Gene-panel and whole-exome analyses are now standard methodologies for mutation detection in Mendelian disease. However, the diagnostic yield achieved is at best 50%, leaving the genetic basis for ...disease unsolved in many individuals. New approaches are thus needed to narrow the diagnostic gap. Whole-genome sequencing is one potential strategy, but it currently has variant-interpretation challenges, particularly for non-coding changes. In this study we focus on transcriptome analysis, specifically total RNA sequencing (RNA-seq), by using monogenetic neuromuscular disorders as proof of principle. We examined a cohort of 25 exome and/or panel “negative” cases and provided genetic resolution in 36% (9/25). Causative mutations were identified in coding and non-coding exons, as well as in intronic regions, and the mutational pathomechanisms included transcriptional repression, exon skipping, and intron inclusion. We address a key barrier of transcriptome-based diagnostics: the need for source material with disease-representative expression patterns. We establish that blood-based RNA-seq is not adequate for neuromuscular diagnostics, whereas myotubes generated by transdifferentiation from an individual’s fibroblasts accurately reflect the muscle transcriptome and faithfully reveal disease-causing mutations. Our work confirms that RNA-seq can greatly improve diagnostic yield in genetically unresolved cases of Mendelian disease, defines strengths and challenges of the technology, and demonstrates the suitability of cell models for RNA-based diagnostics. Our data set the stage for development of RNA-seq as a powerful clinical diagnostic tool that can be applied to the large population of individuals with undiagnosed, rare diseases and provide a framework for establishing minimally invasive strategies for doing so.
Social bees are important insect pollinators of wildflowers and agricultural crops, making their reported declines a global concern. A major factor implicated in these declines is the widespread use ...of neonicotinoid pesticides. Indeed, recent research has demonstrated that exposure to low doses of these neurotoxic pesticides impairs bee behaviours important for colony function and survival. However, our understanding of the molecular‐genetic pathways that lead to such effects is limited, as is our knowledge of how effects may differ between colony members. To understand what genes and pathways are affected by exposure of bumblebee workers and queens to neonicotinoid pesticides, we implemented a transcriptome‐wide gene expression study. We chronically exposed Bombus terrestriscolonies to either clothianidin or imidacloprid at field‐realistic concentrations while controlling for factors including colony social environment and worker age. We reveal that genes involved in important biological processes including mitochondrial function are differentially expressed in response to neonicotinoid exposure. Additionally, clothianidin exposure had stronger effects on gene expression amplitude and alternative splicing than imidacloprid. Finally, exposure affected workers more strongly than queens. Our work demonstrates how RNA‐Seq transcriptome profiling can provide detailed novel insight on the mechanisms mediating pesticide toxicity to a key insect pollinator.
We investigate the level of galaxy assembly bias in the Sloan Digital Sky Survey (SDSS) main galaxy sample using ELUCID, a state-of-the-art constrained simulation that accurately reconstructed the ...initial density perturbations within the SDSS volume. On top of the ELUCID haloes, we develop an extended HOD model that includes the assembly bias of central and satellite galaxies, parameterized as
Q
cen
and
Q
sat
, respectively, to predict a suite of one- and two-point observables. In particular, our fiducial constraint employs the probability distribution of the galaxy number counts measured on 8
h
−1
Mpc scales
N
8
g
and the projected cross-correlation functions of quintiles of galaxies selected by
N
8
g
with our entire galaxy sample. We perform extensive tests of the efficacy of our method by fitting the same observables to mock data using both constrained and non-constrained simulations. We discover that in many cases the level of cosmic variance between the two simulations can produce biased constraints that lead to an erroneous detection of galaxy assembly bias if the non-constrained simulation is used. When applying our method to the SDSS data, the ELUCID reconstruction effectively removes an otherwise strong degeneracy between cosmic variance and galaxy assembly bias in SDSS, enabling us to derive an accurate and stringent constraint on the latter. Our fiducial ELUCID constraint, for galaxies above a stellar mass threshold
M
*
=10
10.2
h
−2
M
⊙
, is
Q
cen
=−0.09 ± 0.05 and
Q
sat
=0.09 ± 0.10, indicating no evidence for a significant (> 2
σ
) galaxy assembly bias in the local Universe probed by SDSS. Finally, our method provides a promising path to the robust modelling of the galaxy-halo connection within future surveys like DESI and PFS.
