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  • 1
    Online Resource
    Online Resource
    Transcriptomic signatures across human tissues identify functional rare genetic variation
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Vol. 369, No. 6509 ( 2020-09-11)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 369, No. 6509 ( 2020-09-11)
    Abstract: Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaz5900
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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  • 2
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    Online Resource
    Author Correction: Tumour lineage shapes BRCA-mediated phenotypes
    Springer Science and Business Media LLC ; 2020
    In:  Nature Vol. 577, No. 7789 ( 2020-01-09), p. E1-E1
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 577, No. 7789 ( 2020-01-09), p. E1-E1
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-019-1839-2
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 120714-3
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  • 3
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    Ribozymes that cleave reovirus genome segment S1 also protect cells from pathogenesis caused by reovirus infection
    Proceedings of the National Academy of Sciences ; 2001
    In:  Proceedings of the National Academy of Sciences Vol. 98, No. 7 ( 2001-03-27), p. 4101-4106
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 7 ( 2001-03-27), p. 4101-4106
    Abstract: Reovirus genome segment S1 encodes protein σ1, which is the receptor binding protein, modulates tissue tropism, and specifies the nature of the antiviral immune response. It makes up less than 2% of reovirus particles and is synthesized in very small amounts in infected cells. Any antiviral strategy aimed at reducing specifically the expression of this genome segment should, in principle, reduce the infectivity of the virus. To test this hypothesis, we have assembled two hammer-head motif-containing ribozymes (Rzs) targeted to cleave at the conserved B and C domains of the reovirus s1 RNA. Protein-independent but Mg 2+ -dependent sequence-specific cleavage of s1 RNA was achieved by both the Rzs in trans. Cells that transiently express these Rzs, when challenged with reovirus, were protected against the cytopathic effects caused by the virus. This protection correlated with the specific intracellular reduction of s1 transcripts that was due to their cleavage by the Rzs. Rz-treated cells that were challenged with reovirus showed almost complete disappearance of protein σ1 without significantly altering the levels of the other reovirus structural proteins. Thus, Rzs, besides acting as antiviral agents, could be exploited as biological tools to delineate specific functions of target genes.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.051013898
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2001
    detail.hit.zdb_id: 209104-5
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  • 4
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    Online Resource
    Adaptor protein-3 produces synaptic vesicles that release phasic dopamine
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 42 ( 2023-10-17)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 42 ( 2023-10-17)
    Abstract: The burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. At many synapses, however, high firing rates deplete synaptic vesicles (SVs), resulting in synaptic depression that limits release. What accounts for the increased release of dopamine by stimulation at high frequency? We find that adaptor protein-3 (AP-3) and its coat protein VPS41 promote axonal dopamine release by targeting vesicular monoamine transporter VMAT2 to the axon rather than dendrites. AP-3 and VPS41 also produce SVs that respond preferentially to high-frequency stimulation, independent of their role in axonal polarity. In addition, conditional inactivation of VPS41 in dopamine neurons impairs reinforcement learning, and this involves a defect in the frequency dependence of release rather than the amount of dopamine released. Thus, AP-3 and VPS41 promote the axonal polarity of dopamine release but enable learning by producing a distinct population of SVs tuned specifically to high firing frequency that confers the phasic release of dopamine.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2309843120
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 5
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    Online Resource
    Alfalfa benefits from Medicago truncatula : The RCT1 gene from M. truncatula confers broad-spectrum resistance to anthracnose in alfalfa
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 34 ( 2008-08-26), p. 12164-12169
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 34 ( 2008-08-26), p. 12164-12169
    Abstract: Alfalfa is economically the most important forage legume worldwide. A recurrent challenge to alfalfa production is the significant yield loss caused by disease. Although knowledge of molecular mechanisms underlying host resistance should facilitate the genetic improvement of alfalfa, the acquisition of such knowledge is hampered by alfalfa's tetrasomic inheritance and outcrossing nature. However, alfalfa is congeneric with the reference legume Medicago truncatula , providing an opportunity to use M. truncatula as a surrogate to clone the counterparts of many agronomically important genes in alfalfa. In particular, the high degree of sequence identity and remarkably conserved genome structure and function between the two species enables M. truncatula genes to be used directly in alfalfa improvement. Here we report the map-based cloning of RCT1 , a host resistance ( R ) gene in M. truncatula that confers resistance to multiple races of Colletotrichum trifolii , a hemibiotrophic fungal pathogen that causes anthracnose disease of alfalfa. RCT1 is a member of the Toll-interleukin-1 receptor/nucleotide-binding site/leucine-rich repeat (TIR-NBS-LRR) class of plant R genes and confers broad-spectrum anthracnose resistance when transferred into susceptible alfalfa plants. Thus, RCT1 provides a novel resource to develop anthracnose-resistant alfalfa cultivars and contributes to our understanding of host resistance against the fungal genus Colletotrichum . This work demonstrates the potential of using M. truncatula genes for genetic improvement of alfalfa.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0802518105
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
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  • 6
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    Transcription factors IRF8 and PU.1 are required for follicular B cell development and BCL6-driven germinal center responses
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 19 ( 2019-05-07), p. 9511-9520
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 19 ( 2019-05-07), p. 9511-9520
