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Genome Research

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https://www.readbyqxmd.com/read/30012835/a-comprehensive-characterization-of-cis-acting-splicing-associated-variants-in-human-cancer
#1
Yuichi Shiraishi, Keisuke Kataoka, Kenichi Chiba, Ai Okada, Yasunori Kogure, Hiroko Tanaka, Seishi Ogawa, Satoru Miyano
Although many driver mutations are thought to promote carcinogenesis via abnormal splicing, the landscape of splicing-associated variants (SAVs) remains unknown due to the complexity of splicing abnormalities. Here, we developed a statistical framework to systematically identify SAVs disrupting or newly creating splice site motifs and applied it to matched whole-exome and transcriptome sequencing data from 8976 samples across 31 cancer types, generating a catalog of 14,438 SAVs. Such a large collection of SAVs enabled us to characterize their genomic features, underlying mutational processes, and influence on cancer driver genes...
July 16, 2018: Genome Research
https://www.readbyqxmd.com/read/30006414/variant-antigen-repertoires-in-trypanosoma-congolense-populations-and-experimental-infections-can-be-profiled-from-deep-sequence-data-with-a-set-of-universal-protein-motifs
#2
Sara Silva Pereira, Aitor Casas-Sanchez, Lee R Haines, Kihara Absolomon, Moses Ogugo, Mandy Sanders, Steve Kemp, Álvaro Acosta-Serrano, Harry Noyes, Matthew Berriman, Andrew P Jackson
African trypanosomes are vector-borne hemoparasites of humans and animals. In the mammal, parasites evade the immune response through antigenic variation. Periodic switching of the Variant Surface Glycoprotein (VSG) coat covering their cell surface allows sequential expansion of serologically distinct parasite clones. Trypanosome genomes contain many hundreds of VSG genes, subject to rapid changes in nucleotide sequence, copy number and chromosomal position. Thus, analysing, or even quantifying, VSG diversity over space and time presents an enormous challenge to conventional techniques...
July 13, 2018: Genome Research
https://www.readbyqxmd.com/read/30002159/plant-24-nt-reproductive-phasirnas-from-intramolecular-duplex-mrnas-in-diverse-monocots
#3
Atul Kakrana, Sandra M Mathioni, Kun Huang, Reza Hammond, Lee Vandivier, Parth Patel, Siwaret Arikit, Olga Shevchenko, Alex E Harkess, Bruce Kingham, Brian D Gregory, James H Leebens-Mack, Blake C Meyers
In grasses, two pathways generate diverse and numerous 21-nt (pre-meiotic) and 24-nt (meiotic) phased siRNAs highly enriched in anthers, the male reproductive organs. These "phasiRNAs" are analogous to mammalian piRNAs, yet their functions and evolutionary origins remain largely unknown. The 24-nt meiotic phasiRNAs have only been described in grasses, wherein their biogenesis is dependent on a specialized Dicer (DCL5). To assess how evolution gave rise to this pathway, we examined reproductive phasiRNA pathways in non-grass monocots: garden asparagus, daylily and lily...
July 12, 2018: Genome Research
https://www.readbyqxmd.com/read/30002158/a-common-pattern-of-dnase-i-footprinting-throughout-the-human-mtdna-unveils-clues-for-a-chromatin-like-organization
#4
Amit Blumberg, Charles G Danko, Anshul Kundaje, Dan Mishmar
Human mitochondrial DNA (mtDNA) is believed to lack chromatin and histones. Instead, it is coated solely by the transcription factor TFAM. We asked whether mtDNA packaging is more regulated than once thought. To address this, we analyzed DNase-seq experiments in 324 human cell types and found, for the first time, a pattern of 29 mtDNA Genomic footprinting (mt-DGF) sites shared by ∼90% of the samples. Their syntenic conservation in mouse DNase-seq experiments reflect selective constraints. Colocalization with known mtDNA regulatory elements, with G-quadruplex structures, in TFAM-poor sites (in HeLa cells) and with transcription pausing sites, suggest a functional regulatory role for such mt-DGFs...
July 12, 2018: Genome Research
https://www.readbyqxmd.com/read/29970452/massive-variation-of-short-tandem-repeats-with-functional-consequences-across-strains-of-arabidopsis-thaliana
#5
Maximilian O Press, Rajiv C McCoy, Ashley N Hall, Joshua M Akey, Christine Queitsch
Short tandem repeat (STR) mutations may comprise more than half of the mutations in eukaryotic coding DNA, yet STR variation is rarely examined as a contributor to complex traits. We assessed this contribution across a collection of 96 strains of Arabidopsis thaliana, genotyping 2,046 STR loci each using highly parallel STR sequencing with molecular inversion probes. We found that 95% of examined STRs are polymorphic, with a median of six alleles per STR across these strains. STR expansions (large copy number increases) are found in most strains, several of which have evident functional effects...
