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


: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.


PLoS Biol


PLoS biology


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




Has Abstract


2010-11-23 00:00:00












  • Sonic Hedgehog promotes tumor cell survival by inhibiting CDON pro-apoptotic activity.

    abstract::The Hedgehog signaling is a determinant pathway for tumor progression. However, while inhibition of the Hedgehog canonical pathway-Patched-Smoothened-Gli-has proved efficient in human tumors with activating mutations in this pathway, recent clinical data have failed to show any benefit in other cancers, even though So...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Delloye-Bourgeois C,Gibert B,Rama N,Delcros JG,Gadot N,Scoazec JY,Krauss R,Bernet A,Mehlen P

    更新日期:2013-01-01 00:00:00

  • Adaptation to Temporally Fluctuating Environments by the Evolution of Maternal Effects.

    abstract::All organisms live in temporally fluctuating environments. Theory predicts that the evolution of deterministic maternal effects (i.e., anticipatory maternal effects or transgenerational phenotypic plasticity) underlies adaptation to environments that fluctuate in a predictably alternating fashion over maternal-offspri...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Dey S,Proulx SR,Teotónio H

    更新日期:2016-02-24 00:00:00

  • Evidence of activity-specific, radial organization of mitotic chromosomes in Drosophila.

    abstract::The organization and the mechanisms of condensation of mitotic chromosomes remain unsolved despite many decades of efforts. The lack of resolution, tight compaction, and the absence of function-specific chromatin labels have been the key technical obstacles. The correlation between DNA sequence composition and its con...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Strukov YG,Sural TH,Kuroda MI,Sedat JW

    更新日期:2011-01-11 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


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

    更新日期:2008-02-01 00:00:00

  • Self-organizing spots get under your skin.

    abstract::Sixty-five years after Turing first revealed the potential of systems with local activation and long-range inhibition to generate pattern, we have only recently begun to identify the biological elements that operate at many scales to generate periodic patterns in nature. In this Primer, we first review the theoretical...

    journal_title:PLoS biology

    pub_type: 杂志文章,评审


    authors: Dalle Nogare D,Chitnis AB

    更新日期:2017-12-20 00:00:00

  • Parallel evolution of the genetic code in arthropod mitochondrial genomes.

    abstract::The genetic code provides the translation table necessary to transform the information contained in DNA into the language of proteins. In this table, a correspondence between each codon and each amino acid is established: tRNA is the main adaptor that links the two. Although the genetic code is nearly universal, sever...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Abascal F,Posada D,Knight RD,Zardoya R

    更新日期:2006-05-01 00:00:00

  • The velvet family of fungal regulators contains a DNA-binding domain structurally similar to NF-κB.

    abstract::Morphological development of fungi and their combined production of secondary metabolites are both acting in defence and protection. These processes are mainly coordinated by velvet regulators, which contain a yet functionally and structurally uncharacterized velvet domain. Here we demonstrate that the velvet domain o...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Ahmed YL,Gerke J,Park HS,Bayram Ö,Neumann P,Ni M,Dickmanns A,Kim SC,Yu JH,Braus GH,Ficner R

    更新日期:2013-12-01 00:00:00

  • Systematic association of genes to phenotypes by genome and literature mining.

    abstract::One of the major challenges of functional genomics is to unravel the connection between genotype and phenotype. So far no global analysis has attempted to explore those connections in the light of the large phenotypic variability seen in nature. Here, we use an unsupervised, systematic approach for associating genes a...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Korbel JO,Doerks T,Jensen LJ,Perez-Iratxeta C,Kaczanowski S,Hooper SD,Andrade MA,Bork P

    更新日期:2005-05-01 00:00:00

  • Placental chemokine compartmentalisation: A novel mammalian molecular control mechanism.

    abstract::Atypical chemokine receptor 2 (ACKR2) is a chemokine-scavenging receptor. ACKR2-/-embryos display a reduction in size of a novel, to our knowledge, embryonic skin macrophage population referred to as 'intermediate' cells. CC chemokine receptor 2 (CCR2)-/-embryos display an identical phenotype, indicating that these ce...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Lee KM,Wilson GJ,Pingen M,Fukuoka A,Hansell CAH,Bartolini R,Medina-Ruiz L,Graham GJ

    更新日期:2019-05-29 00:00:00

  • Posttranscriptional gene regulation by spatial rearrangement of the 3' untranslated region.

