Base by Base

️ Episode 163: Animal origins: looping back in time In this episode of PaperCast Base by Base, we explore how chromatin folding mechanisms emerged alongside animal evolution, focusing on a Spotlight article that synthesizes high-resolution 3D genome maps across unicellular relatives of animals and early-branching metazoans to probe when enhancer–promoter looping first appeared. Study Highlights:This Spotlight reviews evidence from micro-C datasets spanning ichthyosporeans, filastereans, choanoflagellates, sponges, ctenophores, placozoans, and cnidarians, showing that broad A/B-like chromatin compartments and, crucially, enhancer–promoter chromatin loops are features that arise within animals rather than in their unicellular relatives. It emphasizes that loops are readily detected in early metazoans such as ctenophores, placozoans, and cnidarians, while sponges show weaker or absent looping signals, hinting at lineage-specific trajectories or possible secondary loss. The article highlights unusual promoter hubs in placozoans, where hundreds of transcription start sites cluster, potentially coordinating housekeeping expression programs. Mechanistically, ctenophores appear to use abundant C2H2 zinc-finger proteins that bind unmethylated motifs at loop anchors, suggesting alternative loop-formation strategies distinct from the CTCF-driven loop extrusion and insulated TAD architecture characterized in vertebrates. Together, these observations argue that chromatin loops emerged with complex gene regulation in animals and diversified across lineages instead of following a single universal mechanism. Conclusion:Chromatin looping likely originated at the dawn of animal life and diversified across lineages, underpinning the rise of complex gene regulation before the canonical, CTCF-insulated TAD architecture seen in many bilaterians. Reference:Matar, O., & Marlétaz, F. (2025). Animal origins: looping back in time. Trends in Genetics. https://doi.org/10.1016/j.tig.2025.06.013 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Episode Slug: animal-origins-looping-back-in-time Keywords: chromatin loops; animal evolution; Micro-C; ctenophores; enhancer–promoter interactions

️ Episode 196: Impact of Chromatin Accessibility QTLs Across Immune Contexts In this episode of PaperCast Base by Base, we explore how single-cell chromatin accessibility QTLs (caQTLs) reshape the interpretation of immune disease genetics by mapping regulatory variation across major immune cell types and disease-relevant states. Study Highlights:The authors harmonized ∼280,000 PBMC scATAC-seq profiles from 48 individuals—including healthy donors and COVID-19 patients—to build a unified chromatin accessibility atlas. Topic modeling uncovered continuous cell-state programs, including a CD8 effector-memory continuum associated with COVID-19, and enabled the discovery of 37,390 caQTLs plus thousands of dynamic, state-dependent effects. Compared to eQTLs, caQTLs explained roughly 50% more GWAS loci and highlighted that many regulatory variants act through chromatin without detectable steady-state expression changes in current datasets. Extensive sharing of caQTLs across immune cell types contrasted with the context specificity of eQTL colocalizations, underscoring the need to integrate chromatin, expression, enhancer–promoter links, and disease-relevant cellular states to pinpoint causal mechanisms. Conclusion:Chromatin accessibility QTLs substantially expand the fraction of disease loci with molecular support, but reliable causal gene mapping requires convergence of caQTL and eQTL signals within the same cellular context and along relevant cell-state trajectories. Music:Enjoy the music based on this article at the end of the episode. Reference:Mu Z, Randolph HE, Aguirre-Gamboa R, Ketter E, Dumaine A, Locher V, Brandolino C, Liu X, Kaufmann DE, Barreiro LB, Li YI. Impact of disease-associated chromatin accessibility QTLs across immune cell types and contexts. Cell Genomics. 2026;6:101061. https://doi.org/10.1016/j.xgen.2025.101061 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.com/

