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  • Cold Spring Harbor Laboratory  (9)
  • 2010-2014  (9)
  • 1
    Online Resource
    Online Resource
    Estimation of rearrangement phylogeny for cancer genomes
    Cold Spring Harbor Laboratory ; 2012
    In:  Genome Research Vol. 22, No. 2 ( 2012-02), p. 346-361
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 22, No. 2 ( 2012-02), p. 346-361
    Abstract: Cancer genomes are complex, carrying thousands of somatic mutations including base substitutions, insertions and deletions, rearrangements, and copy number changes that have been acquired over decades. Recently, technologies have been introduced that allow generation of high-resolution, comprehensive catalogs of somatic alterations in cancer genomes. However, analyses of these data sets generally do not indicate the order in which mutations have occurred, or the resulting karyotype. Here, we introduce a mathematical framework that begins to address this problem. By using samples with accurate data sets, we can reconstruct relatively complex temporal sequences of rearrangements and provide an assembly of genomic segments into digital karyotypes. For cancer genes mutated in rearranged regions, this information can provide a chronological examination of the selective events that have taken place.
    Type of Medium: Online Resource
    ISSN: 1088-9051
    URL: Article
    DOI: 10.1101/gr.118414.110
    RVK:
    XA 10000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2012
    detail.hit.zdb_id: 1483456-X
    SSG: 12
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  • 2
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    Online Resource
    Bicaudal-D uses a parallel, homodimeric coiled coil with heterotypic registry to coordinate recruitment of cargos to dynein
    Cold Spring Harbor Laboratory ; 2013
    In:  Genes & Development Vol. 27, No. 11 ( 2013-06-01), p. 1233-1246
    Details
    In: Genes & Development, Cold Spring Harbor Laboratory, Vol. 27, No. 11 ( 2013-06-01), p. 1233-1246
    Abstract: Cytoplasmic dynein is the major minus end-directed microtubule motor in eukaryotes. However, there is little structural insight into how different cargos are recognized and linked to the motor complex. Here we describe the 2.2 Å resolution crystal structure of a cargo-binding region of the dynein adaptor Bicaudal-D (BicD), which reveals a parallel coiled-coil homodimer. We identify a shared binding site for two cargo-associated proteins—Rab6 and the RNA-binding protein Egalitarian (Egl)—within a region of the BicD structure with classical, homotypic core packing. Structure-based mutagenesis in Drosophila provides evidence that occupancy of this site drives association of BicD with dynein, thereby coupling motor recruitment to cargo availability. The structure also contains a region in which, remarkably, the same residues in the polypeptide sequence have different heptad registry in each chain. In vitro and in vivo analysis of a classical Drosophila dominant mutation reveals that this heterotypic region regulates the recruitment of dynein to BicD. Our results support a model in which the heterotypic segment is part of a molecular switch that promotes release of BicD autoinhibition following cargo binding to the neighboring, homotypic coiled-coil region. Overall, our data reveal a pivotal role of a highly asymmetric coiled-coil domain in coordinating the assembly of cargo–motor complexes.
    Type of Medium: Online Resource
    ISSN: 0890-9369 , 1549-5477
    URL: Article
    DOI: 10.1101/gad.212381.112
    RVK:
    WA 15000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2013
    detail.hit.zdb_id: 1467414-2
    SSG: 12
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  • 3
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    Genome-wide analysis of promoter architecture in Drosophila melanogaster
    Cold Spring Harbor Laboratory ; 2011
    In:  Genome Research Vol. 21, No. 2 ( 2011-02), p. 182-192
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 21, No. 2 ( 2011-02), p. 182-192
    Abstract: Core promoters are critical regions for gene regulation in higher eukaryotes. However, the boundaries of promoter regions, the relative rates of initiation at the transcription start sites (TSSs) distributed within them, and the functional significance of promoter architecture remain poorly understood. We produced a high-resolution map of promoters active in the Drosophila melanogaster embryo by integrating data from three independent and complementary methods: 21 million cap analysis of gene expression (CAGE) tags, 1.2 million RNA ligase mediated rapid amplification of cDNA ends (RLM-RACE) reads, and 50,000 cap-trapped expressed sequence tags (ESTs). We defined 12,454 promoters of 8037 genes. Our analysis indicates that, due to non-promoter-associated RNA background signal, previous studies have likely overestimated the number of promoter-associated CAGE clusters by fivefold. We show that TSS distributions form a complex continuum of shapes, and that promoters active in the embryo and adult have highly similar shapes in 95% of cases. This suggests that these distributions are generally determined by static elements such as local DNA sequence and are not modulated by dynamic signals such as histone modifications. Transcription factor binding motifs are differentially enriched as a function of promoter shape, and peaked promoter shape is correlated with both temporal and spatial regulation of gene expression. Our results contribute to the emerging view that core promoters are functionally diverse and control patterning of gene expression in Drosophila and mammals.
