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Genome Research

Antoine Molaro, Janet M Young, Harmit S Malik
Eukaryotic genomes must accomplish both compact packaging for genome stability and inheritance, as well as accessibility for gene expression. They do so using post-translational modifications of four ancient canonical histone proteins (H2A, H2B, H3, and H4) and by deploying histone variants with specialized chromatin functions. Some histone variants are conserved across all eukaryotes, whereas others are lineage-specific. Here, we performed detailed phylogenomic analyses of "short H2A histone" variants found in mammalian genomes...
March 16, 2018: Genome Research
Jeremiah A Wala, Pratiti Bandopadhayay, Noah Greenwald, Ryan O'Rourke, Ted Sharpe, Chip Stewart, Steve Schumacher, Yilong Li, Joachim Weischenfeldt, Xiaotong Yao, Chad Nusbaum, Peter Campbell, Gad Getz, Matthew Meyerson, Cheng-Zhong Zhang, Marcin Imielinski, Rameen Beroukhim
Structural variants (SVs), including small insertion and deletion variants (indels), are challenging to detect through standard alignment-based variant calling methods. Sequence assembly offers a powerful approach to identifying SVs, but is difficult to apply at scale genome-wide for SV detection due to its computational complexity and the difficulty of extracting SVs from assembly contigs. We describe SvABA, an efficient and accurate method for detecting SVs from short-read sequencing data using genome-wide local assembly with low memory and computing requirements...
March 13, 2018: Genome Research
Kyuha Choi, Xiaohui Zhao, Andrew J Tock, Christophe Lambing, Charles J Underwood, Thomas J Hardcastle, Heïdi Serra, Juhyun Kim, Hyun Seob Cho, Jaeil Kim, Piotr A Ziolkowski, Nataliya E Yelina, Ildoo Hwang, Robert A Martienssen, Ian R Henderson
Meiotic recombination initiates from DNA double-strand breaks (DSBs) generated by SPO11 topoisomerase-like complexes. Meiotic DSB frequency varies extensively along eukaryotic chromosomes, with hotspots controlled by chromatin and DNA sequence. To map meiotic DSBs throughout a plant genome, we purified and sequenced Arabidopsis thaliana SPO11-1-oligonucleotides. SPO11-1-oligos are elevated in gene promoters, terminators, and introns, which is driven by AT-sequence richness that excludes nucleosomes and allows SPO11-1 access...
March 12, 2018: Genome Research
Charles J Underwood, Kyuha Choi, Christophe Lambing, Xiaohui Zhao, Heïdi Serra, Filipe Borges, Joe Simorowski, Evan Ernst, Yannick Jacob, Ian R Henderson, Robert A Martienssen
Eukaryotic centromeres contain the kinetochore, which connects chromosomes to the spindle allowing segregation. During meiosis, centromeres are suppressed for inter-homolog crossover, as recombination in these regions can cause chromosome missegregation and aneuploidy. Plant centromeres are surrounded by transposon-dense pericentromeric heterochromatin that is epigenetically silenced by histone 3 lysine 9 dimethylation (H3K9me2), and DNA methylation in CG and non-CG sequence contexts. However, the role of these chromatin modifications in control of meiotic recombination in the pericentromeres is not fully understood...
March 12, 2018: Genome Research
Ulrike Böhme, Thomas D Otto, James Cotton, Sascha Steinbiss, Mandy Sanders, Samuel O Oyola, Antoine Nicot, Sylvain Gandon, Kailash P Patra, Colin Herd, Ellen Bushell, Katarzyna K Modrzynska, Oliver Billker, Joseph M Vinetz, Ana Rivero, Chris I Newbold, Matthew Berriman
Avian malaria parasites are prevalent around the world, and infect a wide diversity of bird species. Here we report the sequencing and analysis of high quality draft genome sequences for two avian malaria species, Plasmodium relictum and Plasmodium gallinaceum We identify 50 genes that are specific to avian malaria, located in an otherwise conserved core of the genome that shares gene synteny with all other sequenced malaria genomes. Phylogenetic analysis suggests that the avian malaria species form an outgroup to the mammalian Plasmodium species and using amino acid divergence between species, we estimate the avian and mammalian-infective lineages diverged in the order of 10 million years ago...
March 2, 2018: Genome Research
Bradford H Casey, Rahul K Kollipara, Karine Pozo, Jane E Johnson
During development, transcription factors select distinct gene programs from a shared genome, providing the necessary regulatory complexity for temporal and tissue-specific gene expression. How related factors retain their specificity of activity, especially when they recognize the same DNA motifs, is not understood. We address this paradox using basic Helix-Loop-Helix (bHLH) transcription factors, ASCL1, ASCL2, and MYOD1, crucial mediators of lineage specification. In vivo, these factors recognize the same DNA motifs, yet bind largely different genomic sites and regulate distinct transcriptional programs...
