Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.

Abstract:

:A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+), and balanced 2n compound heterozygous (Deletion/Duplication) copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also "genome regulation." Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Ricard G,Molina J,Chrast J,Gu W,Gheldof N,Pradervand S,Schütz F,Young JI,Lupski JR,Reymond A,Walz K

doi

10.1371/journal.pbio.1000543

subject

Has Abstract

pub_date

2010-11-23 00:00:00

pages

e1000543

issue

11

eissn

1544-9173

issn

1545-7885

journal_volume

8

pub_type

杂志文章
  • Nucleotide de novo synthesis increases breast cancer stemness and metastasis via cGMP-PKG-MAPK signaling pathway.

    abstract::Metabolic reprogramming to fulfill the biosynthetic and bioenergetic demands of cancer cells has aroused great interest in recent years. However, metabolic reprogramming for cancer metastasis has not been well elucidated. Here, we screened a subpopulation of breast cancer cells with highly metastatic capacity to the l...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000872

    authors: Lv Y,Wang X,Li X,Xu G,Bai Y,Wu J,Piao Y,Shi Y,Xiang R,Wang L

    更新日期:2020-11-13 00:00:00

  • The cutaneous rabbit illusion affects human primary sensory cortex somatotopically.

    abstract::We used functional magnetic resonance imaging (fMRI) to study neural correlates of a robust somatosensory illusion that can dissociate tactile perception from physical stimulation. Repeated rapid stimulation at the wrist, then near the elbow, can create the illusion of touches at intervening locations along the arm, a...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0040069

    authors: Blankenburg F,Ruff CC,Deichmann R,Rees G,Driver J

    更新日期:2006-03-01 00:00:00

  • Diverse modes of axon elaboration in the developing neocortex.

    abstract::The development of axonal arbors is a critical step in the establishment of precise neural circuits, but relatively little is known about the mechanisms of axonal elaboration in the neocortex. We used in vivo two-photon time-lapse microscopy to image axons in the neocortex of green fluorescent protein-transgenic mice ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0030272

    authors: Portera-Cailliau C,Weimer RM,De Paola V,Caroni P,Svoboda K

    更新日期:2005-08-01 00:00:00

  • SiCTeC: An inexpensive, easily assembled Peltier device for rapid temperature shifting during single-cell imaging.

    abstract::Single-cell imaging, combined with recent advances in image analysis and microfluidic technologies, have enabled fundamental discoveries of cellular responses to chemical perturbations that are often obscured by traditional liquid-culture experiments. Temperature is an environmental variable well known to impact growt...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000786

    authors: Knapp BD,Zhu L,Huang KC

    更新日期:2020-11-06 00:00:00

  • From dinosaurs to modern bird diversity: extending the time scale of adaptive radiation.

    abstract::What explains why some groups of organisms, like birds, are so species rich? And what explains their extraordinary ecological diversity, ranging from large, flightless birds to small migratory species that fly thousand of kilometers every year? These and similar questions have spurred great interest in adaptive radiat...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001854

    authors: Moen D,Morlon H

    更新日期:2014-05-06 00:00:00

  • Membrane progesterone receptor induces meiosis in Xenopus oocytes through endocytosis into signaling endosomes and interaction with APPL1 and Akt2.

    abstract::The steroid hormone progesterone (P4) mediates many physiological processes through either nuclear receptors that modulate gene expression or membrane P4 receptors (mPRs) that mediate nongenomic signaling. mPR signaling remains poorly understood. Here we show that the topology of mPRβ is similar to adiponectin recepto...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000901

    authors: Nader N,Dib M,Hodeify R,Courjaret R,Elmi A,Hammad AS,Dey R,Huang XY,Machaca K

    更新日期:2020-11-02 00:00:00

  • Capturing hammerhead ribozyme structures in action by modulating general base catalysis.

    abstract::We have obtained precatalytic (enzyme-substrate complex) and postcatalytic (enzyme-product complex) crystal structures of an active full-length hammerhead RNA that cleaves in the crystal. Using the natural satellite tobacco ringspot virus hammerhead RNA sequence, the self-cleavage reaction was modulated by substitutin...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0060234

    authors: Chi YI,Martick M,Lares M,Kim R,Scott WG,Kim SH

    更新日期:2008-09-30 00:00:00

  • Determination of stromal signatures in breast carcinoma.

