A Multiplexed Assay for Exon Recognition Reveals that an Unappreciated Fraction of Rare Genetic Variants Cause Large-Effect Splicing Disruptions.


:Mutations that lead to splicing defects can have severe consequences on gene function and cause disease. Here, we explore how human genetic variation affects exon recognition by developing a multiplexed functional assay of splicing using Sort-seq (MFASS). We assayed 27,733 variants in the Exome Aggregation Consortium (ExAC) within or adjacent to 2,198 human exons in the MFASS minigene reporter and found that 3.8% (1,050) of variants, most of which are extremely rare, led to large-effect splice-disrupting variants (SDVs). Importantly, we find that 83% of SDVs are located outside of canonical splice sites, are distributed evenly across distinct exonic and intronic regions, and are difficult to predict a priori. Our results indicate extant, rare genetic variants can have large functional effects on splicing at appreciable rates, even outside the context of disease, and MFASS enables their empirical assessment at scale.


Mol Cell


Molecular cell


Cheung R,Insigne KD,Yao D,Burghard CP,Wang J,Hsiao YE,Jones EM,Goodman DB,Xiao X,Kosuri S




Has Abstract


2019-01-03 00:00:00














  • Promoter Distortion and Opening in the RNA Polymerase II Cleft.

    abstract::Transcription initiation requires opening of promoter DNA in the RNA polymerase II (Pol II) pre-initiation complex (PIC), but it remains unclear how this is achieved. Here we report the cryo-electron microscopic (cryo-EM) structure of a yeast PIC that contains underwound, distorted promoter DNA in the closed Pol II cl...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Dienemann C,Schwalb B,Schilbach S,Cramer P

    更新日期:2019-01-03 00:00:00

  • p53 Activates the Long Noncoding RNA Pvt1b to Inhibit Myc and Suppress Tumorigenesis.

    abstract::The tumor suppressor p53 transcriptionally activates target genes to suppress cellular proliferation during stress. p53 has also been implicated in the repression of the proto-oncogene Myc, but the mechanism has remained unclear. Here, we identify Pvt1b, a p53-dependent isoform of the long noncoding RNA (lncRNA) Pvt1,...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Olivero CE,Martínez-Terroba E,Zimmer J,Liao C,Tesfaye E,Hooshdaran N,Schofield JA,Bendor J,Fang D,Simon MD,Zamudio JR,Dimitrova N

    更新日期:2020-02-20 00:00:00

  • A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif.

    abstract::HIV-1 Vpu interacts with CD4 in the endoplasmic reticulum and triggers CD4 degradation, presumably by proteasomes. Human beta TrCP identified by interaction with Vpu connects CD4 to this proteolytic machinery, and CD4-Vpu-beta TrCP ternary complexes have been detected by coimmunoprecipitation. beta TrCP binding to Vpu...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Margottin F,Bour SP,Durand H,Selig L,Benichou S,Richard V,Thomas D,Strebel K,Benarous R

    更新日期:1998-03-01 00:00:00

  • Methylation of DNA Ligase 1 by G9a/GLP Recruits UHRF1 to Replicating DNA and Regulates DNA Methylation.

    abstract::DNA methylation is an essential epigenetic mark in mammals that has to be re-established after each round of DNA replication. The protein UHRF1 is essential for this process; it has been proposed that the protein targets newly replicated DNA by cooperatively binding hemi-methylated DNA and H3K9me2/3, but this model le...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Ferry L,Fournier A,Tsusaka T,Adelmant G,Shimazu T,Matano S,Kirsh O,Amouroux R,Dohmae N,Suzuki T,Filion GJ,Deng W,de Dieuleveult M,Fritsch L,Kudithipudi S,Jeltsch A,Leonhardt H,Hajkova P,Marto JA,Arita K,Shinkai Y

    更新日期:2017-08-17 00:00:00

  • The pathway for DNA recognition and RNA integration by a group II intron retrotransposon.

    abstract::Group II intron RNPs are mobile genetic elements that attack and invade duplex DNA. In this work, we monitor the invasion reaction in vitro and establish a quantitative kinetic framework for the steps of this complex cascade. We find that target site specificity is achieved after DNA binding, which occurs nonspecifica...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Aizawa Y,Xiang Q,Lambowitz AM,Pyle AM

