Biology subjects

Jaeger, S.

Publications and source records attributed to Jaeger, S..

9 recordsLinked to original sources

bioRxiv2026

CNVSIM: an interpretable copy-number reference atlas for cancer subtyping

Background: Genome-wide copy-number variation (CNV) profiles provide a structural representation of cancer genomes, but interpreting new profiles within a reusable reference remains challenging. Results: We developed CNVSIM, which organizes CNV profiles into cancer root-specific reference spaces and defines reference subtypes annotated with chromosome-scale and gene-level signatures. Applied to the Progenetix dataset, CNVSIM established 112 CNV-defined subtypes across 19 cancer roots, supported by 155,881 analyses from neoplastic samples. Within each cancer root, samples sharing a broad diagnosis separated into distinct CNV subtypes, whereas individual subtypes spanned multiple diagnostic labels. All subtypes included analyses from multiple assay platforms and data sources, and core subtypes remained reproducible after systematic reduction of reference analyses. Calibrated projection assigned 85.7% of held-out CNV profiles while maintaining high accuracy for supported assignments. Projection of 4,605 cell-line CNV profiles identified cell lines representative for 90/112 cancer subtypes while highlighting gaps in cell line representation. Conclusions: CNVSIM provides a reusable and interpretable CNV reference that complements diagnostic classification for profile comparison, projection, and cell line selection.

genomics↗

bioRxiv2026

Panic at the Discordance: the Asparagaceae Phylogenetic Backbone

The Asparagaceae is an economically and ecologically important angiosperm (monocot) clade, containing iconic garden plants such as asparagus, hyacinth and agave, and arid-adapted keystone species like Joshua tree and dragon blood tree. The approximately 2,500 species in the family are spread across seven subfamilies: Agavoideae, Aphyllanthoideae, Asparagoideae, Brodiaeoideae, Lomandroideae, Nolinoideae and Scilloideae. Relationships among the seven subfamilies are generally unresolved and the sources of gene tree-species tree discordance are largely unknown. Investigating the biology underlying such discordance requires a robust sampling of both taxa and molecular markers, due to the extremely short branches that form the backbone of the Asparagaceae phylogeny. Using targeted sequencing of 1,726 low-copy nuclear genes, and a nearly complete sampling of genera, we interrogate relationships among all seven Asparagaceae subfamilies and investigate the underlying sources of discordance across the phylogeny. Analyses using different phylogenomic approaches (multispecies coalescence vs. nuclear gene supermatrix vs. chloroplast gene supermatrix) each revealed extensive discordance across the Asparagaceae backbone, which may be associated with rapid lineage diversifications that occurred in Africa shortly following the origin of the family ~49 Ma. Specifically, we found that two branches, representing ancestors of Aphyllanthoideae and Nolinoideae, may be responsible for much of the backbone discordance. The placement of Aphyllanthoideae, represented by one extant taxon (Aphyllanthes monspeliensis), is controversial with discordant topologies across many studies. However, multispecies coalescence-based analyses from this study strongly support a sister relationship between Aphyllanthoideae and a larger Agavoideae + Scilloideae + Brodiaeoideae clade. According to gene tree quartet frequencies and ABBA-BABA tests, we cannot reject incomplete lineage sorting (ILS) as the main source of discordance for the placement of Aphyllanthoideae; our results leave open the possibility of an ancient reticulation involving an ancestor of Aphyllanthoideae and an extinct basal Asparagaceae lineage. Regarding Nolinoideae, we found that conflicting support for two possible bifurcating clades (Asparagoideae + Nolinoideae vs. Asparagoideae + Lomandroideae) was associated with skewed support for alternative gene tree topologies, suggesting that phenomena other than ILS may explain the observed discordance. A quartet-based ABBA-BABA analysis, used to test for signatures of introgression, revealed a putative ancient hybridization event between two divergent, ancestral lineages which may have contributed to the origin of the Nolinoideae clade in Africa ~45 Ma. In sum, this study elucidates the long-troublesome backbone of the Asparagaceae phylogeny and advances our understanding of the evolutionary and biogeographical origins of all extant subfamilies. More broadly, this study expands our understanding of the various sources of gene tree discordance that may arise from natural processes associated with rapid lineage radiations across the tree of life.