️ Episode 195: Tiny Shields: Lymphoid Microglia in Alzheimer’s Disease In this episode of PaperCast Base by Base, we explore how a subset of brain immune cells adopts a lymphoid-like program that helps contain inflammation and protect neural circuits in Alzheimer’s disease models. Study Highlights: Using mouse models of amyloid pathology and human Alzheimer’s brain tissue, the authors identify plaque-associated microglia with reduced PU.1 expression that cluster around deposits and express an unexpected set of lymphoid receptors, including CD28. By genetically tuning PU.1 levels specifically in microglia, they show that lowering PU.1 is sufficient to trigger this lymphoid-like transcriptional program, remodel chromatin and generate microglia that compact amyloid plaques, limit tau aggregation and preserve synapses, plasticity and behaviour. These PU.1low microglia display fewer type I interferon and complement signatures, accumulate fewer lipid droplets and extend survival in Alzheimer’s model mice, indicating a broadly neuroprotective state. In contrast, microglia-specific deletion of CD28 amplifies amyloid burden and drives a widespread pro-inflammatory interferon response in the microglial pool, suggesting that a small CD28+ subset exerts outsized control over brain inflammation. Human genetic data further link a PU.1-lowering SPI1 allele with increased abundance of lymphoid-like microglia, supporting the relevance of this protective program in people with Alzheimer’s disease. Conclusion: This work positions PU.1-tuned, CD28-expressing microglia as critical regulators of neuroinflammation and suggests that selectively boosting their lymphoid-style “checkpoint” signals could inspire new immunotherapy strategies for Alzheimer’s disease. Music: Enjoy the music based on this article at the end of the episode. Reference: Ayata P, Crowley JM, Challman MF, et al. Lymphoid gene expression supports neuroprotective microglia function. Nature. 2025. https://doi.org/10.1038/s41586-025-09662-z. License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support: If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.com/ On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 194: Bayesian History of Science: Watson and Crick and the Structure of DNA In this episode of PaperCast Base by Base, we explore how Bayesian reasoning can be used to reconstruct the famous discovery of the DNA double helix by James Watson and Francis Crick, following the sequence of structural models proposed in the early 1950s and the evolving evidence that supported or undermined each hypothesis. Study Highlights:The author applies a naïve Bayes framework to four competing models of DNA proposed by Watson, Crick, and Linus Pauling, treating each model as a target theory evaluated against multiple lines of historical evidence such as X-ray diffraction patterns, base pairing rules, symmetry constraints, and stereochemical feasibility. Conditional probabilities for how well each model accounts for each piece of evidence are manually estimated from historical sources using a simple five-point scale ranging from strongly inconsistent to strongly consistent, and combined with prior probabilities to calculate posteriors and likelihood ratios. By updating priors model by model, the study reconstructs how initial triple-helix proposals were progressively disconfirmed, while intermediate double-helix attempts with incorrect base pairing achieved only modest support despite offering a plausible replication mechanism. A dramatic jump in posterior probability and in the likelihood ratio is observed for the final Watson–Crick model with complementary purine–pyrimidine base pairing, consistent bond geometry, compliance with Chargaff’s rules, and correct symmetry, which the author interprets as a form of “Bayesian surprise” that matches scientists’ retrospective sense of having made a genuine discovery. The analysis also shows how “soft” considerations, such as analogy to Pauling’s alpha helix and the promise of an explanatory replication mechanism, can be incorporated alongside hard experimental data within a Bayesian account of theory choice in the history of science. Conclusion:This work argues that Bayesian analysis provides a coherent way to track how evidence and prior expectations jointly shaped the path from early speculative DNA models to the accepted double-helix structure, offering a quantitative complement to narrative histories of scientific discovery. Reference:Small H. Bayesian history of science: The case of Watson and Crick and the structure of DNA. Quantitative Science Studies. 2023;4(1):209–228. https://doi.org/10.1162/qss_a_00233 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.com/