    abstract::Translation termination at premature termination codons (PTCs) triggers degradation of the aberrant mRNA, but the mechanism by which a termination event is defined as premature is still unclear. Here we show that the physical distance between the termination codon and the poly(A)-binding protein PABPC1 is a crucial de...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Eberle AB,Stalder L,Mathys H,Orozco RZ,Mühlemann O

    更新日期:2008-04-29 00:00:00

  • Autophagy and its effects: making sense of double-edged swords.

    abstract::Autophagy is the mechanism by which cellular material is delivered to lysosomes and degraded. This process has become a major focus of biological and biomedical research with thousands of papers published each year and rapidly growing appreciation that autophagy affects many normal and pathological processes. However,...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Thorburn A

    更新日期:2014-10-14 00:00:00

  • Precise positioning of myosin VI on endocytic vesicles in vivo.

    abstract::Myosin VI has been studied in both a monomeric and a dimeric form in vitro. Because the functional characteristics of the motor are dramatically different for these two forms, it is important to understand whether myosin VI heavy chains are brought together on endocytic vesicles. We have used fluorescence anisotropy m...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Altman D,Goswami D,Hasson T,Spudich JA,Mayor S

    更新日期:2007-08-01 00:00:00

  • Interaction between attention and bottom-up saliency mediates the representation of foreground and background in an auditory scene.

    abstract::The mechanism by which a complex auditory scene is parsed into coherent objects depends on poorly understood interactions between task-driven and stimulus-driven attentional processes. We illuminate these interactions in a simultaneous behavioral-neurophysiological study in which we manipulate participants' attention ...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Elhilali M,Xiang J,Shamma SA,Simon JZ

    更新日期:2009-06-01 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


    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

  • Disruption of state estimation in the human lateral cerebellum.

    abstract::The cerebellum has been proposed to be a crucial component in the state estimation process that combines information from motor efferent and sensory afferent signals to produce a representation of the current state of the motor system. Such a state estimate of the moving human arm would be expected to be used when the...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Miall RC,Christensen LO,Cain O,Stanley J

    更新日期:2007-11-01 00:00:00

  • Coordinate gene regulation during hematopoiesis is related to genomic organization.

    abstract::Gene loci are found in nuclear subcompartments that are related to their expression status. For instance, silent genes are often localized to heterochromatin and the nuclear periphery, whereas active genes tend to be found in the nuclear center. Evidence also suggests that chromosomes may be specifically positioned wi...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Kosak ST,Scalzo D,Alworth SV,Li F,Palmer S,Enver T,Lee JS,Groudine M

    更新日期:2007-11-01 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


    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 systematic approach to pair secretory cargo receptors with their cargo suggests a mechanism for cargo selection by Erv14.

    abstract::The endoplasmic reticulum (ER) is the site of synthesis of secreted and membrane proteins. To exit the ER, proteins are packaged into COPII vesicles through direct interaction with the COPII coat or aided by specific cargo receptors. Despite the fundamental role of such cargo receptors in protein traffic, only a few h...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Herzig Y,Sharpe HJ,Elbaz Y,Munro S,Schuldiner M

    更新日期:2012-01-01 00:00:00

  • Microstructural and functional gradients are increasingly dissociated in transmodal cortices.

    abstract::While the role of cortical microstructure in organising neural function is well established, it remains unclear how structural constraints can give rise to more flexible elements of cognition. While nonhuman primate research has demonstrated a close structure-function correspondence, the relationship between microstru...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Paquola C,Vos De Wael R,Wagstyl K,Bethlehem RAI,Hong SJ,Seidlitz J,Bullmore ET,Evans AC,Misic B,Margulies DS,Smallwood J,Bernhardt BC

    更新日期:2019-05-20 00:00:00

  • An Estimate of the Total DNA in the Biosphere.

    abstract::Modern whole-organism genome analysis, in combination with biomass estimates, allows us to estimate a lower bound on the total information content in the biosphere: 5.3 × 1031 (±3.6 × 1031) megabases (Mb) of DNA. Given conservative estimates regarding DNA transcription rates, this information content suggests biospher...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Landenmark HK,Forgan DH,Cockell CS

    更新日期:2015-06-11 00:00:00

  • Bet hedging in yeast by heterogeneous, age-correlated expression of a stress protectant.