    Type of Medium: Online Resource
    ISSN: 1088-9051
    URL: Article
    DOI: 10.1101/gr.112466.110
    RVK:
    XA 10000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2011
    detail.hit.zdb_id: 1483456-X
    SSG: 12
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  • 4
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    Assemblathon 1: A competitive assessment of de novo short read assembly methods
    Cold Spring Harbor Laboratory ; 2011
    In:  Genome Research Vol. 21, No. 12 ( 2011-12), p. 2224-2241
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 21, No. 12 ( 2011-12), p. 2224-2241
    Abstract: Low-cost short read sequencing technology has revolutionized genomics, though it is only just becoming practical for the high-quality de novo assembly of a novel large genome. We describe the Assemblathon 1 competition, which aimed to comprehensively assess the state of the art in de novo assembly methods when applied to current sequencing technologies. In a collaborative effort, teams were asked to assemble a simulated Illumina HiSeq data set of an unknown, simulated diploid genome. A total of 41 assemblies from 17 different groups were received. Novel haplotype aware assessments of coverage, contiguity, structure, base calling, and copy number were made. We establish that within this benchmark: (1) It is possible to assemble the genome to a high level of coverage and accuracy, and that (2) large differences exist between the assemblies, suggesting room for further improvements in current methods. The simulated benchmark, including the correct answer, the assemblies, and the code that was used to evaluate the assemblies is now public and freely available from http://www.assemblathon.org/ .
    Type of Medium: Online Resource
    ISSN: 1088-9051
    URL: Article
    DOI: 10.1101/gr.126599.111
    RVK:
    XA 10000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2011
    detail.hit.zdb_id: 1483456-X
    SSG: 12
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  • 5
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    Online Resource
    A high-resolution association mapping panel for the dissection of complex traits in mice
    Cold Spring Harbor Laboratory ; 2010
    In:  Genome Research Vol. 20, No. 2 ( 2010-02), p. 281-290
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 20, No. 2 ( 2010-02), p. 281-290
    Abstract: Systems genetics relies on common genetic variants to elucidate biologic networks contributing to complex disease-related phenotypes. Mice are ideal model organisms for such approaches, but linkage analysis has been only modestly successful due to low mapping resolution. Association analysis in mice has the potential of much better resolution, but it is confounded by population structure and inadequate power to map traits that explain less than 10% of the variance, typical of mouse quantitative trait loci (QTL). We report a novel strategy for association mapping that combines classic inbred strains for mapping resolution and recombinant inbred strains for mapping power. Using a mixed model algorithm to correct for population structure, we validate the approach by mapping over 2500 cis -expression QTL with a resolution an order of magnitude narrower than traditional QTL analysis. We also report the fine mapping of metabolic traits such as plasma lipids. This resource, termed the Hybrid Mouse Diversity Panel, makes possible the integration of multiple data sets and should prove useful for systems-based approaches to complex traits and studies of gene-by-environment interactions.
    Type of Medium: Online Resource
    ISSN: 1088-9051
    URL: Article
    DOI: 10.1101/gr.099234.109
    RVK:
    XA 10000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2010
    detail.hit.zdb_id: 1483456-X
    SSG: 12
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  • 6
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    Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver
    Cold Spring Harbor Laboratory ; 2010
    In:  Genome Research Vol. 20, No. 8 ( 2010-08), p. 1020-1036
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 20, No. 8 ( 2010-08), p. 1020-1036
    Abstract: Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis -regulation of P450 expression (especially for CYP2D6 ) and more complex trans -regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH , SLC10A1 , and AKR1D1 . The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.
