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  • Massive reshaping of genome–nuclear lamina interactions during oncogene-induced senescence
    Genome Res. (IF 11.922) Pub Date : 2017-09-15
    Christelle Lenain; Carolyn A. de Graaf; Ludo Pagie; Nils L. Visser; Marcel de Haas; Sandra S. de Vries; Daniel Peric-Hupkes; Bas van Steensel; Daniel S. Peeper

    Cellular senescence is a mechanism that virtually irreversibly suppresses the proliferative capacity of cells in response to various stress signals. This includes the expression of activated oncogenes, which causes Oncogene-Induced Senescence (OIS). A body of evidence points to the involvement in OIS of chromatin reorganization, including the formation of senescence-associated heterochromatic foci (SAHF). The nuclear lamina (NL) is an important contributor to genome organization and has been implicated in cellular senescence and organismal aging. It interacts with multiple regions of the genome called lamina-associated domains (LADs). Some LADs are cell-type specific, whereas others are conserved between cell types and are referred to as constitutive LADs (cLADs). Here, we used DamID to investigate the changes in genome–NL interactions in a model of OIS triggered by the expression of the common BRAFV600E oncogene. We found that OIS cells lose most of their cLADS, suggesting the loss of a specific mechanism that targets cLADs to the NL. In addition, multiple genes relocated to the NL. Unexpectedly, they were not repressed, implying the abrogation of the repressive activity of the NL during OIS. Finally, OIS cells displayed an increased association of telomeres with the NL. Our study reveals that senescent cells acquire a new type of LAD organization and suggests the existence of as yet unknown mechanisms that tether cLADs to the NL and repress gene expression at the NL.

    更新日期:2017-09-15
  • Comparative analysis of alternative polyadenylation in S. cerevisiae and S. pombe
    Genome Res. (IF 11.922) Pub Date : 2017-09-15
    Xiaochuan Liu; Mainul Hoque; Marc Larochelle; Jean-François Lemay; Nathan Yurko; James L. Manley; François Bachand; Bin Tian

    Alternative polyadenylation (APA) is a widespread mechanism that generates mRNA isoforms with distinct properties. Here we have systematically mapped and compared cleavage and polyadenylation sites (PASs) in two yeast species, S. cerevisiae and S. pombe. Although >80% of the mRNA genes in each species were found to display APA, S. pombe showed greater 3′ UTR size differences among APA isoforms than did S. cerevisiae. PASs in different locations of gene are surrounded with distinct sequences in both species and are often associated with motifs involved in the Nrd1-Nab3-Sen1 termination pathway. In S. pombe, strong motifs surrounding distal PASs lead to higher abundances of long 3′ UTR isoforms than short ones, a feature that is opposite in S. cerevisiae. Differences in PAS placement between convergent genes lead to starkly different antisense transcript landscapes between budding and fission yeasts. In both species, short 3′ UTR isoforms are more likely to be expressed when cells are growing in nutrient-rich media, although different gene groups are affected in each species. Significantly, 3′ UTR shortening in S. pombe coordinates with up-regulation of expression for genes involved in translation during cell proliferation. Using S. pombe strains deficient for Pcf11 or Pab2, we show that reduced expression of 3′-end processing factors lengthens 3′ UTR, with Pcf11 having a more potent effect than Pab2. Taken together, our data indicate that APA mechanisms in S. pombe and S. cerevisiae are largely different: S. pombe has many of the APA features of higher species, and Pab2 in S. pombe has a different role in APA regulation than its mammalian homolog, PABPN1.

    更新日期:2017-09-15
  • Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity
    Genome Res. (IF 11.922) Pub Date : 2017-09-14
    Peng Mao; Alexander J. Brown; Ewa P. Malc; Piotr A. Mieczkowski; Michael J. Smerdon; Steven A. Roberts; John J. Wyrick

    DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome-depleted regions, and slower repair and higher mutation density within strongly positioned nucleosomes. Both the translational and rotational settings of lesions within nucleosomes significantly influence BER efficiency; moreover, this effect is asymmetric relative to the nucleosome dyad axis and is regulated by histone modifications. Our data also indicate that MMS-induced mutations at adenine nucleotides are significantly enriched on the nontranscribed strand (NTS) of yeast genes, particularly in BER-deficient strains, due to higher damage formation on the NTS and transcription-coupled repair of the transcribed strand (TS). These findings reveal the influence of chromatin on repair and mutagenesis of base lesions on a genome-wide scale and suggest a novel mechanism for transcription-associated mutation asymmetry, which is frequently observed in human cancers.

    更新日期:2017-09-14
  • Redundant and incoherent regulations of multiple phenotypes suggest microRNAs’ role in stability control
    Genome Res. (IF 11.922) Pub Date : 2017-09-13
    Zhongqi Liufu; Yixin Zhao; Li Guo; Guangxia Miao; Juan Xiao; Yang Lyu; Yuxin Chen; Suhua Shi; Tian Tang; Chung-I Wu

    Each microRNA (miRNA) represses a web of target genes and, through them, controls multiple phenotypes. The difficulties inherent in such controls cast doubt on how effective miRNAs are in driving phenotypic changes. A “simple regulation” model posits “one target–one phenotype” control under which most targeting is nonfunctional. In an alternative “coordinate regulation” model, multiple targets are assumed to control the same phenotypes coherently, and most targeting is functional. Both models have some empirical support but pose different conceptual challenges. Here, we concurrently analyze multiple targets and phenotypes associated with the miRNA-310 family (miR310s) of Drosophila. Phenotypic rescue in the mir310s knockout background is achieved by promoter-directed RNA interference that restores wild-type expression. For one phenotype (eggshell morphology), we observed redundant regulation, hence rejecting “simple regulation” in favor of the “coordinate regulation” model. For other phenotypes (egg-hatching and male fertility), however, one gene shows full rescue, but three other rescues aggravate the phenotype. Overall, phenotypic controls by miR310s do not support either model. Like a thermostat that controls both heating and cooling elements to regulate temperature, redundancy and incoherence in regulation generally suggest some capacity in stability control. Our results therefore support the published view that miRNAs play a role in the canalization of transcriptome and, hence, phenotypes.

