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Genome Research

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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
#1
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
#2
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/28611159/population-genomics-and-the-evolution-of-virulence-in-the-fungal-pathogen-cryptococcus-neoformans
#3
Christopher A Desjardins, Charles Giamberardino, Sean M Sykes, Chen-Hsin Yu, Jennifer L Tenor, Yuan Chen, Timothy Yang, Alexander M Jones, Sheng Sun, Miriam R Haverkamp, Joseph Heitman, Anastasia P Litvintseva, John R Perfect, Christina A Cuomo
Cryptococcus neoformans is an opportunistic fungal pathogen that causes approximately 625,000 deaths per year from nervous system infections. Here, we leveraged a unique, genetically diverse population of C. neoformans from sub-Saharan Africa, commonly isolated from mopane trees, to determine how selective pressures in the environment coincidentally adapted C. neoformans for human virulence. Genome sequencing and phylogenetic analysis of 387 isolates, representing the global VNI and African VNB lineages, highlighted a deep, nonrecombining split in VNB (herein, VNBI and VNBII)...
June 13, 2017: Genome Research
https://www.readbyqxmd.com/read/28596291/ddx54-regulates-transcriptome-dynamics-during-dna-damage-response
#4
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
#5
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/28588068/comprehensive-global-genome-dynamics-of-chlamydia-trachomatis-show-ancient-diversification-followed-by-contemporary-mixing-and-recent-lineage-expansion
#6
James Hadfield, Simon R Harris, Helena M B Seth-Smith, Surendra Parmar, Patiyan Andersson, Philip M Giffard, Julius Schachter, Jeanne Moncada, Louise Ellison, María Lucía Gallo Vaulet, Marcelo Rodríguez Fermepin, Frans Radebe, Suyapa Mendoza, Sander Ouburg, Servaas A Morré, Konrad Sachse, Mirja Puolakkainen, Suvi J Korhonen, Chris Sonnex, Rebecca Wiggins, Hamid Jalal, Tamara Brunelli, Patrizia Casprini, Rachel Pitt, Cathy Ison, Alevtina Savicheva, Elena Shipitsyna, Ronza Hadad, Laszlo Kari, Matthew J Burton, David Mabey, Anthony W Solomon, David Lewis, Peter Marsh, Magnus Unemo, Ian N Clarke, Julian Parkhill, Nicholas R Thomson
Chlamydia trachomatis is the world's most prevalent bacterial sexually transmitted infection and leading infectious cause of blindness, yet it is one of the least understood human pathogens, in part due to the difficulties of in vitro culturing and the lack of available tools for genetic manipulation. Genome sequencing has reinvigorated this field, shedding light on the contemporary history of this pathogen. Here, we analyze 563 full genomes, 455 of which are novel, to show that the history of the species comprises two phases, and conclude that the currently circulating lineages are the result of evolution in different genomic ecotypes...
June 6, 2017: Genome Research
https://www.readbyqxmd.com/read/28546418/single-cell-dna-sequencing-reveals-a-late-dissemination-model-in-metastatic-colorectal-cancer
#7
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/28536180/yy1-and-ctcf-orchestrate-a-3d-chromatin-looping-switch-during-early-neural-lineage-commitment
#8
Jonathan A Beagan, Michael T Duong, Katelyn R Titus, Linda Zhou, Zhendong Cao, Jingjing Ma, Caroline V Lachanski, Daniel R Gillis, Jennifer E Phillips-Cremins
CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naïve/primed pluripotency to multipotent primary neural progenitor cells (NPCs)...
May 23, 2017: Genome Research
https://www.readbyqxmd.com/read/28522613/dehydration-stress-extends-mrna-3-untranslated-regions-with-noncoding-rna-functions-in-arabidopsis
#9
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
#10
Robert J 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 Raphael, Michael C Wendl, Li Ding
Identifying genomic variants is a fundamental first step towards the understanding of the role of inherited and acquired variations 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
#11
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
#12
Matthew R Gazzara, Michael J Mallory, Renat Roytenberg, John 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
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/28487279/single-cell-sequencing-deciphers-a-convergent-evolution-of-copy-number-alterations-from-primary-to-circulating-tumour-cells
#16
Yan Gao, Xiaohui Ni, Hua Guo, Zhe Su, Yi Ba, Zhongsheng Tong, Zhi Guo, Xin Yao, Xixi Chen, Jian Yin, Zhao Yan, Lin Guo, Ying Liu, Fan Bai, Xiaoliang Sunney Xie, Ning Zhang
Copy number alteration (CNA) is a major contributor to genome instability, a hallmark of cancer. Here we studied genomic alterations in single primary tumour cells and circulating tumour cells (CTCs) from the same patient. Single-nucleotide variations (SNVs) in single cells from both samples occurred sporadically, whereas CNAs among primary tumour cells emerged accumulatively rather than abruptly, converging toward that of CTCs. Focal CNAs affecting MYC gene and PTEN gene were observed only in a minor portion of primary tumour cells but were present in all CTCs, suggesting a strong selection toward metastasis...