    更新日期:2003-03-01 00:00:00

  • Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37.

    abstract::Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13, but little is known about the regulation of this essential posttranslational modification. We show that Ser13 of uncomplexed Cdc37 is phosphorylated in vivo, as well as in bin...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Vaughan CK,Mollapour M,Smith JR,Truman A,Hu B,Good VM,Panaretou B,Neckers L,Clarke PA,Workman P,Piper PW,Prodromou C,Pearl LH

    更新日期:2008-09-26 00:00:00

  • R-ChIP Using Inactive RNase H Reveals Dynamic Coupling of R-loops with Transcriptional Pausing at Gene Promoters.

    abstract::R-loop, a three-stranded RNA/DNA structure, has been linked to induced genome instability and regulated gene expression. To enable precision analysis of R-loops in vivo, we develop an RNase-H-based approach; this reveals predominant R-loop formation near gene promoters with strong G/C skew and propensity to form G-qua...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Chen L,Chen JY,Zhang X,Gu Y,Xiao R,Shao C,Tang P,Qian H,Luo D,Li H,Zhou Y,Zhang DE,Fu XD

    更新日期:2017-11-16 00:00:00

  • PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis.

    abstract::K-Ras associates with the plasma membrane (PM) through farnesylation that functions in conjunction with an adjacent polybasic sequence. We show that phosphorylation by protein kinase C (PKC) of S181 within the polybasic region promotes rapid dissociation of K-Ras from the PM and association with intracellular membrane...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Bivona TG,Quatela SE,Bodemann BO,Ahearn IM,Soskis MJ,Mor A,Miura J,Wiener HH,Wright L,Saba SG,Yim D,Fein A,Pérez de Castro I,Li C,Thompson CB,Cox AD,Philips MR

    更新日期:2006-02-17 00:00:00

  • RRM Transcription Factors Interact with NLRs and Regulate Broad-Spectrum Blast Resistance in Rice.

    abstract::Nucleotide-binding site leucine-rich repeat (NLR) receptors perceive pathogen effectors and trigger plant immunity. However, the mechanisms underlying NLR-triggered defense responses remain obscure. The recently discovered Pigm locus in rice encodes a cluster of NLRs, including PigmR, which confers broad-spectrum resi...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Zhai K,Deng Y,Liang D,Tang J,Liu J,Yan B,Yin X,Lin H,Chen F,Yang D,Xie Z,Liu JY,Li Q,Zhang L,He Z

    更新日期:2019-06-06 00:00:00

  • The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis.

    abstract::Trans-sialidases (TS) are GPI-anchored surface enzymes expressed in specific developmental stages of trypanosome parasites like Trypanosoma cruzi, the etiologic agent of Chagas disease, and T. brucei, the causative agent of sleeping sickness. TS catalyzes the transfer of sialic acid residues from host to parasite glyc...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Buschiazzo A,Amaya MF,Cremona ML,Frasch AC,Alzari PM

    更新日期:2002-10-01 00:00:00

  • An acid test for g proteins.

    abstract::In this issue, Isom et al. (2013) report their exciting discovery that G proteins can sense pH changes to fine-tune signaling in response to metabolic changes. ...

    journal_title:Molecular cell

    pub_type: 评论,杂志文章


    authors: Sprang SR

    更新日期:2013-08-22 00:00:00

  • Opposing Functions of BRD4 Isoforms in Breast Cancer.

    abstract::Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein d...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Wu SY,Lee CF,Lai HT,Yu CT,Lee JE,Zuo H,Tsai SY,Tsai MJ,Ge K,Wan Y,Chiang CM

    更新日期:2020-06-18 00:00:00

  • A role for TBP dimerization in preventing unregulated gene expression.

    abstract::The recruitment of the TATA box-binding protein (TBP) to promoters in vivo is often rate limiting in gene expression. We present evidence that TBP negatively autoregulates its accessibility to promoter DNA in yeast through dimerization. The crystal structure of TBP dimers was used to design point mutations in the dime...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Jackson-Fisher AJ,Chitikila C,Mitra M,Pugh BF

    更新日期:1999-06-01 00:00:00

  • Structural basis for interaction of the ribosome with the switch regions of GTP-bound elongation factors.