    更新日期:2017-09-14
  • Sasquatch: predicting the impact of regulatory SNPs on transcription factor binding from cell- and tissue-specific DNase footprints
    Genome Res. (IF 11.922) Pub Date : 2017-09-13
    Ron Schwessinger; Maria C. Suciu; Simon J. McGowan; Jelena Telenius; Stephen Taylor; Doug R. Higgs; Jim R. Hughes

    In the era of genome-wide association studies (GWAS) and personalized medicine, predicting the impact of single nucleotide polymorphisms (SNPs) in regulatory elements is an important goal. Current approaches to determine the potential of regulatory SNPs depend on inadequate knowledge of cell-specific DNA binding motifs. Here, we present Sasquatch, a new computational approach that uses DNase footprint data to estimate and visualize the effects of noncoding variants on transcription factor binding. Sasquatch performs a comprehensive k-mer-based analysis of DNase footprints to determine any k-mer's potential for protein binding in a specific cell type and how this may be changed by sequence variants. Therefore, Sasquatch uses an unbiased approach, independent of known transcription factor binding sites and motifs. Sasquatch only requires a single DNase-seq data set per cell type, from any genotype, and produces consistent predictions from data generated by different experimental procedures and at different sequence depths. Here we demonstrate the effectiveness of Sasquatch using previously validated functional SNPs and benchmark its performance against existing approaches. Sasquatch is available as a versatile webtool incorporating publicly available data, including the human ENCODE collection. Thus, Sasquatch provides a powerful tool and repository for prioritizing likely regulatory SNPs in the noncoding genome.

    更新日期:2017-09-14
  • An atlas of alternative splicing profiles and functional associations reveals new regulatory programs and genes that simultaneously express multiple major isoforms
    Genome Res. (IF 11.922) Pub Date : 2017-08-30
    Javier Tapial; Kevin C.H. Ha; Timothy Sterne-Weiler; Andre Gohr; Ulrich Braunschweig; Antonio Hermoso-Pulido; Mathieu Quesnel-Vallières; Jon Permanyer; Reza Sodaei; Yamile Marquez; Luca Cozzuto; Xinchen Wang; Melisa Gómez-Velázquez; Teresa Rayon; Miguel Manzanares; Julia Ponomarenko; Benjamin Blencowe; Manuel Irimia

    Alternative splicing (AS) generates remarkable regulatory and proteomic complexity in metazoans. However, the functions of most AS events are not known, and programs of regulated splicing remain to be identified. To address these challenges, we describe the Vertebrate Alternative Splicing and Transcription Database (VastDB), the largest resource of genome-wide, quantitative profiles of AS events assembled to date. VastDB provides readily accessible quantitative information on the inclusion levels and functional associations of AS events detected in RNA-seq data from diverse vertebrate cell and tissue types, as well as developmental stages. The VastDB profiles reveal extensive new intergenic and intragenic regulatory relationships among different classes of AS and previously unknown and conserved landscapes of tissue-regulated exons. Contrary to recent reports concluding that nearly all human genes express a single major isoform, VastDB provides evidence that at least 48% of multiexonic protein-coding genes express multiple splice variants that are highly regulated in a cell/tissue-specific manner, and that >18% of genes simultaneously express multiple major isoforms across diverse cell and tissue types. Isoforms encoded by the latter set of genes are generally coexpressed in the same cells and are often engaged by translating ribosomes. Moreover, they are encoded by genes that are significantly enriched in functions associated with transcriptional control, implying they may have an important and wide-ranging role in controlling cellular activities. VastDB thus provides an unprecedented resource for investigations of AS function and regulation.

    更新日期:2017-09-14
  • Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity
    Genome Res. (IF 11.922) Pub Date : 2017-09-13
    Zdenek Andrysik; Matthew D. Galbraith; Anna L. Guarnieri; Sara Zaccara; Kelly D. Sullivan; Ahwan Pandey; Morgan MacBeth; Alberto Inga; Joaquín M. Espinosa

    The tumor suppressor TP53 is the most frequently mutated gene product in human cancer. Close to half of all solid tumors carry inactivating mutations in the TP53 gene, while in the remaining cases, TP53 activity is abrogated by other oncogenic events, such as hyperactivation of its endogenous repressors MDM2 or MDM4. Despite identification of hundreds of genes regulated by this transcription factor, it remains unclear which direct target genes and downstream pathways are essential for the tumor suppressive function of TP53. We set out to address this problem by generating multiple genomic data sets for three different cancer cell lines, allowing the identification of distinct sets of TP53-regulated genes, from early transcriptional targets through to late targets controlled at the translational level. We found that although TP53 elicits vastly divergent signaling cascades across cell lines, it directly activates a core transcriptional program of ∼100 genes with diverse biological functions, regardless of cell type or cellular response to TP53 activation. This core program is associated with high-occupancy TP53 enhancers, high levels of paused RNA polymerases, and accessible chromatin. Interestingly, two different shRNA screens failed to identify a single TP53 target gene required for the anti-proliferative effects of TP53 during pharmacological activation in vitro. Furthermore, bioinformatics analysis of thousands of cancer genomes revealed that none of these core target genes are frequently inactivated in tumors expressing wild-type TP53. These results support the hypothesis that TP53 activates a genetically robust transcriptional program with highly distributed tumor suppressive functions acting in diverse cellular contexts.