️Episode 193: SARM1, DNA, and the Death Signal In this episode of PaperCast Base by Base, we explore how the axon-degenerating enzyme SARM1 acts as a double-stranded DNA sensor that triggers NAD+ loss, cell death, and chemotherapy-induced neuropathy, opening up new possibilities for neuroprotective therapies. Study Highlights:The authors show that the immune adaptor SARM1 directly binds double-stranded DNA via its TIR domain and, once activated, rapidly degrades cellular NAD+ in a sequence-independent but length-dependent manner. Using a combination of biochemical assays and structural analyses, they demonstrate that SARM1 forms multimeric complexes with linear DNA, with optimal activation occurring when DNA fragments are long enough to engage multiple SARM1 molecules. In cells, cytosolic DNA introduced by transfection or released during chemotherapy colocalizes with SARM1, driving NAD+ depletion and promoting cell death, whereas mutations that disrupt DNA binding or complete knockout of SARM1 blunt this response. In mouse models, loss of SARM1 protects against chemotherapy-induced neuropathy, linking DNA sensing by SARM1 directly to treatment-related neurotoxicity and positioning this pathway as a therapeutic target. Conclusion:By revealing SARM1 as a double-stranded DNA sensor that couples cytosolic DNA to NAD+ degradation, cell death, and chemotherapy-induced neuropathy, this study highlights a druggable axis for preserving neural function during cancer treatment. Reference:Wang L, Liu Q, Li S, et al. SARM1 senses dsDNA to promote NAD+ degradation and cell death. Cell. 2025;188:1–18. https://doi.org/10.1016/j.cell.2025.09.026 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/  

️Episode 192: At Base-Pair Resolution: Chromatin’s Cis-Regulatory Conversations In this episode of PaperCast Base by Base, we explore how base-pair resolution maps of chromatin contacts reveal a unified, biophysical model of communication between enhancers, promoters, and other cis-regulatory elements in mammalian cells. Study Highlights:Using Micro Capture-C ultra (MCCu), the authors generate multidimensional chromosome conformation maps with single base-pair pixels, allowing them to resolve contacts between individual transcription factor motifs within cis-regulatory elements in mouse embryonic stem, hematopoietic progenitor, and erythroid cells. They show that nucleosome-depleted regions partition chromatin into nanoscale domains and form highly localized contacts with one another, while surrounding nucleosomes produce distinct patterns of linker spacing that mark inactive regions. By acutely degrading Mediator complex subunits with degron systems, they find that Mediator is critical for fine-scale promoter architecture and transcription complex stabilization but has only minor effects on large-scale enhancer–promoter contacts. Integrating MCCu data with coarse-grained molecular dynamics simulations and super-resolution imaging, they demonstrate that the physicochemical properties of chromatin itself can recapitulate observed contact patterns and help explain how transcription factor binding and nucleosome positioning coordinate cis-regulatory interactions. Conclusion:This work provides a high-resolution framework for linking chromatin biophysics to gene regulation, offering a roadmap for dissecting how specific protein complexes and nucleosome landscapes shape enhancer–promoter communication across the genome. Reference:Li H, Dalgleish JLT, Lister G, et al. Mapping chromatin structure at base-pair resolution unveils a unified model of cis-regulatory element interactions. Cell. 2025;188:1–19. https://doi.org/10.1016/j.cell.2025.10.013 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/  

️ Episode 191: CATphishing: Synthetic Learning as an Alternative to Federated Learning in MRI In this episode of PaperCast Base by Base, we explore a Nature Communications study that proposes CATphishing—an approach that uses latent diffusion models to generate site-specific synthetic 3D brain MRIs for collaborative training without sharing raw data. The work spans seven institutions and 2,491 patients and evaluates whether models trained on synthetic data can match those trained via centralized data sharing or federated learning. Study Highlights:The authors train latent diffusion models locally at each site to capture dataset-specific MRI distributions and then aggregate only synthetic multi-contrast MRIs and tumor masks for downstream model training across centers. In IDH mutation status classification, models trained solely on synthetic data achieved performance comparable to centralized and federated