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Genome Research

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https://www.readbyqxmd.com/read/28720581/hit-ndrive-patient-specific-multi-driver-gene-prioritization-for-precision-oncology
#1
Raunak Shrestha, Ermin Hodzic, Thomas Sauerwald, Phuong Dao, Kendric Wang, Jake Yeung, Shawn Anderson, Fabio Vandin, Gholamreza Haffari, Colin C Collins, Cenk Sahinalp
Prioritizing molecular alterations that act as drivers of cancer remains a crucial bottleneck in therapeutic development. Here we introduce HIT'nDRIVE, a computational method that integrates genomic and transcriptomic data to identify a set of patient-specific, sequence-altered genes, with sufficient collective influence over dysregulated transcripts. HIT'nDRIVE aims to solve the "random walk facility location" (RWFL) problem in a gene (or protein) interaction network, which differs from the standard facility location problem by its use of an alternative distance measure: "multi-hitting time", the expected length of the shortest random walk from any one of the set of sequence-altered genes to an expression-altered target gene...
July 18, 2017: Genome Research
https://www.readbyqxmd.com/read/28720580/detecting-ancient-positive-selection-in-humans-using-extended-lineage-sorting
#2
Séphane Peyégne, Michael James Boyle, Michael Dannemann, Kay Prüfer
Natural selection that affected modern humans early in their evolution has likely shaped some of the traits that set present-day humans apart from their closest extinct and living relatives. The ability to detect ancient natural selection in the human genome could provide insights into the molecular basis for these human-specific traits. Here, we introduce a method for detecting ancient selective sweeps by scanning for extended genomic regions where our closest extinct relatives, Neandertals and Denisovans, fall outside of the present-day human variation...
July 18, 2017: Genome Research
https://www.readbyqxmd.com/read/28720579/recruitment-of-histone-modifications-to-assist-mrna-dosage-maintenance-after-degeneration-of-cytosine-dna-methylation-during-animal-evolution
#3
Andrew Yf Chang, Ben-Yang Liao
Following gene duplication, mRNA expression of the duplicated gene is reduced to maintain mRNA dosage. In mammals, this process is achieved with increased cytosine DNA methylation of the promoters of duplicated genes to suppress transcriptional initiation. However, not all animal species possess a full apparatus for cytosine DNA methylation. For such species such as roundworm (Caenorhabditis elegans, "worm" hereafter) or fruit fly (Drosophila melanogaster, "fly" hereafter), it is unclear how reduced expression of duplicated genes has been achieved evolutionarily...
July 18, 2017: Genome Research
https://www.readbyqxmd.com/read/28720578/systematic-longitudinal-survey-of-invasive-escherichia-coli-in-england-demonstrates-a-stable-population-structure-only-transiently-disturbed-by-the-emergence-of-st131
#4
Teemu Kallonen, Hayley J Brodrick, Simon R Harris, Jukka Corander, Nicholas M Brown, Veronique Martin, Sharon J Peacock, Julian Parkhill
Escherichia coli associated with urinary tract infections and bacteremia has been intensively investigated, including recent work focusing on the virulent, globally disseminated, multidrug-resistant lineage ST131. To contextualize ST131 within the broader E. coli population associated with disease, we used genomics to analyze a systematic 11-yr hospital-based survey of E. coli associated with bacteremia using isolates collected from across England by the British Society for Antimicrobial Chemotherapy and from the Cambridge University Hospitals NHS Foundation Trust...
July 18, 2017: Genome Research
https://www.readbyqxmd.com/read/28687705/annotation-and-cluster-analysis-of-spatiotemporal-and-sex-related-lncrna-expression-in-rhesus-macaque-brain
#5
Siling Liu, Zhengbo Wang, Dong Chen, Bowen Zhang, Renrong Tian, Jing Wu, Ying Zhang, Kaiyu Xu, Liumeng Yang, Chao Cheng, Jian Ma, Longbao Lv, Yongtang Zheng, Xintian Hu, Yi Zhang, Xiangting Wang, Jiali Li
Long noncoding RNA (lncRNA)-mediated epigenetic regulation plays important roles in wide range of biological processes and diseases. Here, we applied comprehensive analyses of RNA-seq and CAGE-seq (cap analysis of gene expression and sequencing) to characterize the dynamic changes in lncRNA expression in rhesus macaque brain in four age groups from postnatal to aged periods. We identified 18 anatomically diverse lncRNA modules and 14 mRNA modules representing spatial, age and sex specificities. Spatiotemporal- and sex-biased changes in lncRNA expression are in general higher than that observed in mRNA expression...