    abstract::Genetically identical cells grown in the same culture display striking cell-to-cell heterogeneity in gene expression and other traits. A crucial challenge is to understand how much of this heterogeneity reflects the noise tolerance of a robust system and how much serves a biological function. In bacteria, stochastic g...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Levy SF,Ziv N,Siegal ML

    更新日期:2012-01-01 00:00:00

  • Unique 5'-P recognition and basis for dG:dGTP misincorporation of ASFV DNA polymerase X.

    abstract::African swine fever virus (ASFV) can cause highly lethal disease in pigs and is becoming a global threat. ASFV DNA Polymerase X (AsfvPolX) is the most distinctive DNA polymerase identified to date; it lacks two DNA-binding domains (the thumb domain and 8-KD domain) conserved in the homologous proteins. AsfvPolX cataly...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Chen Y,Zhang J,Liu H,Gao Y,Li X,Zheng L,Cui R,Yao Q,Rong L,Li J,Huang Z,Ma J,Gan J

    更新日期:2017-02-28 00:00:00

  • Feminizer and doublesex knock-outs cause honey bees to switch sexes.

    abstract::Honey bees are experts at refuting societal norms. Their matriarchal hives are headed by queens, backed by an all-female workforce, and males die soon after copulation. But the biochemical basis of how these distinct castes and sexes (queens, workers, and drones) arise is poorly understood, partly due to a lack of eff...

    journal_title:PLoS biology

    pub_type: 评论,杂志文章


    authors: McAfee A,Pettis JS,Tarpy DR,Foster LJ

    更新日期:2019-05-06 00:00:00

  • The signal sequence coding region promotes nuclear export of mRNA.

    abstract::In eukaryotic cells, most mRNAs are exported from the nucleus by the transcription export (TREX) complex, which is loaded onto mRNAs after their splicing and capping. We have studied in mammalian cells the nuclear export of mRNAs that code for secretory proteins, which are targeted to the endoplasmic reticulum membran...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Palazzo AF,Springer M,Shibata Y,Lee CS,Dias AP,Rapoport TA

    更新日期:2007-12-01 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


    authors: Moen D,Morlon H

    更新日期:2014-05-06 00:00:00

  • Drosophila melanogaster establishes a species-specific mutualistic interaction with stable gut-colonizing bacteria.

    abstract::Animals live together with diverse bacteria that can impact their biology. In Drosophila melanogaster, gut-associated bacterial communities are relatively simple in composition but also have a strong impact on host development and physiology. It is generally assumed that gut bacteria in D. melanogaster are transient a...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Pais IS,Valente RS,Sporniak M,Teixeira L

    更新日期:2018-07-05 00:00:00

  • Decoding the Interactions Regulating the Active State Mechanics of Eukaryotic Protein Kinases.

    abstract::Eukaryotic protein kinases regulate most cellular functions by phosphorylating targeted protein substrates through a highly conserved catalytic core. In the active state, the catalytic core oscillates between open, intermediate, and closed conformations. Currently, the intramolecular interactions that regulate the act...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Meharena HS,Fan X,Ahuja LG,Keshwani MM,McClendon CL,Chen AM,Adams JA,Taylor SS

    更新日期:2016-11-30 00:00:00

  • Cancer cell population growth kinetics at low densities deviate from the exponential growth model and suggest an Allee effect.

    abstract::Most models of cancer cell population expansion assume exponential growth kinetics at low cell densities, with deviations to account for observed slowing of growth rate only at higher densities due to limited resources such as space and nutrients. However, recent preclinical and clinical observations of tumor initiati...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Johnson KE,Howard G,Mo W,Strasser MK,Lima EABF,Huang S,Brock A

    更新日期:2019-08-05 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


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

    更新日期:2006-03-01 00:00:00

  • Microsaccade-rhythmic modulation of neural synchronization and coding within and across cortical areas V1 and V2.

    abstract::Primates sample their visual environment actively through saccades and microsaccades (MSs). Saccadic eye movements not only modulate neural spike rates but might also affect temporal correlations (synchrony) among neurons. Neural synchrony plays a role in neural coding and modulates information transfer between cortic...

    journal_title:PLoS biology

    pub_type: 杂志文章


    authors: Lowet E,Gips B,Roberts MJ,De Weerd P,Jensen O,van der Eerden J

    更新日期:2018-05-31 00:00:00