Genomics is a relatively new scientific discipline, having DNA sequencing as its core technology. As technology has improved the cost and scale of genome characterization over sequencing’s 40-year ...history, the scope of inquiry has commensurately broadened. Massively parallel sequencing has proven revolutionary, shifting the paradigm of genomics to address biological questions at a genome-wide scale. Sequencing now empowers clinical diagnostics and other aspects of medical care, including disease risk, therapeutic identification, and prenatal testing. This Review explores the current state of genomics in the massively parallel sequencing era.
Clonal Architecture of Secondary Acute Myeloid Leukemia Walter, Matthew J; Shen, Dong; Ding, Li ...
New England journal of medicine/The New England journal of medicine,
03/2012, Letnik:
366, Številka:
12
Journal Article
Recenzirano
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Whole-genome sequencing of samples from seven subjects with secondary acute myeloid leukemia identified somatic mutations. These data, together with genotype analysis of the antecedent ...myelodysplastic syndromes (MDS), revealed the clonal evolution of MDS and secondary AML.
The myelodysplastic syndromes, a heterogeneous group of diseases characterized by ineffective hematopoiesis, are the most common cause of acquired bone marrow failure in adults.
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Secondary acute myeloid leukemia (AML) develops in approximately one third of persons with myelodysplastic syndromes.
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Clinical discrimination between the myelodysplastic syndromes and secondary AML currently rests predominantly on cytomorphologic analysis, since patients with myelodysplastic syndromes have dysplastic hematopoiesis and a myeloblast count of less than 20%, whereas those with a myeloblast count of 20% or more have AML. Although considerable overlap exists between the spectrum of cytogenetic and molecular lesions seen in the two disorders, there . . .
Summary
Plants are multifaceted organisms that have evolved numerous solutions to the problem of establishing, growing and reproducing with limited resources. The intrinsic dimensionality of plant ...traits is the minimum number of independent axes of variation that adequately describes the functional variation among plants and is therefore a fundamental quantity in comparative plant ecology. Given the large number of functional traits that are measured on plants, the dimensionality of plant form and function is potentially vast.
A variety of linear and nonlinear methods were used to estimate the intrinsic dimensionality of three large trait data sets. The results of these analyses indicate that while the dimensionality of plant traits is generally larger than we have admitted in the past, it does not exceed six in the most comprehensive data set.
The dimensionality of plant form and function is a blessing, not a curse. The higher the intrinsic dimension of traits in an analysis, the more easily our models will be able to accurately discriminate species in trait space and therefore be able to predict species distributions and abundances. Recent analyses indicate that the ability to predict community composition increases rapidly with additional traits, but reaches a plateau after four to eight traits.
Synthesis. There appears to be a tractable upper limit to the dimensionality of plant traits. To optimize research efficiency for advancing our understanding of trait‐based community assembly, ecologists should minimize the number of traits while maximizing the number of dimensions, because including multiple correlated traits does not yield dividends and including more than eight traits leads to diminishing returns. It is recommended to measure traits from multiple organs whenever possible, especially leaf, stem, root and flowering traits, given their consistent performance in explaining community assembly across different ecosystems.
There appears to be a tractable upper limit to the dimensionality of plant traits. To optimize research efficiency for advancing our understanding of trait‐based community assembly, ecologists should minimise the number of traits while maximising the number of dimensions, because including multiple correlated traits does not yield dividends and including more than eight traits leads to diminishing returns. It is recommended to measure traits from multiple organs whenever possible, especially leaf, stem, root, and flowering traits, given their consistent performance in explaining community assembly across different ecosystems.