approaches, with overall accuracy around 95.5% and AUC near 0.966, versus 96.2% and 0.979 for centralized training. A two‑stage tumor‑type pipeline—separating glioblastoma from IDH‑mutated tumors and then classifying oligodendroglioma versus astrocytoma—likewise showed similar end‑to‑end accuracy for synthetic versus real‑data strategies, landing near 90–92% overall. Fidelity and privacy were examined with FID and no‑reference image‑quality metrics and by a membership‑inference analysis that performed at chance, supporting the case for synthetic data as a viable, privacy‑preserving alternative in multi‑center AI development. Conclusion:CATphishing demonstrates that high‑fidelity synthetic MRI can enable cross‑institutional modeling with accuracy close to real‑data training while reducing privacy, communication, and coordination burdens in multi‑center collaborations. Reference:Truong NCD, Yogananda CGB, Wagner BC, Holcomb JM, Reddy DD, Saadat N, Bowerman J, Hatanpaa KJ, Patel TR, Fei B, Lee MD, Jain R, Bruce RJ, Madhuranthakam AJ, Pinho MC, Maldjian JA. Categorical and phenotypic image synthetic learning as an alternative to federated learning. Nature Communications. 2025;16:9384. https://doi.org/10.1038/s41467-025-64385-z License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 190: Single-Cell Networks Reveal Cell Type–Specific Mechanisms in Type 2 Diabetes In this episode of PaperCast Base by Base, we explore how a network-based analysis of single-cell RNA sequencing from human pancreatic islets uncovers cell type–specific gene-regulatory changes that help explain type 2 diabetes pathophysiology. Study Highlights:The authors develop differential Gene Coordination Network Analysis (dGCNA) to compare gene–gene coordination between non‑T2D and T2D donors in Smart‑seq2 datasets covering >8,000 islet cells from 32 individuals. In beta cells, dGCNA resolves eleven networks with strong ontological specificity, revealing de‑coordination of mitochondria, glycolysis, cytoskeleton, cell cycle, unfolded protein response, and glucose‑response programs, while insulin secretion, lysosomal regulation, and ribosome-related programs show hyper‑coordination. Functional experiments validate predictions by showing that CEBPG modulates the unfolded protein response and insulin production/secretion, and that TMEM176A/B influences actin microfilaments and cAMP‑amplified exocytosis, with supportive phenotypes in knockout mice and human islets. Results replicate across independent datasets and outperform differential expression (DESeq2) in cross‑dataset reproducibility, and analysis of alpha cells reveals distinct T2D‑linked coordination changes involving secretory granules, glycolysis, mitochondria, and ribosomes. Conclusion:By focusing on networks of differentially coordinated genes rather than expression alone, dGCNA provides a robust framework to pinpoint cell type–specific mechanisms and nominate actionable targets for preserving islet function in type 2 diabetes. Reference:Nature Communications (2025). Single-cell mRNA-regulation analysis reveals cell type-specific mechanisms of type 2 diabetes. https://doi.org/10.1038/s41467-025-65060-z License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Episode Slug:  Keywords: single-cell RNA-seq, differential network analysis, pancreatic islets, beta cells, type 2 diabetes

️ Episode 189: DNA methylation patterns facilitate tracing the origin of neuroendocrine neoplasms In this episode of PaperCast Base by Base, we explore how genome-wide DNA methylation profiling can pinpoint the organ of origin for neuroendocrine neoplasms (NEN), with a special focus on lesions detected in the liver and long-debated “primary hepatic NEN”. Study Highlights:Using two independent cohorts totaling 212 NEN tissues, the authors profiled methylation patterns and visualized them with dimensionality-reduction approaches, revealing distinct clusters for most organ sites. Hepatic NEN without a detectable extrahepatic primary did not form a unique liver-specific cluster and instead colocalized with extrahepatic subtypes, frequently showing foregut-like methylation signatures. A latent methylation component–based Random Forest classifier achieved high accuracy in predicting organ site from biopsy material and suggested that many presumed primary hepatic NEN are likely misclassified metastases of unknown primary. Copy-number analyses supported organ‑site–specific patterns and further differentiated grades and subtypes, including NET versus NEC. Conclusion:Methylome profiling offers a practical path to identify the primary site in neuroendocrine neoplasms—including liver-detected cases—supporting more precise diagnosis and treatment selection in real-world pathology workflows. Reference:Goeppert B, Charbel A, Toth R, et al. DNA methylation patterns facilitate tracing the origin of neuroendocrine neoplasms. Nature Communications. 