    更新日期:2017-09-14
  • Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation
    Genome Res. (IF 11.922) Pub Date : 2017-09-13
    Stefano de Pretis; Theresia R. Kress; Marco J. Morelli; Arianna Sabò; Chiara Locarno; Alessandro Verrecchia; Mirko Doni; Stefano Campaner; Bruno Amati; Mattia Pelizzola

    Overexpression of the MYC transcription factor causes its widespread interaction with regulatory elements in the genome but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of transcription and mRNA dynamics following MYC activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing, and mathematical modeling. Transcriptional activation correlated with the highest increases in MYC binding at promoters. Repression followed a reciprocal scenario, with the lowest gains in MYC binding. Altogether, the relative abundance (henceforth, “share”) of MYC at promoters was the strongest predictor of transcriptional responses in diverse cell types, predominating over MYC's association with the corepressor ZBTB17 (also known as MIZ1). MYC activation elicited immediate loading of RNA polymerase II (RNAPII) at activated promoters, followed by increases in pause-release, while repressed promoters showed opposite effects. Gains and losses in RNAPII loading were proportional to the changes in the MYC share, suggesting that repression by MYC may be partly indirect, owing to competition for limiting amounts of RNAPII. Secondary to the changes in RNAPII loading, the dynamics of elongation and pre-mRNA processing were also rapidly altered at MYC regulated genes, leading to the transient accumulation of partially or aberrantly processed mRNAs. Altogether, our results shed light on how overexpressed MYC alters the various phases of the RNAPII cycle and the resulting transcriptional response.

    更新日期:2017-09-14
  • Detection of long repeat expansions from PCR-free whole-genome sequence data
    Genome Res. (IF 11.922) Pub Date : 2017-09-08
    Egor Dolzhenko; Joke J.F.A. van Vugt; Richard J. Shaw; Mitchell A. Bekritsky; Marka van Blitterswijk; Giuseppe Narzisi; Subramanian S. Ajay; Vani Rajan; Bryan Lajoie; Nathan H. Johnson; Zoya Kingsbury; Sean J. Humphray; Raymond D. Schellevis; William J. Brands; Matt Baker; Rosa Rademakers; Maarten Kooyman; Gijs H.P. Tazelaar; Michael A. van Es; Russell McLaughlin; William Sproviero; Aleksey Shatunov; Ashley Jones; Ahmad Al Khleifat; Alan Pittman; Sarah Morgan; Orla Hardiman; Ammar Al-Chalabi; Chris Shaw; Bradley Smith; Edmund J. Neo; Karren Morrison; Pam Shaw; Catherine Reeves; Lara Winterkorn; Nancy S. Wexler; The US-Venezuela Collaborative Research Group; David E. Housman; Christopher W. Ng; Alina L. Li; Ryan J. Taft; Leonard H. van den Berg; David R. Bentley; Jan H. Veldink; Michael A. Eberle

    Identifying large expansions of short tandem repeats (STRs) such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step towards integrating WGS into precision medicine. We have developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3,001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2,786/2,789, 95% CI [0.997, 1.00]) of the wild type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples where every sample had one of eight different pathogenic repeat expansions including those associated with fragile X syndrome, Friedreich's ataxia and Huntington's disease and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions. The software is licensed under GPL v3.0 and the source code is freely available on GitHub.

    更新日期:2017-09-11
  • Transposable elements are the primary source of novelty in primate gene regulation
    Genome Res. (IF 11.922) Pub Date : 2017-08-30
    Marco Trizzino; YoSon Park; Marcia Holsbach-Beltrame; Katherine Aracena; Katelyn Mika; Minal Caliskan; George H. Perry; Vincent J. Lynch; Christopher D. Brown

    Gene regulation shapes the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species using ChIP-seq (H3K27ac and H3K4me1) to profile cis-regulatory elements (CREs) and using RNA-seq to characterize gene expression in the same individuals. To quantify regulatory divergence, we compared CRE activity across species by testing differential ChIP-seq read depths directly measured for orthologous sequences. We show that the primate regulatory landscape is largely conserved across the lineage, with 63% of the tested human liver CREs showing similar activity across species. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell-type specificity, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions. We further demonstrate that conserved CREs bind master regulators, suggesting that while CREs contribute to species adaptation to the environment, core functions remain intact. Newly evolved CREs are enriched in young transposable elements (TEs), including Long-Terminal-Repeats (LTRs) and SINE-VNTR-Alus (SVAs), that significantly affect gene expression. Conversely, only 16% of conserved CREs overlap TEs. We tested the cis-regulatory activity of 69 TE subfamilies by luciferase reporter assays, spanning all major TE classes, and showed that 95.6% of tested TEs can function as either transcriptional activators or repressors. In conclusion, we demonstrated the critical role of TEs in primate gene regulation and illustrated potential mechanisms underlying evolutionary divergence among the primate species through the noncoding genome.