July 7, 2017: Genome Research
https://www.readbyqxmd.com/read/28684555/statistically-robust-methylation-calling-for-whole-transcriptome-bisulfite-sequencing-reveals-distinct-methylation-patterns-for-mouse-rnas
#6
Carine Legrand, Francesca Tuorto, Mark Hartmann, Reinhard Liebers, Dominik Jacob, Mark Helm, Frank Lyko
(Cytosine-5) RNA methylation plays an important role in several biologically and pathologically relevant processes. However, owing to methodological limitations, the transcriptome-wide distribution of this mark has remained largely unknown. We previously established RNA bisulfite sequencing as a method for the analysis of RNA (cytosine-5) methylation patterns at single-base resolution. More recently, next-generation sequencing has provided opportunities to establish transcriptome-wide maps of this modification...
July 6, 2017: Genome Research
https://www.readbyqxmd.com/read/28684554/trans-splicing-enhances-translational-efficiency-in-c-elegans
#7
Yu-Fei Yang, Xiaoqing Zhang, Xuehua Ma, Taolan Zhao, Qiushi Sun, Qing Huan, Shaohuan Wu, Zhuo Du, Wenfeng Qian
Translational efficiency is subject to extensive regulation. However, the factors influencing such regulation are poorly understood. In Caenorhabditis elegans, ~62% genes are trans-spliced to a specific spliced leader (SL1), which replaces part of the native 5' untranslated region (5' UTR). Given the pivotal role 5' UTR plays in the regulation of translational efficiency, we hypothesized that SL1 trans-splicing functions to regulate translational efficiency. With genome-wide analysis on Ribo-seq data, polysome profiling experiments, and CRISPR-Cas9-based genetic manipulation of trans-splicing sites, we found four lines of evidence in support of this hypothesis...
July 6, 2017: Genome Research
https://www.readbyqxmd.com/read/28679620/integrated-single-cell-genetic-and-transcriptional-analysis-suggests-novel-drivers-of-chronic-lymphocytic-leukemia
#8
Lili Wang, Jean Fan, Joshua M Francis, George Georghiou, Sarah Hergert, Shuqiang Li, Rutendo Gambe, Chensheng W Zhou, Chunxiao Yang, Sheng Xiao, Paola Dal Cin, Michaela Bowden, Dylan Kotliar, Sachet A Shukla, Jennifer R Brown, Donna Neuberg, Dario R Alessi, Cheng-Zhong Zhang, Peter V Kharchenko, Kenneth J Livak, Catherine J Wu
Intra-tumoral genetic heterogeneity has been characterized across cancers by genome sequencing of bulk tumors, including chronic lymphocytic leukemia (CLL). In order to more accurately identify subclones, define phylogenetic relationships, and probe genotype-phenotype relationships, we developed methods for targeted mutation detection in DNA and RNA isolated from thousands of single cells from five CLL samples. By clearly resolving phylogenic relationships, we uncovered mutated LCP1 and WNK1 as novel CLL drivers, supported by functional evidence demonstrating their impact on CLL pathways...
July 5, 2017: Genome Research
https://www.readbyqxmd.com/read/28630177/integrated-genome-and-transcriptome-sequencing-identifies-a-noncoding-mutation-in-the-genome-replication-factor-donson-as-the-cause-of-microcephaly-micromelia-syndrome
#9
Gilad D Evrony, Dwight R Cordero, Jun Shen, Jennifer N Partlow, Timothy W Yu, Rachel E Rodin, R Sean Hill, Michael E Coulter, Anh-Thu N Lam, Divya Jayaraman, Dianne Gerrelli, Diana G Diaz, Chloe Santos, Victoria Morrison, Antonella Galli, Ulrich Tschulena, Stefan Wiemann, M Jocelyne Martel, Betty Spooner, Steven C Ryu, Princess C Elhosary, Jillian M Richardson, Danielle Tierney, Christopher A Robinson, Rajni Chibbar, Dana Diudea, Rebecca Folkerth, Sheldon Wiebe, A James Barkovich, Ganeshwaran H Mochida, James Irvine, Edmond G Lemire, Patricia Blakley, Christopher A Walsh
While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS)...