    abstract::Many soft tissue tumors recapitulate features of normal connective tissue. We hypothesize that different types of fibroblastic tumors are representative of different populations of fibroblastic cells or different activation states of these cells. We examined two tumors with fibroblastic features, solitary fibrous tumo...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0030187

    authors: West RB,Nuyten DS,Subramanian S,Nielsen TO,Corless CL,Rubin BP,Montgomery K,Zhu S,Patel R,Hernandez-Boussard T,Goldblum JR,Brown PO,van de Vijver M,van de Rijn M

    更新日期:2005-06-01 00:00:00

  • Host-associated microbiomes drive structure and function of marine ecosystems.

    abstract::The significance of symbioses between eukaryotic hosts and microbes extends from the organismal to the ecosystem level and underpins the health of Earth's most threatened marine ecosystems. Despite rapid growth in research on host-associated microbes, from individual microbial symbionts to host-associated consortia of...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000533

    authors: Wilkins LGE,Leray M,O'Dea A,Yuen B,Peixoto RS,Pereira TJ,Bik HM,Coil DA,Duffy JE,Herre EA,Lessios HA,Lucey NM,Mejia LC,Rasher DB,Sharp KH,Sogin EM,Thacker RW,Vega Thurber R,Wcislo WT,Wilbanks EG,Eisen JA

    更新日期:2019-11-11 00:00:00

  • Measuring global trends in the status of biodiversity: red list indices for birds.

    abstract::The rapid destruction of the planet's biodiversity has prompted the nations of the world to set a target of achieving a significant reduction in the rate of loss of biodiversity by 2010. However, we do not yet have an adequate way of monitoring progress towards achieving this target. Here we present a method for produ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0020383

    authors: Butchart SH,Stattersfield AJ,Bennun LA,Shutes SM,Akçakaya HR,Baillie JE,Stuart SN,Hilton-Taylor C,Mace GM

    更新日期:2004-12-01 00:00:00

  • Role of pleiotropy in the evolution of a cryptic developmental variation in Caenorhabditis elegans.

    abstract::Robust biological systems are expected to accumulate cryptic genetic variation that does not affect the system output in standard conditions yet may play an evolutionary role once phenotypically expressed under a strong perturbation. Genetic variation that is cryptic relative to a robust trait may accumulate neutrally...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001230

    authors: Duveau F,Félix MA

    更新日期:2012-01-01 00:00:00

  • Flight speeds among bird species: allometric and phylogenetic effects.

    abstract::Flight speed is expected to increase with mass and wing loading among flying animals and aircraft for fundamental aerodynamic reasons. Assuming geometrical and dynamical similarity, cruising flight speed is predicted to vary as (body mass)(1/6) and (wing loading)(1/2) among bird species. To test these scaling rules an...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0050197

    authors: Alerstam T,Rosén M,Bäckman J,Ericson PG,Hellgren O

    更新日期:2007-08-01 00:00:00

  • Identification of traits and functional connectivity-based neurotraits of chronic pain.

    abstract::Psychological and personality factors, socioeconomic status, and brain properties all contribute to chronic pain but have essentially been studied independently. Here, we administered a broad battery of questionnaires to patients with chronic back pain (CBP) and collected repeated sessions of resting-state functional ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000349

    authors: Vachon-Presseau E,Berger SE,Abdullah TB,Griffith JW,Schnitzer TJ,Apkarian AV

    更新日期:2019-08-20 00:00:00

  • VirE2: a unique ssDNA-compacting molecular machine.

    abstract::The translocation of single-stranded DNA (ssDNA) across membranes of two cells is a fundamental biological process occurring in both bacterial conjugation and Agrobacterium pathogenesis. Whereas bacterial conjugation spreads antibiotic resistance, Agrobacterium facilitates efficient interkingdom transfer of ssDNA from...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0060044

    authors: Grange W,Duckely M,Husale S,Jacob S,Engel A,Hegner M

    更新日期:2008-02-01 00:00:00

  • The molecular basis for recognition of CD1d/α-galactosylceramide by a human non-Vα24 T cell receptor.