    Type of Medium: Online Resource
    ISSN: 1088-9051
    URL: Article
    DOI: 10.1101/gr.103341.109
    RVK:
    XA 10000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2010
    detail.hit.zdb_id: 1483456-X
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  • 7
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    Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP
    Cold Spring Harbor Laboratory ; 2010
    In:  Genes & Development Vol. 24, No. 13 ( 2010-07-01), p. 1403-1417
    Details
    In: Genes & Development, Cold Spring Harbor Laboratory, Vol. 24, No. 13 ( 2010-07-01), p. 1403-1417
    Abstract: The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD + -dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0890-9369 , 1549-5477
    URL: Article
    DOI: 10.1101/gad.1901210
    RVK:
    WA 15000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2010
    detail.hit.zdb_id: 1467414-2
    SSG: 12
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  • 8
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    Identification of purple sea urchin telomerase RNA using a next-generation sequencing based approach
    Cold Spring Harbor Laboratory ; 2013
    In:  RNA Vol. 19, No. 6 ( 2013-06), p. 852-860
    Details
    In: RNA, Cold Spring Harbor Laboratory, Vol. 19, No. 6 ( 2013-06), p. 852-860
    Abstract: Telomerase is a ribonucleoprotein (RNP) enzyme essential for telomere maintenance and chromosome stability. While the catalytic telomerase reverse transcriptase (TERT) protein is well conserved across eukaryotes, telomerase RNA (TR) is extensively divergent in size, sequence, and structure. This diversity prohibits TR identification from many important organisms. Here we report a novel approach for TR discovery that combines in vitro TR enrichment from total RNA, next-generation sequencing, and a computational screening pipeline. With this approach, we have successfully identified TR from Strongylocentrotus purpuratus (purple sea urchin) from the phylum Echinodermata. Reconstitution of activity in vitro confirmed that this RNA is an integral component of sea urchin telomerase. Comparative phylogenetic analysis against vertebrate TR sequences revealed that the purple sea urchin TR contains vertebrate-like template-pseudoknot and H/ACA domains. While lacking a vertebrate-like CR4/5 domain, sea urchin TR has a unique central domain critical for telomerase activity. This is the first TR identified from the previously unexplored invertebrate clade and provides the first glimpse of TR evolution in the deuterostome lineage. Moreover, our TR discovery approach is a significant step toward the comprehensive understanding of telomerase RNP evolution.
    Type of Medium: Online Resource
    ISSN: 1355-8382 , 1469-9001
    URL: Article
    DOI: 10.1261/rna.039131.113
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2013
    detail.hit.zdb_id: 1475737-0
    SSG: 12
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  • 9
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    The transcriptional diversity of 25 Drosophila cell lines
    Cold Spring Harbor Laboratory ; 2011
    In:  Genome Research Vol. 21, No. 2 ( 2011-02), p. 301-314
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 21, No. 2 ( 2011-02), p. 301-314
    Abstract: Drosophila melanogaster cell lines are important resources for cell biologists. Here, we catalog the expression of exons, genes, and unannotated transcriptional signals for 25 lines. Unannotated transcription is substantial (typically 19% of euchromatic signal). Conservatively, we identify 1405 novel transcribed regions; 684 of these appear to be new exons of neighboring, often distant, genes. Sixty-four percent of genes are expressed detectably in at least one line, but only 21% are detected in all lines. Each cell line expresses, on average, 5885 genes, including a common set of 3109. Expression levels vary over several orders of magnitude. Major signaling pathways are well represented: most differentiation pathways are “off” and survival/growth pathways “on.” Roughly 50% of the genes expressed by each line are not part of the common set, and these show considerable individuality. Thirty-one percent are expressed at a higher level in at least one cell line than in any single developmental stage, suggesting that each line is enriched for genes characteristic of small sets of cells. Most remarkable is that imaginal disc-derived lines can generally be assigned, on the basis of expression, to small territories within developing discs. These mappings reveal unexpected stability of even fine-grained spatial determination. No two cell lines show identical transcription factor expression. We conclude that each line has retained features of an individual founder cell superimposed on a common “cell line“ gene expression pattern.
    Type of Medium: Online Resource
    ISSN: 1088-9051
    URL: Article
    DOI: 10.1101/gr.112961.110
    RVK:
    XA 10000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2011
    detail.hit.zdb_id: 1483456-X
    SSG: 12
    Location Call Number Limitation Availability
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