    更新日期:2017-09-11
  • Toward the human cellular microRNAome
    Genome Res. (IF 11.922) Pub Date : 2017-09-06
    Matthew N. McCall; Min-Sik Kim; Mohammed Adil; Arun H. Patil; Yin Lu; Christopher J. Mitchell; Pamela Leal-Rojas; Jinchong Xu; Manoj Kumar; Valina L. Dawson; Ted M. Dawson; Alexander S. Baras; Avi Z. Rosenberg; Dan E. Arking; Kathleen H. Burns; Akhilesh Pandey; Marc K. Halushka

    MicroRNAs are short RNAs that serve as regulators of gene expression and are essential components of normal development as well as modulators of disease. MicroRNAs generally act cell-autonomously, and thus their localization to specific cell types is needed to guide our understanding of microRNA activity. Current tissue-level data have caused considerable confusion, and comprehensive cell-level data do not yet exist. Here, we establish the landscape of human cell-specific microRNA expression. This project evaluated 8 billion small RNA-seq reads from 46 primary cell types, 42 cancer or immortalized cell lines, and 26 tissues. It identified both specific and ubiquitous patterns of expression that strongly correlate with adjacent superenhancer activity. Analysis of unaligned RNA reads uncovered 207 unknown minor strand (passenger) microRNAs of known microRNA loci and 495 novel putative microRNA loci. Although cancer cell lines generally recapitulated the expression patterns of matched primary cells, their isomiR sequence families exhibited increased disorder, suggesting DROSHA- and DICER1-dependent microRNA processing variability. Cell-specific patterns of microRNA expression were used to de-convolute variable cellular composition of colon and adipose tissue samples, highlighting one use of these cell-specific microRNA expression data. Characterization of cellular microRNA expression across a wide variety of cell types provides a new understanding of this critical regulatory RNA species.

    更新日期:2017-09-08
  • Detection of structural mosaicism from targeted and whole-genome sequencing data
    Genome Res. (IF 11.922) Pub Date : 2017-08-30
    Daniel A. King; Alejandro Sifrim; Tomas W. Fitzgerald; Raheleh Rahbari; Emma Hobson; Tessa Homfray; Sahar Mansour; Sarju G. Mehta; Mohammed Shehla; Susan E. Tomkins; Pradeep C. Vasudevan; Matthew E. Hurles; The Deciphering Developmental Disorders Study

    Structural mosaic abnormalities are large post-zygotic mutations present in a subset of cells and have been implicated in developmental disorders and cancer. Such mutations have been conventionally assessed in clinical diagnostics using cytogenetic or microarray testing. Modern disease studies rely heavily on exome sequencing, yet an adequate method for the detection of structural mosaicism using targeted sequencing data is lacking. Here, we present a method, called MrMosaic, to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next-generation sequencing data. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) simulations were used to calculate detection performance across a range of mosaic event sizes, types, clonalities, and sequencing depths. The tool was applied to 4911 patients with undiagnosed developmental disorders, and 11 events among nine patients were detected. For eight of these 11 events, mosaicism was observed in saliva but not blood, suggesting that assaying blood alone would miss a large fraction, possibly >50%, of mosaic diagnostic chromosomal rearrangements.

    更新日期:2017-09-08
  • Solid-phase reverse transfection for intracellular delivery of functionally active proteins
    Genome Res. (IF 11.922) Pub Date : 2017-09-05
    Ruben Bulkescher; Vytaute Starkuviene; Holger Erfle

    Delivery of large and functionally active biomolecules across cell membranes presents a challenge in cell biological experimentation. For this purpose, we developed a novel solid-phase reverse transfection method that is suitable for the intracellular delivery of proteins into mammalian cells with preservation of their function. We show results for diverse application areas of the method, ranging from antibody-mediated inhibition of protein function to CRISPR/Cas9-based gene editing in living cells. Our method enables prefabrication of “ready to transfect” substrates carrying diverse proteins. This allows their easy distribution and standardization of biological assays across different laboratories.

    更新日期:2017-09-08
  • Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Joshua Traynelis; Michael Silk; Quanli Wang; Samuel F. Berkovic; Liping Liu; David B. Ascher; David J. Balding; Slavé Petrovski

    Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions (P < 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney U test, P < 1 × 10−16). We focus on the application to epilepsy genes; however, the framework is applicable to disease genes beyond epilepsy.

    更新日期:2017-09-08
  • RNA editing in bacteria recodes multiple proteins and regulates an evolutionarily conserved toxin-antitoxin system
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Dan Bar-Yaacov; Ernest Mordret; Ruth Towers; Tammy Biniashvili; Clara Soyris; Schraga Schwartz; Orna Dahan; Yitzhak Pilpel

    Adenosine (A) to inosine (I) RNA editing is widespread in eukaryotes. In prokaryotes, however, A-to-I RNA editing was only reported to occur in tRNAs but not in protein-coding genes. By comparing DNA and RNA sequences of Escherichia coli, we show for the first time that A-to-I editing occurs also in prokaryotic mRNAs and has the potential to affect the translated proteins and cell physiology. We found 15 novel A-to-I editing events, of which 12 occurred within known protein-coding genes where they always recode a tyrosine (TAC) into a cysteine (TGC) codon. Furthermore, we identified the tRNA-specific adenosine deaminase (tadA) as the editing enzyme of all these editing sites, thus making it the first identified RNA editing enzyme that modifies both tRNAs and mRNAs. Interestingly, several of the editing targets are self-killing toxins that belong to evolutionarily conserved toxin-antitoxin pairs. We focused on hokB, a toxin that confers antibiotic tolerance by growth inhibition, as it demonstrated the highest level of such mRNA editing. We identified a correlated mutation pattern between the edited and a DNA hard-coded Cys residue positions in the toxin and demonstrated that RNA editing occurs in hokB in two additional bacterial species. Thus, not only the toxin is evolutionarily conserved but also the editing itself within the toxin is. Finally, we found that RNA editing in hokB increases as a function of cell density and enhances its toxicity. Our work thus demonstrates the occurrence, regulation, and functional consequences of RNA editing in bacteria.