2025;16:9477. https://doi.org/10.1038/s41467-025-65227-8 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 188: Proteomics + Machine Learning for Lyme Neuroborreliosis Diagnosis In this episode of PaperCast Base by Base, we explore how large‑scale mass‑spectrometry proteomics of cerebrospinal fluid and plasma, paired with supervised machine learning, can distinguish Lyme neuroborreliosis from viral meningitis and non‑LNB controls in adults. Study Highlights:The authors analyzed 308 CSF and 207 plasma samples across development and validation cohorts to define host‑response protein signatures and train diagnostic classifiers. CSF proteomics yielded strong discrimination of LNB against viral meningitis and against controls, with independent‑cohort AUCs around 0.92 and 0.90, respectively, and highlighted immunoglobulin chains, complement factors, innate immune proteins, and cytoskeletal markers as key features. A plasma‑based model distinguishing LNB from controls achieved an AUC of about 0.80 in validation and captured systemic innate immunity, complement activation, lipid transport, and coagulation signatures. Across matrices, overlapping proteins illuminated compartmentalized immunity, with many immunoglobulins increased in CSF but relatively lower in plasma for LNB, and SHAP analyses prioritized features linked to humoral and innate responses as well as cell damage and migration. Conclusion:Machine‑learning‑assisted proteomics shows promise for less‑invasive diagnosis and monitoring of Lyme neuroborreliosis and could reduce reliance on lumbar puncture if validated prospectively. Reference:Nielsen AB, Fjordside L, Drici L, Ottenheijm ME, Rasmussen C, Henningsson AJ, Harritshøj LH, Mann M, Mens H, Lebech A‑M, Wewer Albrechtsen NJ. The diagnostic potential of proteomics and machine learning in Lyme neuroborreliosis. Nature Communications. 2025;16:9322. https://doi.org/10.1038/s41467-025-64903-z License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 187: Gapped PARP + Tumor‑Targeted TOP1 in Advanced Tumors In this episode of PaperCast Base by Base, we explore a phase I dose‑escalation trial that pairs a tumor‑targeted topoisomerase I inhibitor (CRLX101, a nanoparticle camptothecin) with optimized, gapped scheduling of the PARP inhibitor olaparib to reduce toxicity while preserving efficacy in advanced solid tumors. Study Highlights:Twenty‑four adults with advanced solid tumors received CRLX101 every two weeks with olaparib started 48 hours later; the maximum tolerated and recommended phase 2 dose was CRLX101 12 mg/m² plus olaparib 250 mg twice daily on days 3–13 and 17–26 of each 28‑day cycle. Pharmacokinetics for both agents were consistent with their single‑agent profiles, and γH2AX pharmacodynamic assays in hair follicles showed higher DNA damage after adding olaparib compared with CRLX101 alone, supporting the mechanistic rationale. Among nineteen evaluable patients, two achieved confirmed partial responses and six had stable disease, with median overall survival of 6.06 months and progression‑free survival of 2.34 months; a patient with myxofibrosarcoma harboring a PALB2 truncation experienced a deep, durable response. Toxicities were manageable and mainly hematologic—leukopenia, anemia, neutropenia, and thrombocytopenia—while the gapped schedule mitigated dose‑limiting myelosuppression seen in prior PARP–TOP1 combinations and enabled higher olaparib dosing. Conclusion:Tumor‑targeted TOP1 delivery combined with gapped PARP inhibition appears to widen the therapeutic window for DDR‑chemotherapy combinations and merits biomarker‑informed expansion studies. Reference:Thomas A, Takahashi N, O’Connor LO, Redon CE, Mohindroo C, Sciuto L, Pongor L, Schmidt KT, Steinberg SM, Aladjem MI, Figg WD, O’Connor MJ, Pommier Y. Tumor‑targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling. Nature Communications. 