Annual social insects are an integral functional group of organisms, particularly in temperate environments. An emblematic part of their annual cycle is the social phase, during which the ...colony-founding queen rears workers that later assist her in rearing sexual progeny (gynes and drones). In many annual social insects, such as species of bees, wasps, and other groups, developing larvae are provisioned gradually as they develop (progressive provisioning) leading to multiple larval generations being reared simultaneously. We present a model for how the queen in such cases should optimize her egg-laying rate throughout the social phase depending on number-size trade-offs, colony age-structure, and energy balance. Complementing previous theory on optimal allocation between workers vs. sexuals in annual social insects and on temporal egg-laying patterns in solitary insects, we elucidate how resource competition among overlapping larval generations can influence optimal egg-laying strategies. With model parameters informed by knowledge of a common bumblebee species, the optimal egg-laying schedule consists of two temporally separated early broods followed by a more continuous rearing phase, matching empirical observations. However, eggs should initially be laid continuously at a gradually increasing rate when resources are scarce or mortality risks high and in cases where larvae are fully supplied with resources at the egg-laying stage (mass-provisioning). These factors, alongside sexual:worker body size ratios, further determine the overall trend in egg-laying rates over the colony cycle. Our analysis provides an inroad to study and mechanistically understand variation in colony development strategies within and across species of annual social insects.
Vertebrate CtIP, and its fission yeast (Ctp1), budding yeast (Sae2) and plant (Com1) orthologs have emerged as key regulatory molecules in cellular responses to DNA double strand breaks (DSBs). By ...modulating the nucleolytic 5′-3′ resection activity of the Mre11/Rad50/Nbs1 (MRN) DSB repair processing and signaling complex, CtIP/Ctp1/Sae2/Com1 is integral to the channeling of DNA double strand breaks through DSB repair by homologous recombination (HR). Nearly two decades since its discovery, emerging new data are defining the molecular underpinnings for CtIP DSB repair regulatory activities. CtIP homologs are largely intrinsically unstructured proteins comprised of expanded regions of low complexity sequence, rather than defined folded domains typical of DNA damage metabolizing enzymes and nucleases. A compact structurally conserved N-terminus forms a functionally critical tetrameric helical dimer of dimers (THDD) region that bridges CtIP oligomers, and is flexibly appended to a conserved C-terminal Sae2-homology DNA binding and DSB repair pathway choice regulatory hub which influences nucleolytic activities of the MRN core nuclease complex. The emerging evidence from structural, biophysical, and biological studies converges on CtIP having functional roles in DSB repair that include: 1) dynamic DNA strand coordination through direct DNA binding and DNA bridging activities, 2) MRN nuclease complex cofactor functions that direct MRN endonucleolytic cleavage of protein-blocked DSB ends and 3) acting as a protein binding hub targeted by the cell cycle regulatory apparatus, which influences CtIP expression and activity via layers of post-translational modifications, protein–protein interactions and DNA binding.
Abstract
We explore the phenomenon commonly known as halo assembly bias, whereby dark matter haloes of the same mass are found to be more or less clustered when a second halo property is considered, ...for haloes in the mass range 3.7 × 1011–5.0 × 1013 h−1 M⊙. Using the Large Suite of Dark Matter Simulations (LasDamas) we consider nine commonly used halo properties and find that a clustering bias exists if haloes are binned by mass or by any other halo property. This secondary bias implies that no single halo property encompasses all the spatial clustering information of the halo population. The mean values of some halo properties depend on their halo's distance to a more massive neighbour. Halo samples selected by having high values of one of these properties therefore inherit a neighbour bias such that they are much more likely to be close to a much more massive neighbour. This neighbour bias largely accounts for the secondary bias seen in haloes binned by mass and split by concentration or age. However, haloes binned by other mass-like properties still show a secondary bias even when the neighbour bias is removed. The secondary bias of haloes selected by their spin behaves differently than that for other halo properties, suggesting that the origin of the spin bias is different than of other secondary biases.
ABSTRACT
We describe our non-linear emulation (i.e. interpolation) framework that combines the halo occupation distribution (HOD) galaxy bias model with N-body simulations of non-linear structure ...formation, designed to accurately predict the projected clustering and galaxy–galaxy lensing signals from luminous red galaxies in the redshift range 0.16 < z < 0.36 on comoving scales 0.6 < rp < 30 $h^{-1} \, \text{Mpc}$. The interpolation accuracy is ≲ 1–2 per cent across the entire physically plausible range of parameters for all scales considered. We correctly recover the true value of the cosmological parameter S8 = (σ8/0.8228)(Ωm/0.3107)0.6 from mock measurements produced via subhalo abundance matching (SHAM)-based light-cones designed to approximately match the properties of the SDSS LOWZ galaxy sample. Applying our model to Baryon Oscillation Spectroscopic Survey (BOSS) Data Release 14 (DR14) LOWZ galaxy clustering and galaxy-shear cross-correlation measurements made with Sloan Digital Sky Survey (SDSS) Data Release 8 (DR8) imaging, we perform a prototype cosmological analysis marginalizing over wCDM cosmological parameters and galaxy HOD parameters. We obtain a 4.4 per cent measurement of S8 = 0.847 ± 0.037, in 3.5σ tension with the Planck cosmological results of 1.00 ± 0.02. We discuss the possibility of underestimated systematic uncertainties or astrophysical effects that could explain this discrepancy.
ABSTRACT
Cluster weak lensing is a sensitive probe of cosmology, particularly the amplitude of matter clustering σ8 and matter density parameter Ωm. The main nuisance parameter in a cluster weak ...lensing cosmological analysis is the scatter between the true halo mass and the relevant cluster observable, denoted $\sigma _{\ln M_\mathrm{ c}}$. We show that combining the cluster weak lensing observable ΔΣ with the projected cluster–galaxy cross-correlation function wp,cg and galaxy autocorrelation function wp,gg can break the degeneracy between σ8 and $\sigma _{\ln M_\mathrm{ c}}$ to achieve tight, per cent-level constraints on σ8. Using a grid of cosmological N-body simulations, we compute derivatives of ΔΣ, wp,cg, and wp,gg with respect to σ8, Ωm, $\sigma _{\ln M_\mathrm{ c}}$, and halo occupation distribution (HOD) parameters describing the galaxy population. We also compute covariance matrices motivated by the properties of the Dark Energy Survey cluster and weak lensing survey and the BOSS CMASS galaxy redshift survey. For our fiducial scenario combining ΔΣ, wp,cg, and wp,gg measured over 0.3−30.0 h−1 Mpc, for clusters at z = 0.35−0.55 above a mass threshold Mc ≈ 2 × 1014 h−1 M⊙, we forecast a $1.4{{\ \rm per\ cent}}$ constraint on σ8 while marginalizing over $\sigma _{\ln M_\mathrm{ c}}$ and all HOD parameters. Reducing the mass threshold to 1 × 1014 h−1 M⊙ and adding a z = 0.15−0.35 redshift bin sharpens this constraint to $0.8{{\ \rm per\ cent}}$. The small-scale (rp < 3.0 h−1 Mpc) ‘mass function’ and large-scale (rp > 3.0 h−1 Mpc) ‘halo-mass cross-correlation’ regimes of ΔΣ have comparable constraining power, allowing internal consistency tests from such an analysis.
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