March 2, 2018: Genome Research
Katri Korpela, Paul Igor Costea, Luis Pedro Coelho, Stefanie Kandels-Lewis, Gonneke Willemsen, Dorret I Boomsma, Nicola Segata, Peer Bork
Vertical transmission of bacteria from mother to infant at birth is postulated to initiate a life-long host-microbe symbiosis, playing an important role in early infant development. However, only the tracking of strictly defined unique microbial strains can clarify where the intestinal bacteria come from, how long the initial colonisers persist and whether colonisation by other strains from the environment can replace existing ones. Using rare single nucleotide variants in fecal metagenomes of infants and their family members, we show strong evidence of selective and persistent transmission of maternal strain populations to the vaginally born infant, and their occasional replacement by strains from the environment, including those from family members, in later childhood...
March 1, 2018: Genome Research
Patrick T West, Alexander J Probst, Igor V Grigoriev, Brian C Thomas, Jillian F Banfield
Microbial eukaryotes are integral components of natural microbial communities and their inclusion is critical for many ecosystem studies yet the majority of published metagenome analyses ignore eukaryotes. In order to include eukaryotes in environmental studies we propose a method to recover eukaryotic genomes from complex metagenomic samples. A key step for genome recovery is separation of eukaryotic and prokaryotic fragments. We developed a k-mer-based strategy, EukRep, for eukaryotic sequence identification and applied it to environmental samples to show that it enables genome recovery, genome completeness evaluation and prediction of metabolic potential...
March 1, 2018: Genome Research
Sojung Kim, Taeyoung Koo, Hyeon-Gun Jee, Hee-Yeon Cho, Gyeorae Lee, Dong-Gyun Lim, Hyoung Shik Shin, Jin-Soo Kim
Here, we report that CRISPR guide RNAs (gRNAs) with a 5'-triphosphate group (5'-ppp gRNAs) produced via in vitro transcription trigger RNA-sensing innate immune responses in human and murine cells, leading to cytotoxicity. 5'-ppp gRNAs in the cytosol are recognized by DDX58, which in turn activates type I interferon responses, causing up to ∼80% cell death. We show that the triphosphate group can be removed by a phosphatase in vitro and that the resulting 5'-hydroxyl gRNAs in complex with Cas9 or Cpf1 avoid innate immune responses and can achieve targeted mutagenesis at a frequency of 95% in primary human CD4+ T cells...
February 22, 2018: Genome Research
Sahin Naqvi, Daniel W Bellott, Kathy S Lin, David C Page
Mammalian X and Y Chromosomes evolved from an ordinary autosomal pair. Genetic decay of the Y led to X Chromosome inactivation (XCI) in females, but some Y-linked genes were retained during the course of sex chromosome evolution, and many X-linked genes did not become subject to XCI. We reconstructed gene-by-gene dosage sensitivities on the ancestral autosomes through phylogenetic analysis of microRNA (miRNA) target sites and compared these preexisting characteristics to the current status of Y-linked and X-linked genes in mammals...
February 15, 2018: Genome Research
Kuan-Ting Lin, Wai Kit Ma, Juergen Scharner, Yun-Ru Liu, Adrian R Krainer
Pre-mRNA splicing can contribute to the switch of cell identity that occurs in carcinogenesis. Here, we analyze a large collection of RNA-seq data sets and report that splicing changes in hepatocyte-specific enzymes, such as AFMID and KHK , are associated with HCC patients' survival and relapse. The switch of AFMID isoforms is an early event in HCC development and is associated with driver mutations in TP53 and ARID1A The switch of AFMID isoforms is human-specific and not detectable in other species, including primates...
February 15, 2018: Genome Research
Joseph G Azofeifa, Mary A Allen, Josephina R Hendrix, Timothy Read, Jonathan D Rubin, Robin D Dowell
Transcription factors (TFs) exert their regulatory influence through the binding of enhancers, resulting in coordination of gene expression programs. Active enhancers are often characterized by the presence of short, unstable transcripts termed enhancer RNAs (eRNAs). While their function remains unclear, we demonstrate that eRNAs are a powerful readout of TF activity. We infer sites of eRNA origination across hundreds of publicly available nascent transcription data sets and show that eRNAs initiate from sites of TF binding...
February 15, 2018: Genome Research
Vinesh Vinayachandran, Rohit Reja, Matthew J Rossi, Bongsoo Park, Lila Rieber, Chitvan Mittal, Shaun Mahony, B Franklin Pugh
Gene expression is controlled by a variety of proteins that interact with the genome. Their precise organization and mechanism of action at every promoter remains to be worked out. To better understand the physical interplay among genome-interacting proteins, we examined the temporal binding of a functionally diverse subset of these proteins: nucleosomes (H3), H2AZ (Htz1), SWR (Swr1), RSC (Rsc1, Rsc3, Rsc58, Rsc6, Rsc9, Sth1), SAGA (Spt3, Spt7, Ubp8, Sgf11), Hsf1, TFIID (Spt15/TBP and Taf1), TFIIB (Sua7), TFIIH (Ssl2), FACT (Spt16), Pol II (Rpb3), and Pol II carboxyl-terminal domain (CTD) phosphorylation at serines 2, 5, and 7...