July 3, 2018: Genome Research
https://www.readbyqxmd.com/read/29970451/switching-roles-for-dna-and-histone-methylation-depend-on-evolutionary-ages-of-human-endogenous-retroviruses
#6
Hitoshi Ohtani, Minmin Liu, Wanding Zhou, Gangning Liang, Peter A Jones
We provide a comprehensive genomic and epigenomic map of the more than 500,000 endogenous retroviruses (ERVs) and fragments that populate the intergenic regions of the human genome. The repressive epigenetic marks associated with the ERVs, particularly long terminal repeats (LTRs), show a remarkable switch in silencing mechanisms, depending on the evolutionary age of the LTRs. Young LTRs tend to be CpG-rich and are mainly suppressed by DNA methylation, whereas intermediate age LTRs are associated predominantly with histone modifications, particularly histone H3 lysine 9 (H3K9) methylation...
July 3, 2018: Genome Research
https://www.readbyqxmd.com/read/29970450/immune-signatures-correlate-with-l1-retrotransposition-in-gastrointestinal-cancers
#7
Hyunchul Jung, Jung Kyoon Choi, Eunjung Alice Lee
Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are normally suppressed in somatic tissues mainly due to DNA methylation and antiviral defense. However, the mechanism to suppress L1s may be disrupted in cancers, thus allowing L1s to act as insertional mutagens and cause genomic rearrangement and instability. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, we report multiple correlates of L1 activity in stomach, colorectal, and esophageal tumors through an integrative analysis of cancer whole genome and matched RNA sequencing profiles...
July 3, 2018: Genome Research
https://www.readbyqxmd.com/read/29954844/complex-rearrangements-and-oncogene-amplifications-revealed-by-long-read-dna-and-rna-sequencing-of-a-breast-cancer-cell-line
#8
Maria Nattestad, Sara Goodwin, Karen Ng, Timour Baslan, Fritz Sedlazeck, Philipp Rescheneder, Tyler Garvin, Han Fang, James Gurtowski, Elizabeth Hutton, Elizabeth Tseng, Jason Chin, Timothy Beck, Yogi Sundaravadanam, Melissa Kramer, Eric Antoniou, John McPherson, James Hicks, W Richard McCombie, Michael C Schatz
The SK-BR-3 cell line is one of the most important models for HER2+ breast cancers, which affect one in five breast cancer patients. SK-BR-3 is known to be highly rearranged although much of the variation is in complex and repetitive regions that may be underreported. Addressing this, we sequenced SK-BR-3 using long-read single molecule sequencing from Pacific Biosciences, and develop one of the most detailed maps of structural variations (SVs) in a cancer genome available with nearly 20,000 variants present, most of which were missed by short read sequencing...
June 28, 2018: Genome Research
https://www.readbyqxmd.com/read/29945882/an-atlas-of-chromatin-accessibility-in-the-adult-human-brain
#9
John F Fullard, Mads E Hauberg, Jaroslav Bendl, Gabor Egervari, Maria Daniela Cirnaru, Sarah M Reach, Jan Motl, Michelle E Ehrlich, Yasmin L Hurd, Panos Roussos
The majority of common genetic risk variants associated with neuropsychiatric disease are non-coding and are thought to exert their effects by disrupting the function of cis regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further our understanding of the complex mechanisms that modulate transcription in the brain, we utilized frozen postmortem samples to generate the largest human brain and cell type-specific open chromatin dataset to date...
June 26, 2018: Genome Research
https://www.readbyqxmd.com/read/29934426/the-organization-of-genome-duplication-is-a-critical-determinant-of-the-landscape-of-genome-maintenance
#10
Blanca Gomez-Escoda, Pei-Yun Jenny Wu
Genome duplication is essential for cell proliferation, and the mechanisms regulating its execution are highly conserved. These processes give rise to a spatiotemporal organization of replication initiation across the genome, referred to as the replication program. Despite the identification of such programs in diverse eukaryotic organisms, their biological importance for cellular physiology remains largely unexplored. We address this fundamental question in the context of genome maintenance, taking advantage of the inappropriate origin firing that occurs when fission yeast cells lacking the ATR/Rad3 checkpoint kinase are subjected to replication stress...
