Abstract:
:The functional contribution of CNV to human biology and disease pathophysiology has undergone limited exploration. Recent observations in humans indicate a tentative link between CNV and weight regulation. Smith-Magenis syndrome (SMS), manifesting obesity and hypercholesterolemia, results from a deletion CNV at 17p11.2, but is sometimes due to haploinsufficiency of a single gene, RAI1. The reciprocal duplication in 17p11.2 causes Potocki-Lupski syndrome (PTLS). We previously constructed mouse strains with a deletion, Df(11)17, or duplication, Dp(11)17, of the mouse genomic interval syntenic to the SMS/PTLS region. We demonstrate that Dp(11)17 is obesity-opposing; it conveys a highly penetrant, strain-independent phenotype of reduced weight, leaner body composition, lower TC/LDL, and increased insulin sensitivity that is not due to alteration in food intake or activity level. When fed with a high-fat diet, Dp(11)17/+ mice display much less weight gain and metabolic change than WT mice, demonstrating that the Dp(11)17 CNV protects against metabolic syndrome. Reciprocally, Df(11)17/+ mice with the deletion CNV have increased weight, higher fat content, decreased HDL, and reduced insulin sensitivity, manifesting a bona fide metabolic syndrome. These observations in the deficiency animal model are supported by human data from 76 SMS subjects. Further, studies on knockout/transgenic mice showed that the metabolic consequences of Dp(11)17 and Df(11)17 CNVs are not only due to dosage alterations of Rai1, the predominant dosage-sensitive gene for SMS and likely also PTLS. Our experiments in chromosome-engineered mouse CNV models for human genomic disorders demonstrate that a CNV can be causative for weight/metabolic phenotypes. Furthermore, we explored the biology underlying the contribution of CNV to the physiology of weight control and energy metabolism. The high penetrance, strain independence, and resistance to dietary influences associated with the CNVs in this study are features distinct from most SNP-associated metabolic traits and further highlight the potential importance of CNV in the etiology of both obesity and MetS as well as in the protection from these traits.
journal_name
PLoS Genetjournal_title
PLoS geneticsauthors
Lacaria M,Saha P,Potocki L,Bi W,Yan J,Girirajan S,Burns B,Elsea S,Walz K,Chan L,Lupski JR,Gu Wdoi
10.1371/journal.pgen.1002713subject
Has Abstractpub_date
2012-01-01 00:00:00pages
e1002713issue
5eissn
1553-7390issn
1553-7404pii
PGENETICS-D-12-00139journal_volume
8pub_type
杂志文章相关文献
PLoS Genetics文献大全abstract::The cell envelope of Gram-negative bacteria is a formidable barrier that is difficult for antimicrobial drugs to penetrate. Thus, the list of treatments effective against these organisms is small and with the rise of new resistance mechanisms is shrinking rapidly. New therapies to treat Gram-negative bacterial infecti...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004056
更新日期:2014-01-01 00:00:00
abstract::It is known that genetic variants can affect gene expression, but it is not yet completely clear through what mechanisms genetic variation mediate this expression. We therefore compared the cis-effect of single nucleotide polymorphisms (SNPs) on gene expression between blood samples from 1,240 human subjects and four ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002431
更新日期:2012-01-01 00:00:00
abstract::Iran, despite its size, geographic location and past cultural influence, has largely been a blind spot for human population genetic studies. With only sparse genetic information on the Iranian population available, we pursued its genome-wide and geographic characterization based on 1021 samples from eleven ethnic grou...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008385
更新日期:2019-09-24 00:00:00
abstract::Neuronal cargos are differentially targeted to either axons or dendrites, and this polarized cargo targeting critically depends on the interaction between microtubules and molecular motors. From a forward mutagenesis screen, we identified a gain-of-function mutation in the C. elegans α-tubulin gene mec-12 that trigger...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004715
更新日期:2014-11-13 00:00:00
abstract::Understanding how axon guidance receptors are activated by their extracellular ligands to regulate growth cone motility is critical to learning how proper wiring is established during development. Roundabout (Robo) is one such guidance receptor that mediates repulsion from its ligand Slit in both invertebrates and ver...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005402
更新日期:2015-09-03 00:00:00
abstract::To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1 × 10(-11) observed for rs917727 w...
