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  • 1
    Online Resource
    Online Resource
    Behavioral idiosyncrasy reveals genetic control of phenotypic variability
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 21 ( 2015-05-26), p. 6706-6711
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 21 ( 2015-05-26), p. 6706-6711
    Abstract: Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a , implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1503830112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Precise Quantification of Behavioral Individuality From 80 Million Decisions Across 183,000 Flies
    Frontiers Media SA ; 2022
    In:  Frontiers in Behavioral Neuroscience Vol. 16 ( 2022-5-26)
    Details
    In: Frontiers in Behavioral Neuroscience, Frontiers Media SA, Vol. 16 ( 2022-5-26)
    Abstract: Individual animals behave differently from each other. This variability is a component of personality and arises even when genetics and environment are held constant. Discovering the biological mechanisms underlying behavioral variability depends on efficiently measuring individual behavioral bias, a requirement that is facilitated by automated, high-throughput experiments. We compiled a large data set of individual locomotor behavior measures, acquired from over 183,000 fruit flies walking in Y-shaped mazes. With this data set we first conducted a “computational ethology natural history” study to quantify the distribution of individual behavioral biases with unprecedented precision and examine correlations between behavioral measures with high power. We discovered a slight, but highly significant, left-bias in spontaneous locomotor decision-making. We then used the data to evaluate standing hypotheses about biological mechanisms affecting behavioral variability, specifically: the neuromodulator serotonin and its precursor transporter, heterogametic sex, and temperature. We found a variety of significant effects associated with each of these mechanisms that were behavior-dependent. This indicates that the relationship between biological mechanisms and behavioral variability may be highly context dependent. Going forward, automation of behavioral experiments will likely be essential in teasing out the complex causality of individuality.
    Type of Medium: Online Resource
    ISSN: 1662-5153
    URL: Article
    DOI: 10.3389/fnbeh.2022.836626
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
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  • 3
    Online Resource
    Online Resource
    Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A
    Cold Spring Harbor Laboratory ; 2013
    In:  Genes & Development Vol. 27, No. 9 ( 2013-05-01), p. 1032-1045
    Details
    In: Genes & Development, Cold Spring Harbor Laboratory, Vol. 27, No. 9 ( 2013-05-01), p. 1032-1045
    Abstract: To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These screens identified the plant homeodomain (PHD)-finger domain protein PHF5A as differentially required for GSC expansion, as compared with untransformed neural stem cells (NSCs) and fibroblasts. Given PHF5A's known involvement in facilitating interactions between the U2 snRNP complex and ATP-dependent helicases, we examined cancer-specific roles in RNA splicing. We found that in GSCs, but not untransformed controls, PHF5A facilitates recognition of exons with unusual C-rich 3′ splice sites in thousands of essential genes. PHF5A knockdown in GSCs, but not untransformed NSCs, astrocytes, or fibroblasts, inhibited splicing of these genes, leading to cell cycle arrest and loss of viability. Notably, pharmacologic inhibition of U2 snRNP activity phenocopied PHF5A knockdown in GSCs and also in NSCs or fibroblasts overexpressing MYC. Furthermore, PHF5A inhibition compromised GSC tumor formation in vivo and inhibited growth of established GBM patient-derived xenograft tumors. Our results demonstrate a novel viability requirement for PHF5A to maintain proper exon recognition in brain tumor-initiating cells and may provide new inroads for novel anti-GBM therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 0890-9369 , 1549-5477
    URL: Article
    DOI: 10.1101/gad.212548.112
    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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  • 4
    Online Resource
    Online Resource
    G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment
    Cold Spring Harbor Laboratory ; 2012
    In:  Genes & Development Vol. 26, No. 22 ( 2012-11-15), p. 2499-2511
    Details
    In: Genes & Development, Cold Spring Harbor Laboratory, Vol. 26, No. 22 ( 2012-11-15), p. 2499-2511
    Abstract: G9a and GLP are conserved protein methyltransferases that play key roles during mammalian development through mono- and dimethylation of histone H3 Lys 9 (H3K9me1/2), modifications associated with transcriptional repression. During embryogenesis, large H3K9me2 chromatin territories arise that have been proposed to reinforce lineage choice by affecting high-order chromatin structure. Here we report that in adult human hematopoietic stem and progenitor cells (HSPCs), H3K9me2 chromatin territories are absent in primitive cells and are formed de novo during lineage commitment. In committed HSPCs, G9a/GLP activity nucleates H3K9me2 marks at CpG islands and other genomic sites within genic regions, which then spread across most genic regions during differentiation. Immunofluorescence assays revealed the emergence of H3K9me2 nuclear speckles in committed HSPCs, consistent with progressive marking. Moreover, gene expression analysis indicated that G9a/GLP activity suppresses promiscuous transcription of lineage-affiliated genes and certain gene clusters, suggestive of regulation of HSPC chromatin structure. Remarkably, HSPCs continuously treated with UNC0638, a G9a/GLP small molecular inhibitor, better retain stem cell-like phenotypes and function during in vitro expansion. These results suggest that G9a/GLP activity promotes progressive H3K9me2 patterning during HSPC lineage specification and that its inhibition delays HSPC lineage commitment. They also inform clinical manipulation of donor-derived HSPCs.