June 22, 2018: Genome Research
https://www.readbyqxmd.com/read/29914971/epigenetic-maintenance-of-topological-domains-in-the-highly-rearranged-gibbon-genome
#11
Nathan H Lazar, Kimberly A Nevonen, Brendan O'Connell, Christine McCann, Rachel J O'Neill, Richard E Green, Thomas J Meyer, Mariam Okhovat, Lucia Carbone
The relationship between evolutionary genome remodeling and the three-dimensional structure of the genome remain largely unexplored. Here, we use the heavily rearranged gibbon genome to examine how evolutionary chromosomal rearrangements impact genome-wide chromatin interactions, topologically associating domains (TADs), and their epigenetic landscape. We use high-resolution maps of gibbon-human breaks of synteny (BOS), apply Hi-C in gibbon, measure an array of epigenetic features, and perform cross-species comparisons...
June 18, 2018: Genome Research
https://www.readbyqxmd.com/read/29914970/genome-scale-identification-of-cellular-pathways-required-for-cell-surface-recognition
#12
Sumana Sharma, S Josefin Bartholdson, Amalie Cm Couch, Kosuke Yusa, Gavin James Wright
Interactions mediated by cell surface receptors initiate important instructive signaling cues but can be difficult to detect in biochemical assays because they are often highly transient and membrane-embedded receptors are difficult to solubilize in their native conformation. Here, we address these biochemical challenges by using a genome-scale cell-based genetic screening approach using CRISPR gene knockout technology to identify cellular pathways required for specific cell surface recognition events. Using high-affinity monoclonal antibodies and low-affinity ligands, we determined the necessary screening parameters including the importance of establishing binding contributions from the glycocalyx that permitted the unequivocal identification of genes encoding directly interacting membrane-embedded receptors with high statistical confidence...
June 18, 2018: Genome Research
https://www.readbyqxmd.com/read/29907613/a-modular-dcas9-suntag-dnmt3a-epigenome-editing-system-overcomes-pervasive-off-target-activity-of-direct-fusion-dcas9-dnmt3a-constructs
#13
Christian Pflueger, Dennis Tan, Tessa Swain, Trung Viet Nguyen, Jahnvi Pflueger, Christian Nefzger, Jose M Polo, Ethan Ford, Ryan Lister
DNA methylation is a covalent modification of the genome that plays important roles in genome regulation and vertebrate development. Although detection of this modification in the genome has been possible for several decades, the ability to deliberately and specifically manipulate local DNA methylation states in the genome has been extremely limited. Consequently, this has impeded the direct determination of the consequence of DNA methylation on transcriptional regulation and transcription factor binding in the native chromatin context...
June 15, 2018: Genome Research
https://www.readbyqxmd.com/read/29907612/predicting-human-genes-susceptible-to-genomic-instability-associated-with-alu-alu-mediated-rearrangements
#14
Xiaofei Song, Christine R Beck, Renqian Du, Ian M Campbell, Zeynep Coban-Akdemir, Shen Gu, Amy M Breman, Pawel Stankiewicz, Grzegorz Ira, Chad A Shaw, James R Lupski
Alu elements, the short interspersed element numbering >1 million copies per human genome, can mediate the formation of copy number variants (CNVs) between substrate pairs. These Alu/Alu-mediated rearrangements (AAMR) can result in pathogenic variants that cause diseases. To investigate the impact of AAMR on gene variation and human health, we first characterized Alus that are involved in mediating CNVs (CNV-Alus) and observed that these Alus tend to be evolutionarily younger. We then computationally generated, with the assistance of a supercomputer, a test dataset consisting of 78 million Alu pairs and predicted ~18% of them are potentially susceptible to AAMR...
June 15, 2018: Genome Research
https://www.readbyqxmd.com/read/29903725/human-primitive-brain-displays-negative-mitochondrial-nuclear-expression-correlation-of-respiratory-genes
#15
Gilad Barshad, Amit Blumberg, Tal Cohen, Dan Mishmar
Oxidative phosphorylation (OXPHOS), a fundamental energy source in all human tissues, requires interactions between mitochondrial (mtDNA)- and nuclear (nDNA)-encoded protein subunits. Although such interactions are fundamental to OXPHOS, bi-genomic coregulation is poorly understood. To address this question, we analyzed ∼8500 RNA-seq experiments from 48 human body sites. Despite well-known variation in mitochondrial activity, quantity, and morphology, we found overall positive mtDNA-nDNA OXPHOS genes' co-expression across human tissues...