February 14, 2018: Genome Research
Mohamed Nadhir Djekidel, Yang Chen, Michael Q Zhang
Polymer-based simulations and experimental studies indicate the existence of a spatial dependency between the adjacent DNA fibers involved in the formation of chromatin loops. However, the existing strategies for detecting differential chromatin interactions assume that the interacting segments are spatially independent from the other segments nearby. To resolve this issue, we developed a new computational method, FIND, which considers the local spatial dependency between interacting loci. FIND uses a spatial Poisson process to detect differential chromatin interactions that show a significant difference in their interaction frequency and the interaction frequency of their neighbors...
February 12, 2018: Genome Research
Meng Chen, Guoliang Lyu, Miao Han, Hongbo Nie, Ting Shen, Wei Chen, Yichi Niu, Yifan Song, Xueping Li, Huan Li, Xinyu Chen, Ziyue Wang, Zheng Xia, Wei Li, Xiao-Li Tian, Chen Ding, Jun Gu, Yufang Zheng, Xinhua Liu, Jinfeng Hu, Gang Wei, Wei Tao, Ting Ni
Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3' untranslated regions (3' UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3' UTRs and reduced gene expression...
February 12, 2018: Genome Research
Manuel Tardaguila, Lorena de la Fuente, Cristina Marti, Cécile Pereira, Francisco Jose Pardo-Palacios, Hector Del Risco, Marc Ferrell, Maravillas Mellado, Marissa Macchietto, Kenneth Verheggen, Mariola Edelmann, Iakes Ezkurdia, Jesus Vazquez, Michael Tress, Ali Mortazavi, Lennart Martens, Susana Rodriguez-Navarro, Victoria Moreno-Manzano, Ana Conesa
High-throughput sequencing of full-length transcripts using long reads has paved the way for the discovery of thousands of novel transcripts, even in well-annotated mammalian species. The advances in sequencing technology have created a need for studies and tools that can characterize these novel variants. Here, we present SQANTI, an automated pipeline for the classification of long-read transcripts that can assess the quality of data and the preprocessing pipeline using 47 unique descriptors. We apply SQANTI to a neuronal mouse transcriptome using Pacific Biosciences (PacBio) long reads and illustrate how the tool is effective in characterizing and describing the composition of the full-length transcriptome...
February 9, 2018: Genome Research
Suhn Kyong Rhie, Lijun Yao, Zhifei Luo, Heather Witt, Shannon Schreiner, Yu Guo, Andrew A Perez, Peggy J Farnham
High expression of the transcription factor ZFX is correlated with proliferation, tumorigenesis, and patient survival in multiple types of human cancers. However, the mechanism by which ZFX influences transcriptional regulation has not been determined. We performed ChIP-seq in four cancer cell lines (representing kidney, colon, prostate, and breast cancers) to identify ZFX binding sites throughout the human genome. We identified ~9,000 ZFX binding sites and found that the majority of the sites are in CpG island promoters...
February 2, 2018: Genome Research
Federico Comoglio, Hyun Jung Park, Stefan Schoenfelder, Iros Barozzi, Daniel Bode, Peter Fraser, Anthony R Green
Thrombopoietin (TPO) is a critical cytokine regulating hematopoietic stem cell maintenance and differentiation into the megakaryocytic lineage. However, the transcriptional and chromatin dynamics elicited by TPO signaling are poorly understood. Here, we study the immediate early transcriptional and cis-regulatory responses to TPO in hematopoietic stem/progenitor cells (HSPCs) and use this paradigm of cytokine signaling to chromatin to dissect the relation between cis- regulatory activity and chromatin architecture...
February 2, 2018: Genome Research
Miguel Luz Soares, Carol A Edwards, Fran L Dearden, Sacramento Rodriguez Ferron, Scott Curran, Jenny Corish, Rebecca Rancourt, Sarah Allen, Marika Charalambous, Malcolm A Ferguson-Smith, Willem Rens, David Adams, Anne C Ferguson-Smith
Around half of the mammalian genome is composed of repetitive sequences and accumulating evidence suggests that some may have an impact on genome function. Here, we characterised a large array class of repeats of long-interspersed elements (LINE-1). Though widely distributed in mammals, locations of such arrays are species-specific. Using targeted deletion, we asked whether a 170 kb LINE-1 array located at a mouse imprinted domain, might function as a modulator of local transcriptional control. The LINE-1 array is lamina-associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed...
January 24, 2018: Genome Research
Beibei Xin, Remo Rohs
The very small fraction of putative binding sites (BSs) that are occupied by transcription factors (TFs) in vivo can be highly variable across different cell types. This observation has been partly attributed to changes in chromatin accessibility and histone modification (HM) patterns surrounding BSs. Previous studies focusing on BSs within DNA regulatory regions found correlations between HM patterns and TF binding specificities. However, a mechanistic understanding of TF-DNA binding specificity determinants is still not available...
January 11, 2018: Genome Research
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