2025;16:9457. https://doi.org/10.1038/s41467-025-64509-5 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 186: TNFα–TGFβ Axis Disrupts Nasal Epithelium in Post‑COVID Syndrome In this episode of PaperCast Base by Base, we explore a single‑cell RNA‑seq study of nasal biopsies showing that persistent immune signaling—not residual virus—drives aberrant epithelial differentiation in people with post‑COVID syndrome. fileciteturn1file0 Study Highlights:Researchers profiled >56,000 cells from nasal tissue of individuals with moderate or severe post‑COVID syndrome, revealing marked depletion of proximal ciliated cells alongside expansion of basal and immune cell populations. Cell–cell communication and pathway analyses identified heightened TNFα and TGFβ signaling, with MIF–CD74 interactions and downstream NF‑κB/EGFR activity linking immune cells to epithelial remodeling. The team validated causality in air‑liquid interface cultures, where exposure to TGFβ and TNFα—alone and especially in combination—reduced ciliated‑cell differentiation and promoted basal‑cell skewing and EMT‑like programs. Viral RNA was undetectable in biopsies and inflammatory markers typical of acute infection were not elevated, indicating pathology independent of ongoing viral load. Conclusion:Targeting the TNFα–TGFβ inflammatory axis may help restore normal epithelial differentiation and mitigate respiratory comorbidities in severe post‑COVID syndrome. Reference:Reddy KD, Maluje Y, Ott F, Saurabh R, Schaaf A, Bohnhorst A, et al. scRNA‑seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post‑COVID syndrome. Nature Communications. 2025;16:9494. https://doi.org/10.1038/s41467-025-64778-0 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 185: Altered Milk Tryptophan in Women Living with HIV In this episode of PaperCast Base by Base, we explore a longitudinal metabolomics study of human milk that reveals how maternal HIV infection reshapes tryptophan metabolism across lactation, with potential implications for infant immunity, growth, and neurodevelopment. Study Highlights:The authors profiled the milk metabolome from hundreds of mothers over the first 18 months postpartum and found a robust, sustained decrease in milk tryptophan alongside higher kynurenine and an elevated kynurenine-to-tryptophan ratio in women living with HIV. Targeted quantification at four months confirmed lower tryptophan and higher kynurenine in milk, and paired plasma analyses mirrored these shifts, indicating systemic depletion rather than altered transfer into milk. An initially unknown metabolite was identified as 3’-deoxy-3’,4’-didehydro-cytidine (ddhC), the free base of an interferon‑inducible antiviral ribonucleotide, and cytosine and dimethylarginine were also elevated, consistent with interferon-driven inflammation. A validation cohort of treated women showed concordant directions of effect and a higher KT ratio, supporting generalizability of the signature beyond the primary cohort. Conclusion:Milk tryptophan depletion and interferon‑linked metabolic remodeling in mothers with HIV may contribute to adverse outcomes in HIV‑exposed, uninfected infants and point to testable interventions targeting the kynurenine pathway. Reference:Tobin NH, Li F, Zhu W, Ferbas KG, Sleasman JW, Raftery D, Kuhn L, Aldrovandi GM. Altered milk tryptophan and tryptophan metabolites in women living with HIV. Nature Communications. 2025;16:9437. https://doi.org/10.1038/s41467-025-64566-w License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 184: High-Accuracy Multiethnic XGBoost for Skin Cancer Identification In this episode of PaperCast Base by Base, we explore a large-scale study that builds a risk factor–based XGBoost model using the All of Us cohort to accurately identify patients with skin cancer across diverse ancestries. Study Highlights:Analyzing more than 400,000 participants, the authors quantify independent associations between genetic ancestry, lifestyle, social determinants of health, prior cancer history, and use of PDE5A inhibitors with skin cancer risk. They compare traditional logistic regression against gradient-boosted trees and show that logistic models have low precision for case identification, motivating a non-linear approach. The resulting multiethnic XGBoost model achieves high accuracy for identifying patients with any skin cancer, with F1 scores of 0.903 in individuals of European ancestry and 0.810 in non-European groups. SHAP importance and interaction analyses reveal strong non-linear effects of age and genotype principal components, and suggest that genetic and socioeconomic factors contribute more heavily to predictions in younger individuals. Conclusion:A multiethnic, non-linear model that integrates genetics, lifestyle, social determinants, and medication exposures can substantially improve early identification of skin cancer patients across ancestries, offering a precision-medicine tool to help reduce outcome disparities. Reference:D’Antonio M, Gonzalez Rivera WG, Greenes RA, Gymrek M, Frazer KA. A highly accurate risk factor–based XGBoost multiethnic model for identifying patients with skin cancer. Nature Communications. 