Israeli drinking subculture. A combined mixed emic–etic theoretical approach incorporating the pilot findings together with a scoping literature review was employed to develop a framework for cultural accommodation of IBIS. A comprehensive framework for cultural accommodation of IBIS is introduced consisting of five chronological stages of IBIS accommodation and four dimensions of accommodation. CONCLUSIONS The proposed framework can serve as a guide for the cultural accommodation of existing IBIS across a diverse range of cultural and geographical settings thus augmenting the ecological validity of IBIS and reducing health disparities worldwide.

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