    Type of Medium: Online Resource
    ISSN: 0890-9369 , 1549-5477
    URL: Article
    DOI: 10.1101/gad.200329.112
    RVK:
    WA 15000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2012
    detail.hit.zdb_id: 1467414-2
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Characterization of a ViI-like Phage Specific to Escherichia coli O157:H7
    Springer Science and Business Media LLC ; 2011
    In:  Virology Journal Vol. 8, No. 1 ( 2011-12)
    Details
    In: Virology Journal, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2011-12)
    Type of Medium: Online Resource
    ISSN: 1743-422X
    URL: Article
    DOI: 10.1186/1743-422X-8-430
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 2160640-7
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  • 6
    Online Resource
    Online Resource
    Abstract A20: Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 5_Supplement ( 2013-05-01), p. A20-A20
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 5_Supplement ( 2013-05-01), p. A20-A20
    Abstract: To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These screens identified the PHD-finger domain protein PHF5A as differentially required for GSC expansion gene, as compared to untransformed neural stem cells (NSCs) and fibroblasts. Given PHF5A's known involvement in facilitating interactions between the U2 snRNP complex and ATP-dependent helicases, we examined cancer-specific roles in RNA splicing. We find that in GSCs, but not untransformed controls, PHF5A facilitates recognition of exons with unusual C-rich 3' splice sites in thousands of essential genes. PHF5A knockdown in GSCs, but not untransformed NSCs, astrocytes, or fibroblasts, inhibited splicing of these genes, leading to cell cycle arrest and loss of viability. Notably, pharmacologic inhibition of U2 snRNP activity phenocopied PHF5A knockdown both in GSCs and in multiple genetically transformed cell types, suggesting that a cancer-specific requirement for PHF5A activity may be generalizable to a wide range of cancers. Furthermore, PHF5A inhibition compromises GSC tumor formation in vivo and dramatically inhibits the growth of established GBM patient-derived xenograft tumors. Together, this work demonstrates an additional mechanism for maintaining splicing fidelity in cancer cells and also suggests that PHF5A activity may provide new in-roads for novel anti-GBM therapeutic strategies. Citation Format: Christopher G. Hubert, Robert K. Bradley, Yu Ding, Toledo M. Chad, Kyobi Skutt-Kakaria, Emily J. Girard, Jerry Davison, Jason Berndt, Philip Corrin, Ryan Basom, Jeffery J. Delrow, Thomas Webb, Steven M. Pollard, Jeongwu Lee, James M. Olson, Patrick J. Paddison. Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr A20.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.PMS-A20
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Discovery Vol. 3, No. 2 ( 2013-02-01), p. 198-211
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 3, No. 2 ( 2013-02-01), p. 198-211
    Abstract: To identify new candidate therapeutic targets for glioblastoma multiforme, we combined functional genetics and glioblastoma network modeling to identify kinases required for the growth of patient-derived brain tumor–initiating cells (BTIC) but that are dispensable to proliferating human neural stem cells (NSC). This approach yielded BUB1B/BUBR1, a critical mitotic spindle checkpoint player, as the top-scoring glioblastoma lethal kinase. Knockdown of BUB1B inhibited expansion of BTIC isolates, both in vitro and in vivo, without affecting proliferation of NSCs or astrocytes. Mechanistic studies revealed that BUB1B's GLE2p-binding sequence (GLEBS) domain activity is required to suppress lethal kinetochore–microtubule (KT–MT) attachment defects in glioblastoma isolates and genetically transformed cells with altered sister KT dynamics, which likely favor KT–MT instability. These results indicate that glioblastoma tumors have an added requirement for BUB1B to suppress lethal consequences of altered KT function and further suggest that sister KT measurements may predict cancer-specific sensitivity to BUB1B inhibition and perhaps other mitotic targets that affect KT–MT stability. Significance: Currently, no effective therapies are available for glioblastoma, the most frequent and aggressive brain tumor. Our results suggest that targeting the GLEBS domain activity of BUB1B may provide a therapeutic window for glioblastoma, as the GLEBS domain is nonessential in untransformed cells. Moreover, the results further suggest that sister KT distances at metaphase may predict sensitivity to anticancer therapeutics targeting KT function. Cancer Discov; 3(2); 198–211. ©2012 AACR. See related commentary by Venere et al., p. 141 This article is highlighted in the In This Issue feature, p. 125
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-12-0353
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2607892-2
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  • 8
    Online Resource
    Online Resource
    The structure of behavioral variation within a genotype
    eLife Sciences Publications, Ltd ; 2021
    In:  eLife Vol. 10 ( 2021-10-19)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 10 ( 2021-10-19)
    Abstract: Individual animals vary in their behaviors. This is true even when they share the same genotype and were reared in the same environment. Clusters of covarying behaviors constitute behavioral syndromes, and an individual’s position along such axes of covariation is a representation of their personality. Despite these conceptual frameworks, the structure of behavioral covariation within a genotype is essentially uncharacterized and its mechanistic origins unknown. Passing hundreds of inbred Drosophila individuals through an experimental pipeline that captured hundreds of behavioral measures, we found sparse but significant correlations among small sets of behaviors. Thus, the space of behavioral variation has many independent dimensions. Manipulating the physiology of the brain, and specific neural populations, altered specific correlations. We also observed that variation in gene expression can predict an individual’s position on some behavioral axes. This work represents the first steps in understanding the biological mechanisms determining the structure of behavioral variation within a genotype.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.64988
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2021
    detail.hit.zdb_id: 2687154-3
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