scholarly journals Idiosyncratic epistasis leads to global fitness-correlated trends

2021 ◽  
Author(s):  
Christopher W Bakerlee ◽  
Alex N. Nguyen Ba ◽  
Yekaterina Shulgina ◽  
Jose I. Rojas-Echenique ◽  
Michael M. Desai
Keyword(s):  
Protein Level ◽  
Experimental Validation ◽  
Budding Yeast ◽  
Theoretical Work ◽  
Fitness Landscapes ◽  
Drive System ◽  
Missense Mutations ◽  
Gene Drive ◽  
Recent Theoretical Work ◽  
Evolutionary Trajectories

Epistasis can dramatically affect evolutionary trajectories. In recent decades, protein-level fitness landscapes have revealed pervasive idiosyncratic epistasis among specific mutations. In contrast, other work has found ubiquitous and apparently non-specific patterns of global diminishing-returns and increasing-costs epistasis among mutations across the genome. Here, we use a hierarchical CRISPR gene drive system to construct all combinations of 10 missense mutations from across the genome in budding yeast, and measure their fitness in six environments. We show that the resulting fitness landscapes exhibit global fitness-correlated trends, but that these trends emerge from specific idiosyncratic interactions. This provides the first experimental validation of recent theoretical work that has argued that fitness-correlated trends are the generic consequence of idiosyncratic epistasis.

scholarly journals Development of a multi-locus CRISPR gene drive system in budding yeast

2018 ◽  
Author(s):  
Yao Yan ◽  
Gregory C. Finnigan
Keyword(s):  
Budding Yeast ◽  
Basic Research ◽  
Single Copy ◽  
Drive System ◽  
Gene Drive ◽  
Agricultural Pests ◽  
Guide Rnas ◽  
And Control ◽  
Gene Drives ◽  
Control Inhibition

ABSTRACTThe discovery of CRISPR/Cas gene editing has allowed for major advances in many biomedical disciplines and basic research. One arrangement of this biotechnology, a nuclease-based gene drive, can rapidly deliver a genetic element through a given population and studies in fungi and metazoans have demonstrated the success of such a system. This methodology has the potential to control biological populations and contribute to eradication of insect-borne diseases, agricultural pests, and invasive species. However, there remain challenges in the design, optimization, and implementation of gene drives including concerns regarding biosafety, containment, and control/inhibition. Given the numerous gene drive arrangements possible, there is a growing need for more advanced designs. In this study, we use budding yeast to develop an artificial multi-locus gene drive system. Our minimal setup requires only a single copy of S. pyogenes Cas9 and three guide RNAs to propagate three separate gene drives. We demonstrate how this system could be used for targeted allele replacement of native genes and to suppress NHEJ repair systems by modifying DNA Ligase IV. A multi-locus gene drive configuration provides an expanded suite of options for complex attributes including pathway redundancy, combatting evolved resistance, and safeguards for control, inhibition, or reversal of drive action.

The light-scattering Mueller matrices for Rayleigh and Rayleigh-Gans-Debye approximation

1990 ◽  
Vol 55 (12) ◽  
pp. 2889-2897
Author(s):  
Jaroslav Holoubek
Keyword(s):  
Light Scattering ◽  
Theoretical Work ◽  
Matrix Elements ◽  
Elastic Light Scattering ◽  
Yield Information ◽  
Recent Theoretical Work ◽  
Particle Parameters ◽  
Complete Set ◽  
Single Matrix ◽  
Scattering Matrix Elements

Recent theoretical work has shown that the complete set of polarized elastic light-scattering studies should yield information about scatterer structure that has so far hardly been utilized. We present here calculations of angular dependences of light-scattering matrix elements for spheres near the Rayleigh and Rayleigh-Gans-Debye limits. The significance of single matrix elements is documented on examples that show how different matrix elements respond to changes in particle parameters. It appears that in the small-particle limit (Rg/λ < 0.1) we do not loose much information by ignoring "large particle" observables.