May 9, 2017: Genome Research
https://www.readbyqxmd.com/read/28483779/heritable-l1-retrotransposition-in-the-mouse-primordial-germline-and-early-embryo
#17
Sandra R Richardson, Patricia Gerdes, Daniel J Gerhardt, Francisco J Sanchez-Luque, Gabriela-Oana Bodea, Martin Munoz-Lopez, J Samuel Jesuadian, Marie-Jeanne H C Kempen, Patricia E Carreira, Jeffrey A Jeddeloh, Jose L Garcia-Perez, Haig H Kazazian, Adam D Ewing, Geoffrey J Faulkner
LINE-1 (L1) retrotransposons are a noted source of genetic diversity and disease in mammals. To expand its genomic footprint, L1 must mobilize in cells that will contribute their genetic material to subsequent generations. Heritable L1 insertions may therefore arise in germ cells and in pluripotent embryonic cells, prior to germline specification, yet the frequency and predominant developmental timing of such events remain unclear. Here, we applied mouse retrotransposon capture sequencing (mRC-seq) and whole-genome sequencing (WGS) to pedigrees of C57BL/6J animals, and uncovered an L1 insertion rate of ≥1 event per 8 births...
May 8, 2017: Genome Research
https://www.readbyqxmd.com/read/28424353/constrained-release-of-lamina-associated-enhancers-and-genes-from-the-nuclear-envelope-during-t-cell-activation-facilitates-their-association-in-chromosome-compartments
#18
Michael I Robson, Jose I de Las Heras, Rafal Czapiewski, Aishwarya Sivakumar, Alastair R W Kerr, Eric Schirmer
The 3D organization of the genome changes concomitantly with expression changes during hematopoiesis and immune activation. Studies have focused either on lamina-associated domains (LADs) or on topologically-associated domains (TADs), defined by preferential local chromatin interactions, and chromosome compartments, defined as higher-order interactions between TADs sharing functionally similar states. However, few studies have investigated how these affect one another. To address this, we mapped LADs using Lamin B1-DamID during Jurkat T-cell activation, finding significant genome re-organization at the nuclear periphery dominated by release of loci frequently important for T-cell function...
April 19, 2017: Genome Research
https://www.readbyqxmd.com/read/28424352/chromatin-module-inference-on-cellular-trajectories-identifies-key-transition-points-and-poised-epigenetic-states-in-diverse-developmental-processes
#19
Sushmita Roy, Rupa Sridharan
Changes in chromatin state play important roles in cell fate transitions. Current computational approaches to analyze chromatin modifications across multiple cell types do not model how the cell types are related on a lineage or over time. To overcome this limitation, we have developed a method called CMINT (Chromatin Module INference on Trees), a probabilistic clustering approach to systematically capture chromatin state dynamics across multiple cell types. Compared to existing approaches, CMINT can handle complex lineage topologies, capture higher quality clusters, and reliably detect chromatin transitions between cell types...
April 19, 2017: Genome Research
https://www.readbyqxmd.com/read/28420691/clustering-of-drosophila-housekeeping-promoters-facilitates-their-expression
#20
Marc Corrales-Berjano, Aranzazu Rosado Diez, Ruggero Cortini, Joris van Arensbergen, Bas van Steensel, Guillaume J Filion
Housekeeping genes of animal genomes cluster in the same chromosomal regions. It has long been suggested that this organization contributes to their steady expression across all the tissues of the organism. Here we show that the activity of Drosophila housekeeping gene promoters depends on the expression of their neighbours. By measuring the expression of ~ 85,000 reporters integrated in Kc167 cells, we identified the best predictors of expression as chromosomal contacts with the promoters and terminators of active genes...
April 18, 2017: Genome Research
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