June 19, 2017: Genome Research
https://www.readbyqxmd.com/read/28619849/the-house-fly-y-chromosome-is-young-and-minimally-differentiated-from-its-ancient-x-chromosome-partner
#10
Richard P Meisel, Christopher A Gonzales, Hoang Luu
Canonical ancient sex chromosome pairs consist of a gene rich X (or Z) chromosome and a male- (or female-) limited Y (or W) chromosome that is gene poor. In contrast to highly differentiated sex chromosomes, nascent sex chromosome pairs are homomorphic or very similar in sequence content. Nascent sex chromosomes can arise if an existing sex chromosome fuses to an autosome or an autosome acquires a new sex-determining locus/allele. Sex chromosomes often differ between closely related species and can even be polymorphic within species, suggesting that nascent sex chromosomes arise frequently over the course of evolution...
June 15, 2017: Genome Research
https://www.readbyqxmd.com/read/28596291/ddx54-regulates-transcriptome-dynamics-during-dna-damage-response
#11
Miha Milek, Koshi Imami, Neelanjan Mukherjee, Francesca De Bortoli, Ulrike Zinnall, Orsalia Hazapis, Christian Trahan, Marlene Oeffinger, Florian Heyd, Uwe Ohler, Matthias Selbach, Markus Landthaler
The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of posttranscriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins including many nucleolar proteins showed increased binding to poly(A) RNA in IR-exposed cells...
June 8, 2017: Genome Research
https://www.readbyqxmd.com/read/28596290/yeast-genetic-interaction-screen-of-human-genes-associated-with-amyotrophic-lateral-sclerosis-identification-of-map2k5-kinase-as-a-potential-drug-target
#12
Myungjin Jo, Ah Young Chung, Nozomu Yachie, Minchul Seo, Hyejin Jeon, Youngpyo Nam, Yeojin Seo, Eunmi Kim, Quan Zhong, Marc Vidal, Hae Chul Park, Frederick Roth, Kyoungho Suk
To understand disease mechanisms, a large-scale analysis of human-yeast genetic interactions was performed. Of 1,305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human-yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4,653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing of yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin (OPTN) and angiogenin (ANG), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport...
June 8, 2017: Genome Research
https://www.readbyqxmd.com/read/28546418/single-cell-dna-sequencing-reveals-a-late-dissemination-model-in-metastatic-colorectal-cancer
#13
Marco L Leung, Alexander Davis, Ruli Gao, Anna Casasent, Yong Wang, Emi Sei, Eduardo Sanchez, Dipen Maru, Scott Kopetz, Nicholas E Navin
Metastasis is a complex biological process that has been difficult to delineate in human colorectal (CRC) cancer patients. A major obstacle in understanding metastatic lineages is the extensive intratumor heterogeneity at the primary and metastatic tumor sites. To address this problem, we developed a highly-multiplexed single cell DNA sequencing approach to trace the metastatic lineages of two CRC patients with matched liver metastases. Single cell copy number or mutational profiling was performed, in addition to bulk exome and targeted deep-sequencing...
May 25, 2017: Genome Research
https://www.readbyqxmd.com/read/28522613/dehydration-stress-extends-mrna-3-untranslated-regions-with-noncoding-rna-functions-in-arabidopsis
#14
Hai-Xi Sun, Yan Li, Qi-Wen Niu, Nam-Hai Chua
The 3' untranslated regions (3' UTRs) of mRNAs play important roles in the regulation of mRNA localization, translation and stability. Alternative cleavage and polyadenylation (APA) generates mRNAs with different 3' UTRs, but the involvement of this process in stress response has not yet been clarified. Here, we report that a subset of stress-related genes exhibits 3' UTR extensions of their mRNAs during dehydration stress. These extended 3' UTRs have characteristics of long noncoding RNAs and likely do not interact with miRNAs...
May 18, 2017: Genome Research
https://www.readbyqxmd.com/read/28522612/genomevip-a-cloud-platform-for-genomic-variant-discovery-and-interpretation
#15
R Jay Mashl, Adam D Scott, Kuan-Lin Huang, Matthew A Wyczalkowski, Christopher J Yoon, Beifang Niu, Erin DeNardo, Venkata D Yellapantula, Robert E Handsaker, Ken Chen, Daniel C Koboldt, Kai Ye, David Fenyö, Benjamin J Raphael, Michael C Wendl, Li Ding
Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional "download and analyze" paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis...