    abstract::Elongation factor G (EF-G) catalyzes tRNA translocation on the ribosome. Here a cryo-EM reconstruction of the 70S*EF-G ribosomal complex at 7.3 A resolution and the crystal structure of EF-G-2*GTP, an EF-G homolog, at 2.2 A resolution are presented. EF-G-2*GTP is structurally distinct from previous EF-G structures, an...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Connell SR,Takemoto C,Wilson DN,Wang H,Murayama K,Terada T,Shirouzu M,Rost M,Schüler M,Giesebrecht J,Dabrowski M,Mielke T,Fucini P,Yokoyama S,Spahn CM

    更新日期:2007-03-09 00:00:00

  • Detection of high-affinity and sliding clamp modes for MSH2-MSH6 by single-molecule unzipping force analysis.

    abstract::Mismatch repair (MMR) is initiated by MutS family proteins (MSH) that recognize DNA mismatches and recruit downstream repair factors. We used a single-molecule DNA-unzipping assay to probe interactions between S. cerevisiae MSH2-MSH6 and a variety of DNA mismatch substrates. This work revealed a high-specificity bindi...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Jiang J,Bai L,Surtees JA,Gemici Z,Wang MD,Alani E

    更新日期:2005-12-09 00:00:00

  • EM visualization of transcription by RNA polymerase II: downstream termination requires a poly(A) signal but not transcript cleavage.

    abstract::We have used EM visualization of active genes on plasmid vectors in Xenopus oocyte nuclei to investigate the relationship between poly(A) signals and RNA polymerase II transcription termination. Although a functional poly(A) signal is required for efficient termination, cotranscriptional RNA cleavage at the poly(A) si...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Osheim YN,Proudfoot NJ,Beyer AL

    更新日期:1999-03-01 00:00:00

  • Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH.

    abstract::DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defec...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Mazouzi A,Battistini F,Moser SC,Ferreira da Silva J,Wiedner M,Owusu M,Lardeau CH,Ringler A,Weil B,Neesen J,Orozco M,Kubicek S,Loizou JI

    更新日期:2017-11-16 00:00:00

  • Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O.

    abstract::The tumor suppressor BAP1 interacts with chromatin-associated proteins and regulates cell proliferation, but its mechanism of action and regulation remain poorly defined. We show that the ubiquitin-conjugating enzyme UBE2O multi-monoubiquitinates the nuclear localization signal of BAP1, thereby inducing its cytoplasmi...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Mashtalir N,Daou S,Barbour H,Sen NN,Gagnon J,Hammond-Martel I,Dar HH,Therrien M,Affar el B

    更新日期:2014-05-08 00:00:00

  • Distinct signals generate repeating striped pattern in the embryonic parasegment.

    abstract::How repeating striped patterns arise across cellular fields is unclear. To address this we examined the repeating pattern of Stripe (Sr) expression across the parasegment (PS) in Drosophila. This pattern is generated in two steps. First, the ligands Hedgehog (Hh) and Wingless (Wg) subdivide the PS into smaller territo...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Hatini V,DiNardo S

    更新日期:2001-01-01 00:00:00

  • Y14 and hUpf3b form an NMD-activating complex.

    abstract::Messenger RNAs with premature translation termination codons (PTCs) are degraded by nonsense-mediated mRNA decay (NMD). In mammals, PTCs are discriminated from physiological stop codons by a process thought to involve the splicing-dependent deposition of an exon junction complex (EJC), EJC-mediated recruitment of Upf3...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Gehring NH,Neu-Yilik G,Schell T,Hentze MW,Kulozik AE

    更新日期:2003-04-01 00:00:00

  • Acetylation regulates transcription factor activity at multiple levels.

    abstract::CREB-binding protein (CBP) possesses an intrinsic acetyltransferase activity capable of acetylating nucleosomal histones as well as several nonhistone proteins. Here, it is shown that CBP can acetylate hepatocyte nuclear factor-4 (HNF-4), a member of the nuclear hormone receptor family, at lysine residues within the n...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Soutoglou E,Katrakili N,Talianidis I

    更新日期:2000-04-01 00:00:00

  • Mechanism of membrane insertion of a multimeric beta-barrel protein: perfringolysin O creates a pore using ordered and coupled conformational changes.