journal_title:PLoS genetics
pub_type: 杂志文章,meta分析
doi:10.1371/journal.pgen.1002718
更新日期:2012-07-01 00:00:00
abstract::Synonymous mutations do not alter the specified amino acid but may alter the structure or function of an mRNA in ways that impact fitness. There are few examples in the literature, however, in which the effects of synonymous mutations on microbial growth rates have been measured, and even fewer for which the underlyin...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007615
更新日期:2018-08-27 00:00:00
abstract::With multiple genome-wide association studies (GWAS) performed across autoimmune diseases, there is a great opportunity to study the homogeneity of genetic architectures across autoimmune disease. Previous approaches have been limited in the scope of their analysis and have failed to properly incorporate the direction...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000792
更新日期:2009-12-01 00:00:00
abstract::Despite strong vetting for disease activity, only 10% of candidate new molecular entities in early stage clinical trials are eventually approved. Analyzing historical pipeline data, Nelson et al. 2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely t...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008489
更新日期:2019-12-12 00:00:00
abstract::Prostate cancer incidence is increasing in younger men. We investigated whether men diagnosed with Gleason 7 (3+4) T2 prostate cancer at younger ages (≤ 45 years, young cohort) had different mRNA and miRNA expression profiles than men diagnosed at older ages (71-74 years, older cohort). We identified differentially ex...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006477
更新日期:2016-12-27 00:00:00
abstract::Gene expression responds to changes in conditions but also stochastically among individuals. In budding yeast, both expression responsiveness across conditions ("plasticity") and cell-to-cell variation ("noise") have been quantified for thousands of genes and found to correlate across genes. It has been argued therefo...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1001185
更新日期:2010-11-04 00:00:00
abstract::In Saccharomyces cerevisiae, the conserved phosphatase Cdc14 is required for the exit from mitosis. It is anchored on nucleolar chromatin by the Cfi1/Net1 protein until early anaphase, at which time it is released into the nucleoplasm. Two poorly understood, redundant pathways promote Cdc14 release, the FEAR (Cdc four...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000588
更新日期:2009-08-01 00:00:00
abstract::The hallmark of canonical Wnt signaling is the transcriptional induction of Wnt target genes by the beta-catenin/TCF complex. Several studies have proposed alternative interaction partners for beta-catenin or TCF, but the relevance of potential bifurcations in the distal Wnt pathway remains unclear. Here we study on a...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006700
更新日期:2017-04-03 00:00:00
abstract::Recent studies have demonstrated that the DNA methylome changes with age. This epigenetic drift may have deep implications for cellular differentiation and disease development. However, it remains unclear how much of this drift is functional or caused by underlying changes in cell subtype composition. Moreover, no stu...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004996
更新日期:2015-02-18 00:00:00
abstract::Cockayne syndrome (CS) is a devastating progeria most often caused by mutations in the CSB gene encoding a SWI/SNF family chromatin remodeling protein. Although all CSB mutations that cause CS are recessive, the complete absence of CSB protein does not cause CS. In addition, most CSB mutations are located beyond exon ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000031
更新日期:2008-03-21 00:00:00
abstract::MicroRNAs (miRNAs) are small, non-coding RNAs that play essential roles in plant growth, development, and stress response. We conducted a genome-wide survey of maize miRNA genes, characterizing their structure, expression, and evolution. Computational approaches based on homology and secondary structure modeling ident...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000716
更新日期:2009-11-01 00:00:00
abstract::Papillorenal syndrome (PRS, also known as renal-coloboma syndrome) is an autosomal dominant disease characterized by potentially-blinding congenital optic nerve excavation and congenital kidney abnormalities. Many patients with PRS have mutations in the paired box transcription factor gene, PAX2. Although most mutatio...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000870
更新日期:2010-03-05 00:00:00
abstract::An important follow-up step after genetic markers are found to be associated with a disease outcome is a more detailed analysis investigating how the implicated gene or chromosomal region and an established environment risk factor interact to influence the disease risk. The standard approach to this study of gene-envi...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002482