evolutionary biology↗

bioRxiv2026

Sexually dimorphic effects of mutations in ccRCC driver genes in renal proximal tubule cells

Clear cell renal cell carcinoma (ccRCC) arises more frequently in men than in women, but it remains unclear why this is the case. Mouse models that mimic the truncal mutation of the two most commonly affected tumor suppressor genes in human ccRCC revealed that the transcriptional effects of Vhl or Vhl/Pbrm1 mutation in male and female proximal tubule cells only partially overlap. Cellular responses to mutations in these genes were also sex-specific. Vhl and Vhl/Pbrm1 mutation in females, but only Vhl/Pbrm1 mutation in males, induced the accumulation of PLIN2-coated lipid droplets. The accumulation of optically-clear lipid droplets, reflecting the hallmark clear-cell histological feature of ccRCC, only arose in Vhl/Pbrm1 mutant male mice. Consistent with lipotoxic tubular damage, markers of tubular repair and ongoing epithelial cell proliferation correlated with the lipid accumulation phenotypes. Vhl/Pbrm1 mutation caused stronger clonal expansion than Vhl mutation in males, but not in females. These findings suggest that there are likely to be sexual dimorphisms at the very earliest stages of ccRCC evolution that result from the interplay of intrinsic and mutation-induced transcriptional differences between male and female proximal tubule cells.

cancer biology↗

bioRxiv2024

Application of machine learning in a rodent malaria model for rapid, accurate, and consistent parasite counts

Rodent malaria models serve as important preclinical antimalarial and vaccine testing tools. Evaluating treatment outcomes in these models often requires manually counting parasite-infected red blood cells (iRBCs), a time-consuming process, which can be inconsistent between individuals and labs. We have developed an easy-to-use machine learning (ML)-based software, Malaria Screener R, to expedite and standardize such studies by automating the counting of Plasmodium iRBCs in rodents. This software can process Giemsa-stained blood smear images captured by any camera-equipped microscope. It features an intuitive graphical user interface that facilitates image processing and visualization of the results. The software has been developed as a desktop application that processes images on standard Windows and Mac OS computers. A previous ML model created by the authors designed to count P. falciparum-infected human RBCs did not perform well counting Plasmodium-infected mouse RBCs. We leveraged that model by loading the pre-trained weights and training the algorithm with newly collected data to target P. yoelii and P. berghei mouse iRBCs. This new model reliably measured both P. yoelii and P. berghei parasitemia (R2 = 0.9916). Additional rounds of training data to incorporate variances due to length of Giemsa staining, microscopes etc, have produced a generalizable model, meeting WHO Competency Level 1 for the sub-category of parasite counting using independent microscopes. Reliable, automated analyses of blood-stage parasitemia will facilitate rapid and consistent evaluation of novel vaccines and antimalarials across labs in an easily accessible in vivo malaria model.

microbiology↗

bioRxiv2023

PROxAb Shuttle: A non-covalent plug-and-play platform for the rapid generation of tumor-targeting antibody-PROTAC conjugates

Proteolysis-targeting chimeras (PROTACs) have evolved in recent years from an academic idea to a therapeutic modality with more than 25 active clinical programs. However, achieving oral bioavailability and cell-type specificity remains a challenge, especially for PROTACs recruiting the von Hippel-Lindau (VHL) E3 ligase. Herein, we present an unprecedented, plug- and-play platform for VHL-recruiting PROTACs to overcome these limitations. Our platform allows for the generation of non-covalent antibody-PROTAC complexes within minutes and obviates the need for prior PROTAC modification, antibody-drug linker chemistry optimization or bioconjugation. Our technology relies on camelid-derived antibody domains (VHHs) which can easily be engineered into existing therapeutic antibody scaffolds. The resulting targeted, bispecific fusion proteins can be complexed with PROTACs at defined PROTAC-to-antibody ratios and have been termed PROxAb Shuttles. PROxAb Shuttles can prolong the half-life of PROTACs from hours to days, demonstrate anti-tumor efficacy in vivo and have the potential for reloading in vivo to further boost efficacy.

biochemistry↗

bioRxiv2022

ShIVA, a user-friendly and interactive interface giving biologists control over their single-cell RNA-seq data.