    abstract::CD1d-mediated presentation of glycolipid antigens to T cells is capable of initiating powerful immune responses that can have a beneficial impact on many diseases. Molecular analyses have recently detailed the lipid antigen recognition strategies utilized by the invariant Vα24-Jα18 TCR rearrangements of iNKT cells, wh...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001412

    authors: López-Sagaseta J,Kung JE,Savage PB,Gumperz J,Adams EJ

    更新日期:2012-01-01 00:00:00

  • Inferring the dynamics of diversification: a coalescent approach.

    abstract::Recent analyses of the fossil record and molecular phylogenies suggest that there are fundamental limits to biodiversity, possibly arising from constraints in the availability of space, resources, or ecological niches. Under this hypothesis, speciation rates decay over time and biodiversity eventually saturates, with ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1000493

    authors: Morlon H,Potts MD,Plotkin JB

    更新日期:2010-09-28 00:00:00

  • Phosphatidylserine externalization, "necroptotic bodies" release, and phagocytosis during necroptosis.

    abstract::Necroptosis is a regulated, nonapoptotic form of cell death initiated by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins. It is considered to be a form of regulated necrosis, and, by lacking the "find me" and "eat me" signals that are a feature of apoptosis, necroptos...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2002711

    authors: Zargarian S,Shlomovitz I,Erlich Z,Hourizadeh A,Ofir-Birin Y,Croker BA,Regev-Rudzki N,Edry-Botzer L,Gerlic M

    更新日期:2017-06-26 00:00:00

  • Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.

    abstract::STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatr...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001923

    authors: Xu J,Chatterjee M,Baguley TD,Brouillette J,Kurup P,Ghosh D,Kanyo J,Zhang Y,Seyb K,Ononenyi C,Foscue E,Anderson GM,Gresack J,Cuny GD,Glicksman MA,Greengard P,Lam TT,Tautz L,Nairn AC,Ellman JA,Lombroso PJ

    更新日期:2014-08-05 00:00:00

  • Podoplanin+ tumor lymphatics are rate limiting for breast cancer metastasis.

    abstract::Metastatic dissemination employs both the blood and lymphatic vascular systems. Solid tumors dynamically remodel and generate both vessel types during cancer progression. Lymphatic vessel invasion and cancer cells in the tumor-draining lymph nodes (LNs) are prognostic markers for breast cancer metastasis and patient o...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2005907

    authors: Chen Y,Keskin D,Sugimoto H,Kanasaki K,Phillips PE,Bizarro L,Sharpe A,LeBleu VS,Kalluri R

    更新日期:2018-12-28 00:00:00

  • The evolution of mutualism in gut microbiota via host epithelial selection.

    abstract::The human gut harbours a large and genetically diverse population of symbiotic microbes that both feed and protect the host. Evolutionary theory, however, predicts that such genetic diversity can destabilise mutualistic partnerships. How then can the mutualism of the human microbiota be explained? Here we develop an i...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001424

    authors: Schluter J,Foster KR

    更新日期:2012-01-01 00:00:00

  • Interactive youth science workshops benefit student participants and graduate student mentors.

    abstract::Science communication and outreach are essential for training the next generation of scientists and raising public awareness for science. Providing effective science, technology, engineering, and mathematics (STEM) educational outreach to students in classrooms is challenging because of the need to form partnerships w...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000668

    authors: Kompella P,Gracia B,LeBlanc L,Engelman S,Kulkarni C,Desai N,June V,March S,Pattengale S,Rodriguez-Rivera G,Ryu SW,Strohkendl I,Mandke P,Clark G

    更新日期:2020-03-30 00:00:00

  • A Low-Correlation Resting State of the Striatum during Cortical Avalanches and Its Role in Movement Suppression.