scholarly journals Magnetospheric Structure of Rotation-Powered Neutron Stars

1992 ◽  
Vol 128 ◽  
pp. 56-77 ◽  
Author(s):  
Jonathan Arons
Keyword(s):  
Radio Emission ◽  
Gamma Radiation ◽  
Heavy Ions ◽  
Theoretical Work ◽  
Future Research ◽  
Observational Constraints ◽  
Polar Caps ◽  
Recent Theoretical Work ◽  
Density Flow ◽  
Promising Avenue

AbstractI survey recent theoretical work on the structure of the magnetospheres of rotation-powered pulsars, within the observational constraints set by their observed spindown, their ability to power synchrotron nebulae and their ability to produce beamed collective radio emission, while putting only a small fraction of their energy into incoherent X- and gamma radiation. I find no single theory has yet given a consistent description of the magnetosphere, but I conclude that models based on a dense outflow of pairs from the polar caps, permeated by a lower density flow of heavy ions, are the most promising avenue for future research.

scholarly journals THE EXOTIC BARIUM BISMUTHATES

1996 ◽  
Vol 10 (08) ◽  
pp. 863-955 ◽  
Author(s):  
A. TARAPHDER ◽  
RAHUL PANDIT ◽  
H. R. KRISHNAMURTHY ◽  
T. V. RAMAKRISHNAN
Keyword(s):  
Bound States ◽  
Random Phase ◽  
Density Wave ◽  
Mean Field ◽  
Experimental Tests ◽  
Theoretical Work ◽  
Recent Theoretical Work ◽  
Effects Of Disorder ◽  
Exotic Physics ◽  
Transport Gaps

We review the remarkable properties, including superconductivity, charge-density-wave ordering and metal–insulator transitions, of lead- and potassium-doped barium bismuthate. We will discuss some of the early theoretical studies of these systems. Our recent theoretical work, on the negative-U, extended-Hubbard model for these systems, will also be described. Both the large- and intermediate-U regimes of this model were examined, using mean-field and random-phase approximations, particularly with a view to fitting various experimental properties of these bismuthates. On the basis of our studies, we point out possibilities for exotic physics in these systems. We also emphasize the different consequences of electronic and phonon-mediated mechanisms for the negative U. We show that, for an electronic mechanism, the semiconducting phases of these bismuthates must be unique, with their transport properties dominated by charge±2eCooperon bound states. This can explain the observed difference between the optical and transport gaps. We propose other experimental tests for this novel mechanism of charge transport and comment on the effects of disorder.

scholarly journals A Budding Yeast Model for Human Disease Mutations in the EXOSC2 Cap Subunit of the RNA Exosome

2020 ◽  
Author(s):  
Maria C. Sterrett ◽  
Liz Enyenihi ◽  
Sara W. Leung ◽  
Laurie Hess ◽  
Sarah E. Strassler ◽  
...  
Keyword(s):  
Amino Acid ◽  
Budding Yeast ◽  
Amino Acid Substitutions ◽  
Missense Mutations ◽  
Subunit Gene ◽  
Rna Targets ◽  
Genes Encoding ◽  
Rna Exosome ◽  
Transcriptomic Changes

AbstractRNA exosomopathies, a growing family of tissue-specific diseases, are linked to missense mutations in genes encoding the structural subunits of the conserved 10-subunit exoribonuclease complex, the RNA exosome. Such mutations in the cap subunit gene EXOSC2 cause the novel syndrome SHRF (Short stature, Hearing loss, Retinitis pigmentosa and distinctive Facies). In contrast, exosomopathy mutations in the cap subunit gene EXOSC3 cause pontocerebellar hypoplasia type 1b (PCH1b). Though having strikingly different disease pathologies, EXOSC2 and EXOSC3 exosomopathy mutations result in amino acid substitutions in similar, conserved domains of the cap subunits, suggesting that these exosomopathy mutations have distinct consequences for RNA exosome function. We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by introducing the EXOSC2 mutations in the orthologous S. cerevisiae gene RRP4. The resulting rrp4 mutant cells have defects in cell growth and RNA exosome function. We detect significant transcriptomic changes in both coding and non-coding RNAs in the rrp4 variant, rrp4-G226D, which models EXOSC2 p.Gly198Asp. Comparing this rrp4-G226D mutant to the previously studied S. cerevisiae model of EXOSC3 PCH1b mutation, rrp40-W195R, reveals that these mutants have disparate effects on certain RNA targets, providing the first evidence for different mechanistic consequences of these exosomopathy mutations. Congruently, we detect specific negative genetic interactions between RNA exosome cofactor mutants and rrp4-G226D but not rrp40-W195R. These data provide insight into how SHRF mutations could alter the function of the RNA exosome and allow the first direct comparison of exosomopathy mutations that cause distinct pathologies.