    更新日期:2017-09-08
  • The Mobile Element Locator Tool (MELT): Population-scale mobile element discovery and biology
    Genome Res. (IF 11.922) Pub Date : 2017-08-30
    Eugene J. Gardner; Vincent K. Lam; Daniel N. Harris; Nelson T. Chuang; Emma C. Scott; William S. Pittard; Ryan E. Mills; 1000 Genomes Project Consortium; Scott E. Devine

    Mobile element insertions (MEIs) represent ~25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by: i) diverse rates of MEI production from source elements, ii) diverse patterns of MEI inheritance, and iii) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans, and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings.

    更新日期:2017-09-08
  • HiCRep: assessing the reproducibility of Hi-C data using a stratum- adjusted correlation coefficient
    Genome Res. (IF 11.922) Pub Date : 2017-08-30
    Tao Yang; Feipeng Zhang; Galip Gurkan Yardimci; Fan Song; Ross C Hardison; William Stafford Noble; Feng Yue; Qunhua Li

    Hi-C is a powerful technology for studying genome-wide chromatin interactions. However, current methods for assessing Hi-C data reproducibility can produce misleading results because they ignore spatial features in Hi-C data, such as domain structure and distance dependence. We present HiCRep, a framework for assessing the reproducibility of Hi-C data that systematically accounts for these features. In particular, we introduce a novel similarity measure, the stratum adjusted correlation coefficient (SCC), for quantifying the similarity between Hi-C interaction matrices. Not only does it provide a statistically sound and reliable evaluation of reproducibility, SCC can also be used to quantify differences between Hi-C contact matrices and to determine the optimal sequencing depth for a desired resolution. The measure consistently shows higher accuracy than existing approaches in distinguishing subtle differences in reproducibility and depicting interrelationships of cell lineages. The proposed measure is straightforward to interpret and easy to compute, making it well-suited for providing standardized, interpretable, automatable, and scalable quality control. The freely available R package HiCRep implements our approach.

    更新日期:2017-09-08
  • Discovering novel pharmacogenomic biomarkers by imputing drug response in cancer patients from large genomics studies
    Genome Res. (IF 11.922) Pub Date : 2017-08-28
    Paul Geeleher; Zhenyu Zhang; Fan Wang; Robert F. Gruener; Aritro Nath; Gladys Morrison; Steven Bhutra; Robert L. Grossman; R. Stephanie Huang

    Obtaining accurate drug response data in large cohorts of cancer patients is very challenging; thus, most cancer pharmacogenomics discovery is conducted in preclinical studies, typically using cell lines and mouse models. However, these platforms suffer from serious limitations, including small sample sizes. Here, we have developed a novel computational method that allows us to impute drug response in very large clinical cancer genomics data sets, such as The Cancer Genome Atlas (TCGA). The approach works by creating statistical models relating gene expression to drug response in large panels of cancer cell lines and applying these models to tumor gene expression data in the clinical data sets (e.g., TCGA). This yields an imputed drug response for every drug in each patient. These imputed drug response data are then associated with somatic genetic variants measured in the clinical cohort, such as copy number changes or mutations in protein coding genes. These analyses recapitulated drug associations for known clinically actionable somatic genetic alterations and identified new predictive biomarkers for existing drugs.

    更新日期:2017-09-08
  • The evolution of duplicate gene expression in mammalian organs
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Katerina Guschanski; Maria Warnefors; Henrik Kaessmann

    Gene duplications generate genomic raw material that allows the emergence of novel functions, likely facilitating adaptive evolutionary innovations. However, global assessments of the functional and evolutionary relevance of duplicate genes in mammals were until recently limited by the lack of appropriate comparative data. Here, we report a large-scale study of the expression evolution of DNA-based functional gene duplicates in three major mammalian lineages (placental mammals, marsupials, egg-laying monotremes) and birds, on the basis of RNA sequencing (RNA-seq) data from nine species and eight organs. We observe dynamic changes in tissue expression preference of paralogs with different duplication ages, suggesting differential contribution of paralogs to specific organ functions during vertebrate evolution. Specifically, we show that paralogs that emerged in the common ancestor of bony vertebrates are enriched for genes with brain-specific expression and provide evidence for differential forces underlying the preferential emergence of young testis- and liver-specific expressed genes. Further analyses uncovered that the overall spatial expression profiles of gene families tend to be conserved, with several exceptions of pronounced tissue specificity shifts among lineage-specific gene family expansions. Finally, we trace new lineage-specific genes that may have contributed to the specific biology of mammalian organs, including the little-studied placenta. Overall, our study provides novel and taxonomically broad evidence for the differential contribution of duplicate genes to tissue-specific transcriptomes and for their importance for the phenotypic evolution of vertebrates.

    更新日期:2017-09-08
  • Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumors
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Mi Ni Huang; Willie Yu; Wei Wei Teoh; Maude Ardin; Apinya Jusakul; Alvin Wei Tian Ng; Arnoud Boot; Behnoush Abedi-Ardekani; Stephanie Villar; Swe Swe Myint; Rashidah Othman; Song Ling Poon; Adriana Heguy; Magali Olivier; Monica Hollstein; Patrick Tan; Bin Tean Teh; Kanaga Sabapathy; Jiri Zavadil; Steven G. Rozen

    Aflatoxin B1 (AFB1) is a mutagen and IARC (International Agency for Research on Cancer) Group 1 carcinogen that causes hepatocellular carcinoma (HCC). Here, we present the first whole-genome data on the mutational signatures of AFB1 exposure from a total of >40,000 mutations in four experimental systems: two different human cell lines, in liver tumors in wild-type mice, and in mice that carried a hepatitis B surface antigen transgene—this to model the multiplicative effects of aflatoxin exposure and hepatitis B in causing HCC. AFB1 mutational signatures from all four experimental systems were remarkably similar. We integrated the experimental mutational signatures with data from newly sequenced HCCs from Qidong County, China, a region of well-studied aflatoxin exposure. This indicated that COSMIC mutational signature 24, previously hypothesized to stem from aflatoxin exposure, indeed likely represents AFB1 exposure, possibly combined with other exposures. Among published somatic mutation data, we found evidence of AFB1 exposure in 0.7% of HCCs treated in North America, 1% of HCCs from Japan, but 16% of HCCs from Hong Kong. Thus, aflatoxin exposure apparently remains a substantial public health issue in some areas. This aspect of our study exemplifies the promise of future widespread resequencing of tumor genomes in providing new insights into the contribution of mutagenic exposures to cancer incidence.

    更新日期:2017-09-08
  • Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    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 P. Roth; Kyoungho Suk

    To understand disease mechanisms, a large-scale analysis of human–yeast genetic interactions was performed. Of 1305 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 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify 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. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases.

    更新日期:2017-09-08
  • HOXA1 and TALE proteins display cross-regulatory interactions and form a combinatorial binding code on HOXA1 targets
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Bony De Kumar; Hugo J. Parker; Ariel Paulson; Mark E. Parrish; Irina Pushel; Narendra Pratap Singh; Ying Zhang; Brian D. Slaughter; Jay R. Unruh; Laurence Florens; Julia Zeitlinger; Robb Krumlauf

    Hoxa1 has diverse functional roles in differentiation and development. We identify and characterize properties of regions bound by HOXA1 on a genome-wide basis in differentiating mouse ES cells. HOXA1-bound regions are enriched for clusters of consensus binding motifs for HOX, PBX, and MEIS, and many display co-occupancy of PBX and MEIS. PBX and MEIS are members of the TALE family and genome-wide analysis of multiple TALE members (PBX, MEIS, TGIF, PREP1, and PREP2) shows that nearly all HOXA1 targets display occupancy of one or more TALE members. The combinatorial binding patterns of TALE proteins define distinct classes of HOXA1 targets, which may create functional diversity. Transgenic reporter assays in zebrafish confirm enhancer activities for many HOXA1-bound regions and the importance of HOX-PBX and TGIF motifs for their regulation. Proteomic analyses show that HOXA1 physically interacts on chromatin with PBX, MEIS, and PREP family members, but not with TGIF, suggesting that TGIF may have an independent input into HOXA1-bound regions. Therefore, TALE proteins appear to represent a wide repertoire of HOX cofactors, which may coregulate enhancers through distinct mechanisms. We also discover extensive auto- and cross-regulatory interactions among the Hoxa1 and TALE genes, indicating that the specificity of HOXA1 during development may be regulated though a complex cross-regulatory network of HOXA1 and TALE proteins. This study provides new insight into a regulatory network involving combinatorial interactions between HOXA1 and TALE proteins.

    更新日期:2017-09-08
  • Trans-splicing enhances translational efficiency in C. elegans
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    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% of 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 the 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. First, SL1 trans-spliced genes have higher translational efficiencies than non-trans-spliced genes. Second, SL1 trans-spliced genes have higher translational efficiencies than non-trans-spliced orthologous genes in other nematode species. Third, an SL1 trans-spliced isoform has higher translational efficiency than the non-trans-spliced isoform of the same gene. Fourth, deletion of trans-splicing sites of endogenous genes leads to reduced translational efficiency. Importantly, we demonstrated that SL1 trans-splicing plays a key role in enhancing translational efficiencies of essential genes. We further discovered that SL1 trans-splicing likely enhances translational efficiency by shortening the native 5′ UTRs, hence reducing the presence of upstream start codons (uAUG) and weakening mRNA secondary structures. Taken together, our study elucidates the global function of trans-splicing in enhancing translational efficiency in nematodes, paving the way for further understanding the genomic mechanisms of translational regulation.

    更新日期:2017-09-08
  • Recruitment of histone modifications to assist mRNA dosage maintenance after degeneration of cytosine DNA methylation during animal evolution
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Andrew Ying-Fei 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 the 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. Here, we hypothesize that in the absence of a classical cytosine DNA methylation pathway, histone modifications play an increasing role in maintaining mRNA dosage following gene duplication. We initially verified that reduced gene expression of duplicated genes had occurred in the worm, fly, and mouse (Mus musculus). Next, several histone marks, with the capacity to control mRNA abundance in the models studied, were examined. In the worm and fly, but not in the mouse, multiple histone modifications were found to assist mRNA dosage maintenance following gene duplication events and the possible involvement of adenine DNA methylation in this process was excluded. Furthermore, the histone marks and acting regions that mediated the reduction in duplicated gene expression were found to be largely organism specific. Thus, it appears that many of the histone marks that maintain mRNA dosage were independently recruited during the evolution of worms and flies to compensate for the loss of cytosine DNA methylation machinery from their genomes.