更新日期:2012-01-01 00:00:00
abstract::Endoplasmic reticulum (ER) stress activates the Unfolded Protein Response, a compensatory signaling response that is mediated by the IRE-1, PERK/PEK-1, and ATF-6 pathways in metazoans. Genetic studies have implicated roles for UPR signaling in animal development and disease, but the function of the UPR under physiolog...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002391
更新日期:2011-11-01 00:00:00
abstract::Hexavalent chromium [Cr(VI)] damages DNA and causes cancer, but it is unclear which DNA damage responses (DDRs) most critically protect cells from chromate toxicity. Here, genome-wide quantitative functional profiling, DDR measurements and genetic interaction assays in Schizosaccharomyces pombe reveal a chromate toxic...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007595
更新日期:2018-08-27 00:00:00
abstract::Mutants of trt-1, the Caenorhabditis elegans telomerase reverse transcriptase, reproduce normally for several generations but eventually become sterile as a consequence of telomere erosion and end-to-end chromosome fusions. Telomere erosion and uncapping do not cause an increase in apoptosis in the germlines of trt-1 ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.0020018
更新日期:2006-02-01 00:00:00
abstract::For many genes, proper gene expression requires coordinated and dynamic interactions between multiple regulatory elements, each of which can either promote or silence transcription. In Drosophila, the complexity of the regulatory landscape is further complicated by the tight physical pairing of homologous chromosomes,...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008152
更新日期:2019-05-10 00:00:00
abstract::Examination of the human transcriptome reveals higher levels of RNA editing than in any other organism tested to date. This is indicative of extensive double-stranded RNA (dsRNA) formation within the human transcriptome. Most of the editing sites are located in the primate-specific retrotransposed element called Alu. ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000204
更新日期:2008-09-26 00:00:00
abstract::Dimethylation of histone H3 lysine 9 (H3K9m2) and trimethylation of histone H3 lysine 27 (H3K27m3) are two hallmarks of transcriptional repression in many organisms. In Arabidopsis thaliana, H3K27m3 is targeted by Polycomb Group (PcG) proteins and is associated with silent protein-coding genes, while H3K9m2 is correla...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003062
更新日期:2012-01-01 00:00:00
abstract::Tolerance to high levels of ethanol is an ecologically and industrially relevant phenotype of microbes, but the molecular mechanisms underlying this complex trait remain largely unknown. Here, we use long-term experimental evolution of isogenic yeast populations of different initial ploidy to study adaptation to incre...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005635
更新日期:2015-11-06 00:00:00
abstract::At the molecular level, the evolution of new traits can be broadly divided between changes in gene expression and changes in protein-coding sequence. For proteins, the evolution of novel functions is generally thought to proceed through sequential point mutations or recombination of whole functional units. In Saccharo...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007786
更新日期:2019-04-04 00:00:00
abstract::Proteins secreted by pathogens during host colonization largely determine the outcome of pathogen-host interactions and are commonly called 'effectors'. In fungal plant pathogens, coordinated transcriptional up-regulation of effector genes is a key feature of pathogenesis and effectors are often encoded in genomic reg...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006401
更新日期:2016-11-17 00:00:00
abstract::Histidine kinase QseE and response regulator QseF compose a two-component system in Enterobacteriaceae. In Escherichia coli K-12 QseF activates transcription of glmY and of rpoE from Sigma 54-dependent promoters by binding to upstream activating sequences. Small RNA GlmY and RpoE (Sigma 24) are important regulators of...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007547
更新日期:2018-07-24 00:00:00
abstract::A universal Tree of Life (TOL) has long been a goal of molecular phylogeneticists, but reticulation at the level of genes and possibly at the levels of cells and species renders any simple interpretation of such a TOL, especially as applied to prokaryotes, problematic. ...
journal_title:PLoS genetics
pub_type: 杂志文章,评审
doi:10.1371/journal.pgen.1005912
更新日期:2016-04-14 00:00:00
abstract::Deedu (DU) Mongolians, who migrated from the Mongolian steppes to the Qinghai-Tibetan Plateau approximately 500 years ago, are challenged by environmental conditions similar to native Tibetan highlanders. Identification of adaptive genetic factors in this population could provide insight into coordinated physiological...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003634
更新日期:2013-01-01 00:00:00