scholarly journals Landauer in the age of synthetic biology: energy consumption and information processing in biochemical networks

2015 ◽  
Author(s):  
Pankaj Mehta ◽  
Alex H Lang ◽  
David J Schwab
Keyword(s):  
Information Processing ◽  
Energy Consumption ◽  
Synthetic Biology ◽  
Protein Modification ◽  
Theoretical Work ◽  
Biochemical Networks ◽  
Fundamental Physics ◽  
Recent Theoretical Work ◽  
Cellular Circuits ◽  
Molecular Components

A central goal of synthetic biology is to design sophisticated synthetic cellular circuits that can perform complex computations and information processing tasks in response to specific inputs. The tremendous advances in our ability to understand and manipulate cellular information processing networks raises several fundamental physics questions: How do the molecular components of cellu- lar circuits exploit energy consumption to improve information processing? Can one utilize ideas from thermodynamics to improve the design of synthetic cellular circuits and modules? Here, we summarize recent theoretical work addressing these questions. Energy consumption in cellular cir- cuits serves five basic purposes: (1) increasing specificity, (2) manipulating dynamics, (3) reducing variability, (4) amplifying signal, and (5) erasing memory. We demonstrate these ideas using several simple examples and discuss the implications of these theoretical ideas for the emerging field of synthetic biology. We conclude by discussing how it may be possible to overcome these limitations using “post-translational” synthetic biology that exploits reversible protein modification.

scholarly journals Mixed-polarity random-dot stereograms alter GABA and Glx concentration in the early visual cortex

2019 ◽  
Author(s):  
Reuben Rideaux ◽  
Nuno Goncalves ◽  
Andrew E Welchman
Keyword(s):  
Visual Cortex ◽  
Three Dimensional ◽  
Theoretical Work ◽  
Dimensional Structure ◽  
Resonance Spectroscopy ◽  
Gaba Concentration ◽  
Recent Theoretical Work ◽  
Random Dot Stereograms ◽  
Mixed Polarity ◽  
Early Visual Cortex

ABSTRACTThe offset between images projected onto the left and right retinae (binocular disparity) provides a powerful cue to the three-dimensional structure of the environment. It was previously shown that depth judgements are better when images comprise both light and dark features, rather than only dark or only light elements. Since Harris and Parker (1995) discovered the “mixed-polarity benefit”, there has been limited evidence supporting their hypothesis that the benefit is due to separate bright and dark channels. Goncalves and Welchman (2017) observed that single- and mixed-polarity stereograms evoke different levels of positive and negative activity in a deep neural network trained on natural images to make depth judgements, which also showed the mixed-polarity benefit. Motivated by this discovery, here we seek to test the potential for changes in the balance of excitation and inhibition that are produced by viewing these stimuli. In particular, we use magnetic resonance spectroscopy to measure Glx and GABA concentration in the early visual cortex of adult humans while viewing single- and mixed-polarity random-dot stereograms (RDS). We find that observers’ Glx concentration is significantly higher while GABA concentration is significantly lower when viewing mixed-polarity RDS than when viewing single-polarity RDS. These results indicate that excitation and inhibition facilitate processing of single- and mixed-polarity stereograms in the early visual cortex to different extents, consistent with recent theoretical work (Goncalves & Welchman, 2017).

Sign in / Sign up

Export Citation Format

Share Document