    更新日期:2017-09-08
  • Rapid evolution of female-biased genes among four species of Anopheles malaria mosquitoes
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Francesco Papa; Nikolai Windbichler; Robert M. Waterhouse; Alessia Cagnetti; Rocco D'Amato; Tania Persampieri; Mara K.N. Lawniczak; Tony Nolan; Philippos Aris Papathanos

    Understanding how phenotypic differences between males and females arise from the sex-biased expression of nearly identical genomes can reveal important insights into the biology and evolution of a species. Among Anopheles mosquito species, these phenotypic differences include vectorial capacity, as it is only females that blood feed and thus transmit human malaria. Here, we use RNA-seq data from multiple tissues of four vector species spanning the Anopheles phylogeny to explore the genomic and evolutionary properties of sex-biased genes. We find that, in these mosquitoes, in contrast to what has been found in many other organisms, female-biased genes are more rapidly evolving in sequence, expression, and genic turnover than male-biased genes. Our results suggest that this atypical pattern may be due to the combination of sex-specific life history challenges encountered by females, such as blood feeding. Furthermore, female propensity to mate only once in nature in male swarms likely diminishes sexual selection of post-reproductive traits related to sperm competition among males. We also develop a comparative framework to systematically explore tissue- and sex-specific splicing to document its conservation throughout the genus and identify a set of candidate genes for future functional analyses of sex-specific isoform usage. Finally, our data reveal that the deficit of male-biased genes on the X Chromosomes in Anopheles is a conserved feature in this genus and can be directly attributed to chromosome-wide transcriptional regulation that de-masculinizes the X in male reproductive tissues.

    更新日期:2017-09-08
  • A genome-wide transcriptome and translatome analysis of Arabidopsis transposons identifies a unique and conserved genome expression strategy for Ty1/Copia retroelements
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Stefan Oberlin; Alexis Sarazin; Clément Chevalier; Olivier Voinnet; Arturo Marí-Ordóñez

    Retroelements, the prevalent class of plant transposons, have major impacts on host genome integrity and evolution. They produce multiple proteins from highly compact genomes and, similar to viruses, must have evolved original strategies to optimize gene expression, although this aspect has been seldom investigated thus far. Here, we have established a high-resolution transcriptome/translatome map for the near-entirety of Arabidopsis thaliana transposons, using two distinct DNA methylation mutants in which transposon expression is broadly de-repressed. The value of this map to study potentially intact and transcriptionally active transposons in A. thaliana is illustrated by our comprehensive analysis of the cotranscriptional and translational features of Ty1/Copia elements, a family of young and active retroelements in plant genomes, and how such features impact their biology. Genome-wide transcript profiling revealed a unique and widely conserved alternative splicing event coupled to premature termination that allows for the synthesis of a short subgenomic RNA solely dedicated to production of the GAG structural protein and that preferentially associates with polysomes for efficient translation. Mutations engineered in a transgenic version of the Arabidopsis EVD Ty1/Copia element further show how alternative splicing is crucial for the appropriate coordination of full-length and subgenomic RNA transcription. We propose that this hitherto undescribed genome expression strategy, conserved among plant Ty1/Copia elements, enables an excess of structural versus catalytic components, mandatory for mobilization.

    更新日期:2017-09-08
  • Detecting ancient positive selection in humans using extended lineage sorting
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Stéphane Peyrégne; 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. Regions that are unusually long indicate the presence of lineages that reached fixation in the human population faster than expected under neutral evolution. Using simulations, we show that the method is able to detect ancient events of positive selection and that it can differentiate those from background selection. Applying our method to the 1000 Genomes data set, we find evidence for ancient selective sweeps favoring regulatory changes and present a list of genomic regions that are predicted to underlie positively selected human specific traits.

    更新日期:2017-09-08
  • HIT'nDRIVE: patient-specific multidriver gene prioritization for precision oncology
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Raunak Shrestha; Ermin Hodzic; Thomas Sauerwald; Phuong Dao; Kendric Wang; Jake Yeung; Shawn Anderson; Fabio Vandin; Gholamreza Haffari; Colin C. Collins; S. 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: “multihitting 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. When applied to 2200 tumors from four major cancer types, HIT'nDRIVE revealed many potentially clinically actionable driver genes. We also demonstrated that it is possible to perform accurate phenotype prediction for tumor samples by only using HIT'nDRIVE-seeded driver gene modules from gene interaction networks. In addition, we identified a number of breast cancer subtype-specific driver modules that are associated with patients’ survival outcome. Furthermore, HIT'nDRIVE, when applied to a large panel of pan-cancer cell lines, accurately predicted drug efficacy using the driver genes and their seeded gene modules. Overall, HIT'nDRIVE may help clinicians contextualize massive multiomics data in therapeutic decision making, enabling widespread implementation of precision oncology.