    abstract::During quiet resting behavior, involuntary movements are suppressed. Such movement control is attributed to cortico-basal ganglia loops, yet population dynamics within these loops during resting and their relation to involuntary movements are not well characterized. Here, we show by recording cortical and striatal ong...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002582

    authors: Klaus A,Plenz D

    更新日期:2016-12-06 00:00:00

  • ULK1-ATG13 and their mitotic phospho-regulation by CDK1 connect autophagy to cell cycle.

    abstract::Unc-51-like autophagy activating kinase 1 (ULK1)-autophagy-related 13 (ATG13) is the most upstream autophagy initiation complex that is phosphorylated by mammalian target-of-rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK) to induce autophagy in asynchronous conditions. However, their phospho-regul...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000288

    authors: Li Z,Tian X,Ji X,Wang J,Chen H,Wang D,Zhang X

    更新日期:2020-06-09 00:00:00

  • The credibility crisis in research: Can economics tools help?

    abstract::The issue of nonreplicable evidence has attracted considerable attention across biomedical and other sciences. This concern is accompanied by an increasing interest in reforming research incentives and practices. How to optimally perform these reforms is a scientific problem in itself, and economics has several scient...

    journal_title:PLoS biology

    pub_type: 杂志文章,评审

    doi:10.1371/journal.pbio.2001846

    authors: Gall T,Ioannidis JPA,Maniadis Z

    更新日期:2017-04-26 00:00:00

  • Active listening for spatial orientation in a complex auditory scene.

    abstract::To successfully negotiate a complex environment, an animal must control the timing of motor behaviors in coordination with dynamic sensory information. Here, we report on adaptive temporal control of vocal-motor behavior in an echolocating bat, Eptesicus fuscus, as it captured tethered insects close to background vege...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0040079

    authors: Moss CF,Bohn K,Gilkenson H,Surlykke A

    更新日期:2006-04-01 00:00:00

  • High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography.

    abstract::Mycobacterium tuberculosis infects one third of the human world population and kills someone every 15 seconds. For more than a century, scientists and clinicians have been distinguishing between the human- and animal-adapted members of the M. tuberculosis complex (MTBC). However, all human-adapted strains of MTBC have...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0060311

    authors: Hershberg R,Lipatov M,Small PM,Sheffer H,Niemann S,Homolka S,Roach JC,Kremer K,Petrov DA,Feldman MW,Gagneux S

    更新日期:2008-12-16 00:00:00

  • Cell-by-cell dissection of gene expression and chromosomal interactions reveals consequences of nuclear reorganization.

    abstract::The functional consequences of long-range nuclear reorganization were studied in a cell-by-cell analysis of gene expression and long-range chromosomal interactions in the Drosophila eye and eye imaginal disk. Position-effect variegation was used to stochastically perturb gene expression and probe nuclear reorganizatio...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0030067

    authors: Harmon B,Sedat J

    更新日期:2005-03-01 00:00:00

  • Meta-research: Why research on research matters.

    abstract::Meta-research is the study of research itself: its methods, reporting, reproducibility, evaluation, and incentives. Given that science is the key driver of human progress, improving the efficiency of scientific investigation and yielding more credible and more useful research results can translate to major benefits. T...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2005468

    authors: Ioannidis JPA

    更新日期:2018-03-13 00:00:00

  • Correction: Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy.

    abstract::[This corrects the article DOI: 10.1371/journal.pbio.2001951.]. ...

    journal_title:PLoS biology

    pub_type: 已发布勘误

    doi:10.1371/journal.pbio.1002603

    authors: Di Biase S,Shim HS,Kim KH,Vinciguerra M,Rappa F,Wei M,Brandhorst S,Cappello F,Mirzaei H,Lee C,Longo VD

    更新日期:2017-05-01 00:00:00

  • Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.

    abstract::Mitochondrial shape is determined by fission and fusion reactions catalyzed by large GTPases of the dynamin family, mutation of which can cause neurological dysfunction. While fission-inducing protein phosphatases have been identified, the identity of opposing kinase signaling complexes has remained elusive. We report...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1000612

    authors: Merrill RA,Dagda RK,Dickey AS,Cribbs JT,Green SH,Usachev YM,Strack S

    更新日期:2011-04-01 00:00:00