    Abstract: The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune cell development and function. However, the understanding of the molecular mechanisms of each family member has been limited due to their redundancy and broad effects on multiple lineages of cells. Here, we report that double deletion of floxed Irf8 and Spi1 (encoding PU.1) by Mb1-Cre (designated DKO mice) in the B cell lineage resulted in severe defects in the development of follicular and germinal center (GC) B cells. Class-switch recombination and antibody affinity maturation were also compromised in DKO mice. RNA-seq (sequencing) and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in follicular and activated B cells. DKO B cells had diminished expression of target genes vital for maintaining follicular B cell identity and GC development. Moreover, our findings reveal that expression of B-cell lymphoma protein 6 (BCL6), which is critical for development of germinal center B cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B cells.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1901258116
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 7
    Online Resource
    Online Resource
    American mastodon extirpation in the Arctic and Subarctic predates human colonization and terminal Pleistocene climate change
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 52 ( 2014-12-30), p. 18460-18465
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 52 ( 2014-12-30), p. 18460-18465
    Abstract: Existing radiocarbon ( 14 C) dates on American mastodon ( Mammut americanum ) fossils from eastern Beringia (Alaska and Yukon) have been interpreted as evidence they inhabited the Arctic and Subarctic during Pleistocene full-glacial times (∼18,000 14 C years B.P.). However, this chronology is inconsistent with inferred habitat preferences of mastodons and correlative paleoecological evidence. To establish a last appearance date (LAD) for M. americanum regionally, we obtained 53 new 14 C dates on 36 fossils, including specimens with previously published dates. Using collagen ultrafiltration and single amino acid (hydroxyproline) methods, these specimens consistently date to beyond or near the ∼50,000 y B.P. limit of 14 C dating. Some erroneously “young” 14 C dates are due to contamination by exogenous carbon from natural sources and conservation treatments used in museums. We suggest mastodons inhabited the high latitudes only during warm intervals, particularly the Last Interglacial [Marine Isotope Stage (MIS) 5] when boreal forests existed regionally. Our 14 C dataset suggests that mastodons were extirpated from eastern Beringia during the MIS 4 glacial interval (∼75,000 y ago), following the ecological shift from boreal forest to steppe tundra. Mastodons thereafter became restricted to areas south of the continental ice sheets, where they suffered complete extinction ∼10,000 14 C years B.P. Mastodons were already absent from eastern Beringia several tens of millennia before the first humans crossed the Bering Isthmus or the onset of climate changes during the terminal Pleistocene. Local extirpations of mastodons and other megafaunal populations in eastern Beringia were asynchrononous and independent of their final extinction south of the continental ice sheets.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1416072111
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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  • 8
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    Comparative genomics of biotechnologically important yeasts
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 35 ( 2016-08-30), p. 9882-9887
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 35 ( 2016-08-30), p. 9882-9887
    Abstract: Ascomycete yeasts are metabolically diverse, with great potential for biotechnology. Here, we report the comparative genome analysis of 29 taxonomically and biotechnologically important yeasts, including 16 newly sequenced. We identify a genetic code change, CUG-Ala, in Pachysolen tannophilus in the clade sister to the known CUG-Ser clade. Our well-resolved yeast phylogeny shows that some traits, such as methylotrophy, are restricted to single clades, whereas others, such as l -rhamnose utilization, have patchy phylogenetic distributions. Gene clusters, with variable organization and distribution, encode many pathways of interest. Genomics can predict some biochemical traits precisely, but the genomic basis of others, such as xylose utilization, remains unresolved. Our data also provide insight into early evolution of ascomycetes. We document the loss of H3K9me2/3 heterochromatin, the origin of ascomycete mating-type switching, and panascomycete synteny at the MAT locus. These data and analyses will facilitate the engineering of efficient biosynthetic and degradative pathways and gateways for genomic manipulation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1603941113
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 9
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    Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 7 ( 2017-02-14)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 7 ( 2017-02-14)
    Abstract: MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1613091114
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 10
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    Unraveling the disease consequences and mechanisms of modular structure in animal social networks
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 16 ( 2017-04-18), p. 4165-4170
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 16 ( 2017-04-18), p. 4165-4170
    Abstract: Disease risk is a potential cost of group living. Although modular organization is thought to reduce this cost in animal societies, empirical evidence toward this hypothesis has been conflicting. We analyzed empirical social networks from 43 animal species to motivate our study of the epidemiological consequences of modular structure in animal societies. From these empirical studies, we identified the features of interaction patterns associated with network modularity and developed a theoretical network model to investigate when and how subdivisions in social networks influence disease dynamics. Contrary to prior work, we found that disease risk is largely unaffected by modular structure, although social networks beyond a modular threshold experience smaller disease burden and longer disease duration. Our results illustrate that the lowering of disease burden in highly modular social networks is driven by two mechanisms of modular organization: network fragmentation and subgroup cohesion. Highly fragmented social networks with cohesive subgroups are able to structurally trap infections within a few subgroups and also cause a structural delay to the spread of disease outbreaks. Finally, we show that network models incorporating modular structure are necessary only when prior knowledge suggests that interactions within the population are highly subdivided. Otherwise, null networks based on basic knowledge about group size and local contact heterogeneity may be sufficient when data-limited estimates of epidemic consequences are necessary. Overall, our work does not support the hypothesis that modular structure universally mitigates the disease impact of group living.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1613616114
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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