Single-cell technologies have revolutionised biological research and applications. As they continue to evolve with multi-omics and spatial resolution, analysing single-cell datasets is becoming increasingly complex. For biologists lacking expert data analysis resources, the problem is even more crucial, even for the simplest single-cell transcriptomics datasets. We propose ShIVA, an interface for the analysis of single-cell RNA-seq and CITE-seq data specifically dedicated to biologists. Intuitive, iterative and documented by video tutorials, ShIVA allows biologists to follow a robust and reproducible analysis process, mostly based on the Seurat v4 R package, to fully explore and quantify their dataset, to produce useful figures and tables and to export their work to allow more complex analyses performed by experts.

bioinformatics↗

bioRxiv2020

Activation of group II metabotropic receptors attenuates cortical E-I imbalance in a 15q13.3 microdeletion mouse model

Animal models reflecting human risk for schizophrenia are essential research tools for gaining further insight into the convergence of CNS pathology and clinical biomarkers. Amongst the variety of animal models that display schizophrenia-related neuronal network deficits, transgenic mice for rare and highly penetrant copy number variants (CNVs) provide a unique opportunity to study pathological correlates in models with strong construct validity. The Df(h15q13)/+ mouse model of the human 15q13.3 microdeletion CNV has been shown to mimic deficits in parvalbumin positive (PV+) interneuron and cortical network function. However, the corresponding changes in synapse density and activity within the medial prefrontal cortex (mPFC) have not been described. Using high-content immunofluorescence imaging, we have shown a reduced density of PV+ neurons and inhibitory synapses in the mPFC of Df(h15q13)/+ mice. We found that the reduced detection of PV+ synapses were accompanied by changes in spontaneous inhibitory and excitatory synaptic activity onto layer 2/3 pyramidal neurons. The aberrant cortical function was also evident in awake animals by a reduced high frequency auditory steady-state responses (ASSR), reliably monitored by EEG. Importantly, the imbalance of excitatory to inhibitory function could be attenuated on a cellular and cortical network level by activation of mGlu2/3 receptors, indicating the relevance of excessive excitatory transmission to the cortical network deficit in the Df(15q13)/+ mouse model. Our findings highlight the preclinical value of genetic risk and in particular CNV models such as the Df(15q13)/+ mice to investigate pathological network correlates of schizophrenia risk and to probe therapeutic opportunities based on clinically relevant biomarkers.

neuroscience↗

bioRxiv2017

An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses

Although macrophages are armed with potent anti-bacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage-intrinsic bacterial control, and the Mtb strategies to overcome them are poorly understood. To further study these processes, we used a systematic affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two new factors involved in Mtb pathogenesis - the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl-/- macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between anti-bacterial and anti-viral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map as a resource for developing a deeper understanding of the intricate interactions between Mtb and its host.

microbiology↗

bioRxiv2017

A dynamical model of TCRβ gene recombination: Coupling the initiation of Dβ-Jβ rearrangement to TCRβ allelic exclusion

One paradigm of random monoallelic gene expression is that of T-cell receptor (TCR){beta} allelic exclusion in T lymphocytes. However, the dynamics that sustain asymmetric choice in TCR{beta} dual allele usage and the production of TCR{beta} monoallelic expressing T-cells remain poorly understood. Here, we develop a computational model to explore a scheme of TCR{beta} allelic exclusion based on the stochastic initiation of DNA rearrangement [V(D)J recombination] at homologous alleles in T-cell progenitors, and thus account for the genotypic profiles typically associated with allelic exclusion in differentiated T-cells. Disturbances in these dynamics at the level of an individual allele have limited consequences on these pro1les, robust feature of the system that is underscored by our simulations. Our study predicts a biological system in which locus-specific, prime epigenetic allelic activation effects set the stage to both optimize the production of TCR{beta} allelically excluded T-cells and curtail the emergence of their allelically included counterparts.

immunology↗