    abstract::Perfringolysin O, a bacterial cytolytic toxin, forms unusually large pores in cholesterol-containing membranes by the spontaneous insertion of two of its four domains into the bilayer. By monitoring the kinetics of domain-specific conformational changes and pore formation using fluorescence spectroscopy, the temporal ...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Heuck AP,Hotze EM,Tweten RK,Johnson AE

    更新日期:2000-11-01 00:00:00

  • Molecular mechanism and evolution of guanylate kinase regulation by (p)ppGpp.

    abstract::The nucleotide (p)ppGpp mediates bacterial stress responses, but its targets and underlying mechanisms of action vary among bacterial species and remain incompletely understood. Here, we characterize the molecular interaction between (p)ppGpp and guanylate kinase (GMK), revealing the importance of this interaction in ...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Liu K,Myers AR,Pisithkul T,Claas KR,Satyshur KA,Amador-Noguez D,Keck JL,Wang JD

    更新日期:2015-02-19 00:00:00

  • Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs.

    abstract::Argonaute proteins associate with small RNAs that guide mRNA degradation, translational repression, or a combination of both. The human Argonaute family has eight members, four of which (Ago1 through Ago4) are closely related and coexpressed in many cell types. To understand the biological function of the different Ag...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Meister G,Landthaler M,Patkaniowska A,Dorsett Y,Teng G,Tuschl T

    更新日期:2004-07-23 00:00:00

  • Eukaryotic stress granules: the ins and outs of translation.

    abstract::The stress response in eukaryotic cells often inhibits translation initiation and leads to the formation of cytoplasmic RNA-protein complexes referred to as stress granules. Stress granules contain nontranslating mRNAs, translation initiation components, and many additional proteins affecting mRNA function. Stress gra...

    journal_title:Molecular cell

    pub_type: 杂志文章,评审


    authors: Buchan JR,Parker R

    更新日期:2009-12-25 00:00:00

  • Bidirectional Transcription Arises from Two Distinct Hubs of Transcription Factor Binding and Active Chromatin.

    abstract::Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the regulation or function of anti-sense promoters and the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Scruggs BS,Gilchrist DA,Nechaev S,Muse GW,Burkholder A,Fargo DC,Adelman K

    更新日期:2015-06-18 00:00:00

  • Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination.

    abstract::How polycomb group proteins repress gene expression in vivo is not known. While histone-modifying activities of the polycomb repressive complexes (PRCs) have been studied extensively, in vitro data have suggested a direct activity of the PRC1 complex in compacting chromatin. Here, we investigate higher-order chromatin...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Eskeland R,Leeb M,Grimes GR,Kress C,Boyle S,Sproul D,Gilbert N,Fan Y,Skoultchi AI,Wutz A,Bickmore WA

    更新日期:2010-05-14 00:00:00

  • Mph1 and Mus81-Mms4 prevent aberrant processing of mitotic recombination intermediates.

    abstract::Homology-dependent repair of double-strand breaks (DSBs) from nonsister templates has the potential to generate loss of heterozygosity or genome rearrangements. Here we show that the Saccharomyces cerevisiae Mph1 helicase prevents crossovers between ectopic sequences by removing substrates for Mus81-Mms4 or Rad1-Rad10...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Mazón G,Symington LS

    更新日期:2013-10-10 00:00:00

  • Emerging Principles of Gene Expression Programs and Their Regulation.

    abstract::Many mechanisms contribute to regulation of gene expression to ensure coordinated cellular behaviors and fate decisions. Transcriptional responses to external signals can consist of many hundreds of genes that can be parsed into different categories based on kinetics of induction, cell-type and signal specificity, and...

    journal_title:Molecular cell

    pub_type: 杂志文章,评审


    authors: Pope SD,Medzhitov R

    更新日期:2018-08-02 00:00:00

  • Structure of the Epstein-Barr virus gp42 protein bound to the MHC class II receptor HLA-DR1.

    abstract::Epstein-Barr virus (EBV) causes infectious mononucleosis, establishes long-term latent infections, and is associated with a variety of human tumors. The EBV gp42 glycoprotein binds MHC class II molecules, playing a critical role in infection of B lymphocytes. EBV gp42 belongs to the C-type lectin superfamily, with hom...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Mullen MM,Haan KM,Longnecker R,Jardetzky TS

    更新日期:2002-02-01 00:00:00