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform ...an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cancer is a disease driven by genetic variation and mutation. Exome sequencing can be utilized for discovering these variants and mutations across hundreds of tumors. Here we present an analysis ...tool, VarScan 2, for the detection of somatic mutations and copy number alterations (CNAs) in exome data from tumor-normal pairs. Unlike most current approaches, our algorithm reads data from both samples simultaneously; a heuristic and statistical algorithm detects sequence variants and classifies them by somatic status (germline, somatic, or LOH); while a comparison of normalized read depth delineates relative copy number changes. We apply these methods to the analysis of exome sequence data from 151 high-grade ovarian tumors characterized as part of the Cancer Genome Atlas (TCGA). We validated some 7790 somatic coding mutations, achieving 93% sensitivity and 85% precision for single nucleotide variant (SNV) detection. Exome-based CNA analysis identified 29 large-scale alterations and 619 focal events per tumor on average. As in our previous analysis of these data, we observed frequent amplification of oncogenes (e.g., CCNE1, MYC) and deletion of tumor suppressors (NF1, PTEN, and CDKN2A). We searched for additional recurrent focal CNAs using the correlation matrix diagonal segmentation (CMDS) algorithm, which identified 424 significant events affecting 582 genes. Taken together, our results demonstrate the robust performance of VarScan 2 for somatic mutation and CNA detection and shed new light on the landscape of genetic alterations in ovarian cancer.
Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum ...associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally ...induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.
Massively parallel sequencing technology and the associated rapidly decreasing sequencing costs have enabled systemic analyses of somatic mutations in large cohorts of cancer cases. Here we introduce ...a comprehensive mutational analysis pipeline that uses standardized sequence-based inputs along with multiple types of clinical data to establish correlations among mutation sites, affected genes and pathways, and to ultimately separate the commonly abundant passenger mutations from the truly significant events. In other words, we aim to determine the Mutational Significance in Cancer (MuSiC) for these large data sets. The integration of analytical operations in the MuSiC framework is widely applicable to a broad set of tumor types and offers the benefits of automation as well as standardization. Herein, we describe the computational structure and statistical underpinnings of the MuSiC pipeline and demonstrate its performance using 316 ovarian cancer samples from the TCGA ovarian cancer project. MuSiC correctly confirms many expected results, and identifies several potentially novel avenues for discovery.
Motivation: The sequencing of tumors and their matched normals is frequently used to study the genetic composition of cancer. Despite this fact, there remains a dearth of available software tools ...designed to compare sequences in pairs of samples and identify sites that are likely to be unique to one sample.
Results: In this article, we describe the mathematical basis of our SomaticSniper software for comparing tumor and normal pairs. We estimate its sensitivity and precision, and present several common sources of error resulting in miscalls.
Availability and implementation: Binaries are freely available for download at http://gmt.genome.wustl.edu/somatic-sniper/current/, implemented in C and supported on Linux and Mac OS X.
Contact:
delarson@wustl.edu; lding@wustl.edu
Supplementary information:
Supplementary data are available at Bioinformatics online.
A comparison of the genomic sequence of a tumor sample from a patient with acute myeloid leukemia (AML) and that of a normal skin sample from the same patient revealed an estimated 750 somatic ...mutations, of which 12 were in the coding sequences of genes and 52 were in conserved regions or regions with regulatory potential. Four mutations were found to be recurrent in AML, including mutations in
NRAS, NPM1, IDH1,
and a conserved region on chromosome 10.
A comparison of the genomic sequence of a tumor sample from a patient with acute myeloid leukemia (AML) and that of a normal skin sample from the same patient revealed an estimated 750 somatic mutations. Four mutations were found to be recurrent in AML.
Acute myeloid leukemia (AML) is a clonal hematopoietic disease caused by both inherited and acquired genetic alterations.
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Current AML classification and prognostic systems incorporate genetic information but are limited to known abnormalities that have previously been identified with the use of cytogenetics, array comparative genomic hybridization (CGH), gene-expression profiling, and the resequencing of candidate genes (see the Glossary).
The karyotyping of AML cells remains the most powerful predictor of the outcome in patients with AML and is routinely used by clinicians.
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As an adjunct to cytogenetic studies, small subcytogenetic amplifications and deletions can be identified with the use . . .
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