Spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity

Signal transduction proteins are often multi-domain proteins that arose through the fusion of previously independent proteins. How such a change in the spatial arrangement of proteins impacts their evolution and the selective pressures acting on individual residues is largely unknown. We explored this problem in the context of bacterial two-component signalling pathways, which typically involve a sensor histidine kinase that specifically phosphorylates a single cognate response regulator. Although usually found as separate proteins, these proteins are sometimes fused into a so-called hybrid histidine kinase. Here, we demonstrate that the isolated kinase domains of hybrid kinases exhibit a dramatic reduction in phosphotransfer specificity in vitro relative to canonical histidine kinases. However, hybrid kinases phosphotransfer almost exclusively to their covalently attached response regulator domain, whose effective concentration exceeds that of all soluble response regulators. These findings indicate that the fused response regulator in a hybrid kinase normally prevents detrimental cross-talk between pathways. More generally, our results shed light on how the spatial properties of signalling pathways can significantly affect their evolution, with additional implications for the design of synthetic signalling systems.National Science Foundation (U.S.) (CAREER Award)National Science Foundation (U.S.). Graduate Research Fellowship Progra

Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis

BackgroundCausal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort.MethodsGS was performed for 744 individuals with rare disease who were genetically undiagnosed. Analysis included review of single nucleotide, indel, structural, and mitochondrial variants.ResultsWe successfully solved 218/744 (29.3%) cases using GS, with most solves involving established disease genes (157/218, 72.0%). Of all solved cases, 148 (67.9%) had previously had non-diagnostic ES. We systematically evaluated the 218 causal variants for features requiring GS to identify and 61/218 (28.0%) met these criteria, representing 8.2% of the entire cohort. These included small structural variants (13), copy neutral inversions and complex rearrangements (8), tandem repeat expansions (6), deep intronic variants (15), and coding variants that may be more easily found using GS related to uniformity of coverage (19).ConclusionWe describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative

Search for diphoton events with large missing transverse momentum in 1 fb(-1) of 7 TeV proton-proton collision data with the ATLAS detector ATLAS Collaboration

A search for diphoton events with large missing transverse momentum has been performed using 1.07 fb -1 of proton-proton collision data at s=7 TeV recorded with the ATLAS detector. No excess of events was observed above the Standard Model prediction and 95% Confidence Level (CL) upper limits are set on the production cross section for new physics. The limits depend on each model parameter space and vary as follows: Λ<(22-129) fb in the context of a generalised model of gauge-mediated supersymmetry breaking (GGM) with a bino-like lightest neutralino, σ<(27-91) fb in the context of a minimal model of gauge-mediated supersymmetry breaking (SPS8), and σ<(15-27) fb in the context of a specific model with one universal extra dimension (UED). A 95% CL lower limit of 805 GeV, for bino masses above 50 GeV, is set on the GGM gluino mass. Lower limits of 145 TeV and 1.23 TeV are set on the SPS8 breaking scale Λ and on the UED compactification scale 1/R, respectively. These limits provide the most stringent tests of these models to date. © 2012 CERN

Search for diphoton events with large missing transverse momentum in 1 fb(-1) of 7 TeV proton-proton collision data with the ATLAS detector ATLAS Collaboration

A search for diphoton events with large missing transverse momentum has been performed using 1.07 fb(-1) of proton-proton collision data at root s = 7 TeV recorded with the ATLAS detector. No excess of events was observed above the Standard Model prediction and 95% Confidence Level (CL) upper limits are set on the production cross section for new physics. The limits depend on each model parameter space and vary as follows: sigma < (22-129) fb in the context of a generalised model of gauge-mediated supersymmetry breaking (GGM) with a bino-like lightest neutralino, sigma < (27-91) fb in the context of a minimal model of gauge-mediated supersymmetry breaking (SPS8), and sigma < (15-27) fb in the context of a specific model with one universal extra dimension (UED). A 95% CL lower limit of 805 GeV, for bino masses above 50 GeV, is set on the GGM gluino mass. Lower limits of 145 TeV and 1.23 TeV are set on the SPS8 breaking scale Lambda and on the UED compactification scale 1/R, respectively. These limits provide the most stringent tests of these models to date. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved. RI Sivoklokov, Sergey/D-8150-2012; Li, Xuefei/C-3861-2012; Smirnov, Sergei/F-1014-2011; Gladilin, Leonid/B-5226-2011; Barreiro, Fernando/D-9808-2012; Prokoshin, Fedor/E-2795-2012; Fazio, Salvatore /G-5156-2010; Orlov, Ilya/E-6611-2012; Doyle, Anthony/C-5889-2009; Alexa, Calin/F-6345-2010; Moorhead, Gareth/B-6634-2009; Livan, Michele/D-7531-2012; Takai, Helio/C-3301-2012; Petrucci, Fabrizio/G-8348-2012; Jones, Roger/H-5578-2011; Fabbri, Laura/H-3442-2012; Kurashige, Hisaya/H-4916-2012; Villa, Mauro/C-9883-2009; Delmastro, Marco/I-5599-201

Search for diphoton events with large missing transverse momentum in 1 fb^-1 of 7 TeV proton–proton collision data with the ATLAS detector

A search for diphoton events with large missing transverse momentum has been performed using 1.07 fb−1of proton–proton collision data at &#8730;s=7  TeV recorded with the ATLAS detector. No excess of events was observed above the Standard Model prediction and 95% Confidence Level (CL) upper limits are set on the production cross section for new physics. The limits depend on each model parameter space and vary as follows: &#963;&#60;(22–129) fb in the context of a generalised model of gauge-mediated supersymmetry breaking (GGM) with a bino-like lightest neutralino, &#963;&#60;(27–91) fb in the context of a minimal model of gauge-mediated supersymmetry breaking (SPS8), and &#963;&#60; (15–27) fb in the context of a specific model with one universal extra dimension (UED). A 95% CL lower limit of 805 GeV, for bino masses above 50 GeV, is set on the GGM gluino mass. Lower limits of 145 TeV and 1.23 TeV are set on the SPS8 breaking scale &#8743; and on the UED compactification scale 1/R, respectively. These limits provide the most stringent tests of these models to date

Search for diphoton events with large missing transverse momentum in 1 fb(-1) of 7 TeV proton-proton collision data with the ATLAS detector ATLAS Collaboration

A search for diphoton events with large missing transverse momentum has been performed using 1.07 fb(-1) of proton-proton collision data at root s = 7 TeV recorded with the ATLAS detector. No excess of events was observed above the Standard Model prediction and 95% Confidence Level (CL) upper limits are set on the production cross section for new physics. The limits depend on each model parameter space and vary as follows: sigma < (22-129) fb in the context of a generalised model of gauge-mediated supersymmetry breaking (GGM) with a bino-like lightest neutralino, sigma < (27-91) fb in the context of a minimal model of gauge-mediated supersymmetry breaking (SPS8), and sigma < (15-27) fb in the context of a specific model with one universal extra dimension (UED). A 95% CL lower limit of 805 GeV, for bino masses above 50 GeV, is set on the GGM gluino mass. Lower limits of 145 TeV and 1.23 TeV are set on the SPS8 breaking scale Lambda and on the UED compactification scale 1/R, respectively. These limits provide the most stringent tests of these models to date. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved