The tandem duplicator phenotype (TDP) is a genome-wide instability configuration primarily observed in breast, ovarian, and endometrial carcinomas. Here, we stratify TDP tumors by classifying their ...tandem duplications (TDs) into three span intervals, with modal values of 11 kb, 231 kb, and 1.7 Mb, respectively. TDPs with ∼11 kb TDs feature loss of TP53 and BRCA1. TDPs with ∼231 kb and ∼1.7 Mb TDs associate with CCNE1 pathway activation and CDK12 disruptions, respectively. We demonstrate that p53 and BRCA1 conjoint abrogation drives TDP induction by generating short-span TDP mammary tumors in genetically modified mice lacking them. Lastly, we show how TDs in TDP tumors disrupt heterogeneous combinations of tumor suppressors and chromatin topologically associating domains while duplicating oncogenes and super-enhancers.
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•Abundant and distributed tandem duplications form a distinct chromotype in cancer•Six recurrent tandem duplicator phenotypes (TDPs) are characterized by TD span size•Conjoint abrogation of BRCA1 and TP53 causes TDPs with ∼11 kb TDs•CCNE1 pathway activation and CDK12 mutations associate with ∼231 kb and ∼1.7 Mb TDs
Menghi et al. stratify tandem duplicator phenotype tumors by classifying their tandem duplications (TDs) into three span sizes associated with different pathway alterations and show how TDs disrupt tumor suppressors and chromatin topologically associating domains while duplicating oncogenes and super-enhancers.
Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer's disease (AD) have largely been developed using these ...classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models. Two widely used AD-relevant transgenes, APPswe and PS1de9 (APP/PS1), were backcrossed from B6 to three wild-derived strains CAST/EiJ, WSB/EiJ, PWK/PhJ, representative of three Mus musculus subspecies. These new AD strains were characterized using metabolic, functional, neuropathological and transcriptional assays. Strain-, sex- and genotype-specific differences were observed in cognitive ability, neurodegeneration, plaque load, cerebrovascular health and cerebral amyloid angiopathy. Analyses of brain transcriptional data showed strain was the greatest driver of variation. We identified significant variation in myeloid cell numbers in wild type mice of different strains as well as significant differences in plaque-associated myeloid responses in APP/PS1 mice between the strains. Collectively, these data support the use of wild-derived strains to better model the complexity of human AD.
ABSTRACT
We present new observations of the transmission spectrum of the hot Jupiter WASP-6b both from the ground with the Very Large Telescope FOcal Reducer and Spectrograph (FORS2) from 0.45 to ...0.83 μm, and space with the Transiting Exoplanet Survey Satellite from 0.6 to 1.0 μm and the Hubble Space Telescope (HST) Wide Field Camera 3 from 1.12 to 1.65 μm. Archival data from the HST Space Telescope Imaging Spectrograph (STIS) and Spitzer are also re-analysed on a common Gaussian process framework, of which the STIS data show a good overall agreement with the overlapping FORS2 data. We also explore the effects of stellar heterogeneity on our observations and its resulting implications towards determining the atmospheric characteristics of WASP-6b. Independent of our assumptions for the level of stellar heterogeneity we detect Na i, K i, and H2O absorption features and constrain the elemental oxygen abundance to a value of O/H ≃ −0.9 ± 0.3 relative to solar. In contrast, we find that the stellar heterogeneity correction can have significant effects on the retrieved distributions of the Na/H and K/H abundances, primarily through its degeneracy with the sloping optical opacity of scattering haze species within the atmosphere. Our results also show that despite this presence of haze, WASP-6b remains a favourable object for future atmospheric characterization with upcoming missions such as the James Webb Space Telescope.
Late-Onset Alzheimer's disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major ...challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10-8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.
Abstract
WASP-121b is a transiting gas giant exoplanet orbiting close to its Roche limit, with an inflated radius nearly double that of Jupiter and a dayside temperature comparable to a late M dwarf ...photosphere. Secondary eclipse observations covering the 1.1–$1.6\, \mu{\rm m}$ wavelength range have revealed an atmospheric thermal inversion on the dayside hemisphere, likely caused by high-altitude absorption at optical wavelengths. Here we present secondary eclipse observations made with the Hubble Space Telescope Wide Field Camera 3 spectrograph that extend the wavelength coverage from $1.1\, \mu{\rm m}$ down to $0.8\, \mu{\rm m}$. To determine the atmospheric properties from the measured eclipse spectrum, we performed a retrieval analysis assuming chemical equilibrium, with the effects of thermal dissociation and ionization included. Our best-fitting model provides a good fit to the data with reduced $\chi ^2_\nu =1.04$. The data diverge from a blackbody spectrum and instead exhibit emission due to H− shortward of $1.1\, \mu{\rm m}$. The best-fitting model does not reproduce a previously reported bump in the spectrum at $1.25\,\mu{\rm m}$, possibly indicating this feature is a statistical fluctuation in the data rather than a VO emission band as had been tentatively suggested. We estimate an atmospheric metallicity of ${\rm M}/{\rm H}= {1.09}_{-0.69}^{+0.57}$, and fit for the carbon and oxygen abundances separately, obtaining ${\rm C}/{\rm H}= {-0.29}_{-0.48}^{+0.61}$ and ${\rm O}/{\rm H}= {0.18}_{-0.60}^{+0.64}$. The corresponding carbon-to-oxygen ratio is ${\rm C/O} = 0.49_{-0.37}^{+0.65}$, which encompasses the solar value of 0.54, but has a large uncertainty.
Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to ...recombination hot spots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hot spots and provide access for the DNA double-strand break (DSB) machinery. Recombination hot spots are decorated by a unique combination of histone modifications not found at other regulatory elements. HELLS is recruited to hot spots by PRDM9 and is necessary for both histone modifications and DNA accessibility at hot spots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hot spot activation in which HELLS and PRDM9 form a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.
Genetic and genome-wide association studies suggest a central role for microglia in Alzheimer’s disease (AD). However, single-cell RNA sequencing (scRNA-seq) of microglia in mice, a key preclinical ...model, has shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains (WSB/EiJ, CAST/EiJ, and PWK/PhJ) with and without APP/PS1 demonstrates that genetic diversity significantly alters features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. Results show significant variation in the abundance of microglial subtypes or states, including numbers of previously identified disease-associated and interferon-responding microglia, across the strains. For each subtype, significant differences in the expression of many genes are observed in wild-derived strains relative to B6, including 19 genes previously associated with human AD including Apoe, Trem2, and Sorl1. This resource is critical in the development of appropriately targeted therapeutics for AD and other neurological diseases.
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•Genetic diversity of mouse strain is a major driver of variation in brain myeloid cells•WSB.APP/PS1 did not exhibit an increase in DAM or a decrease in homeostatic microglia•PWK.APP/PS1 is the only strain to show a significant increase in IRM compared to WT•Core marker genes for microglia subtypes are highlighted in mouse and human studies
Neuroinflammation is a key component of Alzheimer’s disease. Yang et al. perform single-cell sequencing of microglia in wild-derived mouse strains that carry amyloid and show that these strains differ from the commonly used strains, exhibiting significant variation in abundance of microglial subtypes, including numbers of disease-associated and interferon-responding microglia.
The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that ...have been generated to study Alzheimer's disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram,
imaging, biochemical characterization, and behavioral assessments. The data from this study is publicly available through the AD Knowledge Portal.
Molecular characterization of late-onset Alzheimer's disease (LOAD), the leading cause of age-related dementia, has revealed transcripts, proteins, and pathway alterations associated with disease. ...Assessing these postmortem signatures of LOAD in experimental model systems can further elucidate their relevance to disease origins and progression. Model organisms engineered with human genetic factors further link these signatures to disease-associated variants, especially when studies are designed to leverage homology across species. Here we assess differential gene splicing patterns in aging mouse models carrying humanized APOE4 and/or the Trem2*R47H variant on a C57BL/6J background. We performed a differential expression of gene (DEG) and differential splicing analyses on whole brain transcriptomes at multiple ages. To better understand the difference between differentially expressed and differentially spliced genes, we evaluated enrichment of KEGG pathways and cell-type specific gene signatures of the adult brain from each alteration type. To determine LOAD relevance, we compared differential splicing results from mouse models with multiple human AD splicing studies.
We found that differentially expressed genes in Trem2*R47H mice were significantly enriched in multiple AD-related pathways, including immune response, osteoclast differentiation, and metabolism, whereas differentially spliced genes were enriched for neuronal related functions, including GABAergic synapse and glutamatergic synapse. These results were reinforced by the enrichment of microglial genes in DEGs and neuronal genes in differentially spliced genes in Trem2*R47H mice. We observed significant overlap between differentially spliced genes in Trem2*R47H mice and brains from human AD subjects. These effects were absent in APOE4 mice and suppressed in APOE4.Trem2*R47H double mutant mice relative to Trem2*R47H mice.
The cross-species observation that alternative splicing observed in LOAD are present in Trem2*R47H mouse models suggests a novel link between this candidate risk gene and molecular signatures of LOAD in neurons and demonstrates how deep molecular analysis of new genetic models links molecular disease outcomes to a human candidate gene.
RNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's ...disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYK-tSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM, however, these compounds lack selectivity and this limits their utility as chemical tools.
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