May 18, 2017: Genome Research
https://www.readbyqxmd.com/read/28522611/long-terminal-repeats-power-evolution-of-genes-and-gene-expression-programs-in-mammalian-oocytes-and-zygotes
#16
Vedran Franke, Sravya Ganesh, Rosa Karlic, Radek Malik, Josef Pasulka, Filip Horvat, Maja Kuzman, Helena Fulka, Marketa Cernohorska, Jana Urbanova, Eliska Svobodova, Jun Ma, Yutaka Suzuki, Fugaku Aoki, Richard M Schultz, Kristian Vlahovicek, Petr Svoboda
Retrotransposons are 'copy-and-paste' insertional mutagens that substantially contribute to mammalian genome content. Retrotransposons often carry long terminal repeats (LTRs) for retrovirus-like reverse transcription and integration into the genome. We report an extraordinary impact of a group of LTRs from the mammalian endogenous retrovirus-related ERVL retrotransposon class on gene expression in the germline and beyond. In mouse, we identified >800 LTRs from ORR1, MT, MT2, and MLT families, which resemble mobile gene-remodeling platforms that supply promoters and first exons...
May 18, 2017: Genome Research
https://www.readbyqxmd.com/read/28512194/ancient-antagonism-between-celf-and-rbfox-families-tunes-mrna-splicing-outcomes
#17
Matthew R Gazzara, Michael J Mallory, Renat Roytenberg, John P Lindberg, Anupama Jha, Kristen W Lynch, Yoseph Barash
Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors...
May 16, 2017: Genome Research
https://www.readbyqxmd.com/read/28512193/dna-replication-timing-during-development-anticipates-transcriptional-programs-and-parallels-enhancer-activation
#18
Joseph C Siefert, Constantin Georgescu, Jonathan D Wren, Amnon Koren, Christopher L Sansam
In dividing cells, DNA replication occurs in a precise order, but many questions remain regarding the mechanisms of replication timing establishment and regulation. We now have generated genome-wide, high-resolution replication timing maps throughout zebrafish development. Unexpectedly, in the rapid cell cycles preceding the midblastula transition, a defined timing program was present that predicted the initial wave of zygotic transcription. Replication timing was thereafter progressively and continuously remodeled across the majority of the genome, and epigenetic changes involved in enhancer activation frequently paralleled developmental changes in replication timing...
May 16, 2017: Genome Research
https://www.readbyqxmd.com/read/28512192/human-mismatch-repair-system-balances-mutation-rates-between-strands-by-removing-more-mismatches-from-the-lagging-strand
#19
Maria Andrianova, Georgii Bazykin, Sergey Nikolaev, Vladimir Seplyarskiy
Mismatch repair (MMR) is one of the main systems maintaining fidelity of replication. Differences in correction of errors produced during replication of the leading and the lagging DNA strands were reported in yeast and in human cancers, but the causes of these differences remain unclear. Here, we analyze data on human cancers with somatic mutations in two of the major DNA polymerases, delta and epsilon, that replicate the genome. We show that these cancers demonstrate a substantial asymmetry of the mutations between the leading and the lagging strands...
May 16, 2017: Genome Research
https://www.readbyqxmd.com/read/28487280/the-identification-and-functional-annotation-of-rna-structures-conserved-in-vertebrates
#20
Stefan E Seemann, Aashiq H Mirza, Claus Hansen, Claus H Bang-Berthelsen, Christian Garde, Mikkel Christensen-Dalsgaard, Elfar Torarinsson, Zizhen Yao, Christopher T Workman, Flemming Pociot, Henrik Nielsen, Niels Tommerup, Walter L Ruzzo, Jan Gorodkin
Structured elements of RNA molecules are essential in, e.g., RNA stabilization, localization and protein interaction, and their conservation across species suggests a common functional role. We computationally screened vertebrate genomes for Conserved RNA Structures (CRSs), leveraging structure-based, rather than sequence-based, alignments. After careful correction for sequence identity and GC content, we predict ~516k human genomic regions containing CRSs. We find that a substantial fraction of human-mouse CRS regions (i) co-localize consistently with binding sites of the same RNA binding proteins (RBPs) or (ii) are transcribed in corresponding tissues...
May 9, 2017: Genome Research
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