June 14, 2018: Genome Research
https://www.readbyqxmd.com/read/29903724/parent-of-origin-dependent-nucleosome-organization-correlates-with-genomic-imprinting-in-maize
#16
Xiaomei Dong, Jian Chen, Tong Li, En Li, Xiangbo Zhang, Mei Zhang, Weibin Song, Haiming Zhao, Jinsheng Lai
Genomic imprinting refers to allele-specific expression of genes depending on their parental origin. Nucleosomes, the fundamental units of chromatin, play a critical role in gene transcriptional regulation. However, it remains unknown whether differential nucleosome organization is related to the allele-specific expression of imprinted genes. Here, we generated a genome-wide map of allele-specific nucleosome occupancy in maize endosperm and presented an integrated analysis of its relationship with parent-of-origin-dependent gene expression and DNA methylation...
June 14, 2018: Genome Research
https://www.readbyqxmd.com/read/29903723/long-read-sequencing-of-nascent-rna-reveals-coupling-among-rna-processing-events
#17
Lydia Herzel, Korinna Straube, Karla M Neugebauer
Pre-mRNA splicing is accomplished by the spliceosome, a megadalton complex that assembles de novo on each intron. Because spliceosome assembly and catalysis occur cotranscriptionally, we hypothesized that introns are removed in the order of their transcription in genomes dominated by constitutive splicing. Remarkably little is known about splicing order and the regulatory potential of nascent transcript remodeling by splicing, due to the limitations of existing methods that focus on analysis of mature splicing products (mRNAs) rather than substrates and intermediates...
June 14, 2018: Genome Research
https://www.readbyqxmd.com/read/29903722/epigen-brazil-initiative-resources-a-latin-american-imputation-panel-and-the-scientific-workflow
#18
Wagner C S Magalhães, Nathalia M Araujo, Thiago P Leal, Gilderlanio S Araujo, Paula J S Viriato, Fernanda S Kehdy, Gustavo N Costa, Mauricio L Barreto, Bernardo L Horta, Maria Fernanda Lima-Costa, Alexandre C Pereira, Eduardo Tarazona-Santos, Maíra R Rodrigues
EPIGEN-Brazil is one of the largest Latin American initiatives at the interface of human genomics, public health, and computational biology. Here, we present two resources to address two challenges to the global dissemination of precision medicine and the development of the bioinformatics know-how to support it. To address the underrepresentation of non-European individuals in human genome diversity studies, we present the EPIGEN-5M+1KGP imputation panel-the fusion of the public 1000 Genomes Project (1KGP) Phase 3 imputation panel with haplotypes derived from the EPIGEN-5M data set (a product of the genotyping of 4...
June 14, 2018: Genome Research
https://www.readbyqxmd.com/read/29898900/principled-multi-omic-analysis-reveals-gene-regulatory-mechanisms-of-phenotype-variation
#19
Casey Hanson, Junmei Cairns, Liewei Wang, Saurabh Sinha
Recent studies have analyzed large scale data sets of gene expression to identify genes associated with inter-individual variation in phenotypes ranging from cancer sub-types to drug sensitivity, promising new avenues of research in personalized medicine. However, gene expression data alone is limited in its ability to reveal cis-regulatory mechanisms underlying phenotypic differences. In this study, we develop a new probabilistic model, called pGENMi, that integrates multi-omic data to investigate the transcriptional regulatory mechanisms underlying inter-individual variation of a specific phenotype - that of cell line response to cytotoxic treatment...
June 13, 2018: Genome Research
https://www.readbyqxmd.com/read/29898899/linking-transcriptional-and-genetic-tumor-heterogeneity-through-allele-analysis-of-single-cell-rna-seq-data
#20
Jean Fan, Hae-Ock Lee, Soohyun Lee, Da-Eun Ryu, Semin Lee, Catherine Xue, Seok Jin Kim, Kihyun Kim, Nikolas Barkas, Peter J Park, Woong-Yang Park, Peter V Kharchenko
Characterization of intratumoral heterogeneity is critical to cancer therapy, as presence of phenotypically diverse cell populations commonly fuels relapse and resistance to treatment. Although genetic variation is a well-studied source of intratumoral heterogeneity, the functional impact of most genetic alterations remains unclear. Even less understood is the relative importance of other factors influencing heterogeneity, such as epigenetic state or tumor microenvironment. To investigate the relationship between genetic and transcriptional heterogeneity in a context of cancer progression, we devised a computational approach called HoneyBADGER to identify copy number variation and loss-of-heterozygosity in individual cells from single-cell RNA-sequencing data...
June 13, 2018: Genome Research
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