    更新日期:2017-09-08
  • Statistically robust methylation calling for whole-transcriptome bisulfite sequencing reveals distinct methylation patterns for mouse RNAs
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    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. Here, we present a computational approach that integrates tailored filtering and data-driven statistical modeling to eliminate many of the artifacts that are known to be associated with bisulfite sequencing. By using RNAs from mouse embryonic stem cells, we performed a comprehensive methylation analysis of mouse tRNAs, rRNAs, and mRNAs. Our approach identified all known methylation marks in tRNA and two previously unknown but evolutionary conserved marks in 28S rRNA. In addition, mRNAs were found to be very sparsely methylated or not methylated at all. Finally, the tRNA-specific activity of the DNMT2 methyltransferase could be resolved at single-base resolution, which provided important further validation. Our approach can be used to profile cytosine-5 RNA methylation patterns in many experimental contexts and will be important for understanding the function of cytosine-5 RNA methylation in RNA biology and in human disease.

    更新日期:2017-09-08
  • Assembly and analysis of 100 full MHC haplotypes from the Danish population
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Jacob M. Jensen; Palle Villesen; Rune M. Friborg; The Danish Pan-Genome Consortium; Thomas Mailund; Søren Besenbacher; Mikkel H. Schierup; Lasse Maretty; Jacob Malte Jensen; Bent Petersen; Jonas Andreas Sibbesen; Siyang Liu; Palle Villesen; Laurits Skov; Kirstine Belling; Christian Theil Have; Jose M.G. Izarzugaza; Marie Grosjean; Jette Bork-Jensen; Jakob Grove; Thomas D. Als; Shujia Huang; Yuqi Chang; Ruiqi Xu; Weijian Ye; Junhua Rao; Xiaosen Guo; Jihua Sun; Hongzhi Cao; Chen Ye; Johan v Beusekom; Thomas Espeseth; Esben Flindt; Rune M. Friborg; Anders E. Halager; Stephanie Le Hellard; Christina M. Hultman; Francesco Lescai; Shengting Li; Ole Lund; Peter Løngren; Thomas Mailund; Maria Luisa Matey-Hernandez; Ole Mors; Christian N.S. Pedersen; Thomas Sicheritz-Pontén; Patrick Sullivan; Ali Syed; David Westergaard; Rachita Yadav; Ning Li; Xun Xu; Torben Hansen; Anders Krogh; Lars Bolund; Thorkild I.A. Sørensen; Oluf Pedersen; Ramneek Gupta; Simon Rasmussen; Søren Besenbacher; Anders D. Børglum; Jun Wang; Hans Eiberg; Karsten Kristiansen; Søren Brunak; Mikkel Heide Schierup

    Genes in the major histocompatibility complex (MHC, also known as HLA) play a critical role in the immune response and variation within the extended 4-Mb region shows association with major risks of many diseases. Yet, deciphering the underlying causes of these associations is difficult because the MHC is the most polymorphic region of the genome with a complex linkage disequilibrium structure. Here, we reconstruct full MHC haplotypes from de novo assembled trios without relying on a reference genome and perform evolutionary analyses. We report 100 full MHC haplotypes and call a large set of structural variants in the regions for future use in imputation with GWAS data. We also present the first complete analysis of the recombination landscape in the entire region and show how balancing selection at classical genes have linked effects on the frequency of variants throughout the region.

    更新日期:2017-09-08
  • Annotation and cluster analysis of spatiotemporal- and sex-related lncRNA expression in rhesus macaque brain
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Siling Liu; Zhengbo Wang; Dong Chen; Bowen Zhang; Ren-Rong Tian; Jing Wu; Ying Zhang; Kaiyu Xu; Liu-Meng Yang; Chao Cheng; Jian Ma; Longbao Lv; Yong-Tang Zheng; Xintian Hu; Yi Zhang; Xiangting Wang; Jiali Li

    Long noncoding RNAs (lncRNAs) mediate important epigenetic regulation in a wide range of biological processes and diseases. 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 (Macaca mulatta) brain in four representative age groups. 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 were generally higher than those observed in mRNA expression. A negative correlation between lncRNA and mRNA expression in cerebral cortex was observed and functionally validated. Our findings offer a fresh insight into spatial-, age-, and sex-biased changes in lncRNA expression in macaque brain and suggest that the changes represent a previously unappreciated regulatory system that potentially contributes to brain development and aging.

    更新日期:2017-09-08
  • Corrigendum: The evolution of African great ape subtelomeric heterochromatin and the fusion of human chromosome 2
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Mario Ventura; Claudia R. Catacchio; Saba Sajjadian; Laura Vives; Peter H. Sudmant; Tomas Marques-Bonet; Tina A. Graves; Richard K. Wilson; Evan E. Eichler

    Genome Research 22: 1036–1049 (2012)

    更新日期:2017-09-08
  • Corrigendum: Transcriptome analyses of rhesus monkey preimplantation embryos reveal a reduced capacity for DNA double-strand break repair in primate oocytes and early embryos
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Xinyi Wang; Denghui Liu; Dajian He; Shengbao Suo; Xian Xia; Xiechao He; Jing-Dong J. Han; Ping Zheng

    Genome Research 27: 567–579 (2017)

    更新日期:2017-09-08
  • Corrigendum: Building a genomic framework for prospective MRSA surveillance in the United Kingdom and the Republic of Ireland
    Genome Res. (IF 11.922) Pub Date : 2017-09-01
    Sandra Reuter; M. Estée Török; Matthew T.G. Holden; Rosy Reynolds; Kathy E. Raven; Beth Blane; Tjibbe Donker; Stephen D. Bentley; David M. Aanensen; Hajo Grundmann; Edward J. Feil; Brian G. Spratt; Julian Parkhill; Sharon J. Peacock

    Genome Research 26: 263–270 (2016)

    更新日期:2017-09-08
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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