2025;16:9542. https://doi.org/10.1038/s41467-025-64556-y License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 183: The Genetic Lottery Goes to School: Better Schools Compensate for Genetic Differences In this episode of PaperCast Base by Base, we explore a large causal study from Norway asking whether school quality can offset genetic differences in students’ academic skills. Using parent–offspring genetic trios from the Norwegian Mother, Father, and Child Cohort (MoBa) and nationwide administrative data, the authors combine within-family polygenic indices for educational attainment with school value-added measures to test if better schools compensate for genetic disparities. Study Highlights:The researchers computed polygenic indices for educational attainment for children while controlling for parental indices to isolate random within-family genetic variation and paired these with causal value-added estimates of school quality derived from population registers. They found a negative gene–environment interaction for reading, indicating that higher-quality schools reduce the impact of polygenic differences on reading scores by about six percent per one standard deviation of school quality exposure in grade 8, with the effect driven by gains among students at the lower end of the polygenic index distribution. For numeracy, the interaction was null despite clear main effects of both genetics and school value-added, a pattern consistent with higher persistence of numeracy skills during this developmental period. Validation analyses supported exogeneity of the within-family genetic component and of the school value-added measures, and sensitivity checks suggested that the findings are not artifacts of test scaling or ceiling effects. fileciteturn0file0 Conclusion:In a causally identified framework, better schools can partially compensate for genetic differences in reading but not numeracy during lower secondary school, implying that investments in school quality may narrow genetically correlated gaps in foundational literacy. Reference:Cheesman R, Borgen N, Sandsør AMJ, Hufe P. The genetic lottery goes to school: Better schools compensate for the effects of students’ genetic differences. Proceedings of the National Academy of Sciences. 2025;122(43):e2511715122. https://doi.org/10.1073/pnas.2511715122 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 182: Genotypic, Functional, and Phenotypic Characterization in CTNNB1 Neurodevelopmental Syndrome In this episode of PaperCast Base by Base, we explore a large cross-sectional cohort study that integrates genetics, cellular functional assays, and deep phenotyping to map the landscape of CTNNB1 neurodevelopmental syndrome. The authors analyze variant types across 127 individuals from 20 countries, probe Wnt/β-catenin signaling consequences in vitro, and connect genotypes to clinical trajectories and everyday function. Study Highlights:The cohort revealed 88 distinct CTNNB1 variants with a strong enrichment for predicted loss-of-function changes, and functional luciferase assays confirmed reduced Wnt/β-catenin pathway activity for most variants. A subset of truncating variants showed dominant-negative behavior, while a rare missense change (G575R) behaved as a gain-of-function with increased protein stability and signaling. Systematic clinical assessments documented frequent motor impairment, hypotonia, dysmorphic features, visual issues such as strabismus, and developmental delays including later independent walking. Missense variants tended to associate with comparatively milder phenotypes, with earlier walking and better communication, social, and feeding skills than frameshift, nonsense, splice, or deletion variants. Conclusion:By combining genomic curation, mechanistic assays, and standardized clinical measures, this study refines the natural history of CTNNB1 syndrome and highlights therapeutic avenues that may upregulate CTNNB1 expression while cautioning about variant-specific effects. Reference:Zakelj N, Gosar D, Miroševič Š, Sanders SJ, Ljungdahl A, Kohani S, Huang S, Leong LI, An Y, Teo MJ, Moultrie F, Jerala R, Lainšek D, Forstnerič V, Sušjan P, Lisowski L, Perez-Iturralde A, Orazem Mrak J, Chan HYE, Osredkar D. Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome. Human Genetics and Genomics Advances. 2025;6:100483. https://doi.org/10.1016/j.xhgg.2025.100483 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 181: Creatine Transporter SLC6A8: Conservation and Variant Impact In this episode of PaperCast Base by Base, we explore how the creatine transporter gene SLC6A8 (CRT1) is evolutionarily conserved across terrestrial mammals and how disease-associated variants alter creatine uptake in vitro, shedding light on genotype–phenotype relationships in creatine transporter deficiency. fileciteturn0file0 Study Highlights:The authors compared CRT1 amino acid sequences among multiple species and found striking conservation, with human transmembrane domains 1–10 identical across the mammals analyzed and most interspecies differences confined to terminal or loop regions. They curated benign and pathogenic missense variants from public databases and mapped them onto CRT1, observing that missense changes in N‑ and C‑termini are more often tolerated, whereas variants within core transmembrane domains and specific loop regions are frequently pathogenic. Functional assays in transfected cells demonstrated that eight of nine tested patient variants—most located in transmembrane segments—caused severe reductions in creatine transport, while a peripheral extracellular loop variant produced a more modest decrease. Integrating intolerance profiling with phylogenetic and experimental data, the study highlights a hotspot between amino acids 305–415 and underscores strong structural constraints that shape CRT1 function. Conclusion:Together, these results provide a practical framework for interpreting SLC6A8 variants in the clinic and suggest that domain-aware assessments can better predict which alterations are likely to impair creatine transport and contribute to neurodevelopmental disease. Reference:Diep T, Lipshutz GS. Evaluation of SLC6A8 species conservation and the effect of pathogenic variants on creatine transport. Human Genetics and Genomics Advances. 2025;6:100489. https://doi.org/10.1016/j.xhgg.2025.100489 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 180: Leveraging Global Genetics Resources for Equitable Polygenic Prediction In this episode of PaperCast Base by Base, we explore how multi-ancestry genome-wide association study resources and modern polygenic score methodologies can improve prediction accuracy across African, East Asian, and European populations, with a focus on practical, computationally efficient strategies that work even when individual-level data are unavailable. Study Highlights:This article systematically benchmarks leading single-source and multi-source polygenic score methods across 10 complex traits using GWAS summary statistics from Ugandan Genome Resource, Biobank Japan, UK Biobank, and the Million Veteran Program. The authors show that combining ancestry-aligned and European GWAS improves prediction in non-European targets and that independently optimized multi-source approaches often outperform jointly optimized methods while being far more computationally efficient. They introduce a generalizable use of the LEOPARD framework to estimate optimal linear combinations of population-specific scores using only summary statistics, achieving performance comparable to individual-level tuning in many settings. All methods are implemented in the GenoPred pipeline, providing an accessible, reference-standardized workflow for equitable polygenic prediction across diverse populations. Conclusion:Multi-source, summary-statistics–friendly approaches implemented in GenoPred offer a practical path to more accurate and equitable polygenic prediction, particularly when leveraging diverse GWAS resources and efficient tuning frameworks like LEOPARD. Reference:Pain O. Leveraging global genetics resources to enhance polygenic prediction across ancestrally diverse populations. Human Genetics and Genomics Advances. 2025;6:100482. https://doi.org/10.1016/j.xhgg.2025.100482 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Chapters (00:00:14) - Placing genetic science to better health(00:02:34) - PGS: The science of genetics(00:06:31) - The comparative methods of ancestry science(00:07:43) - Sumstat Tune: The genomic precision benchmark(00:10:06) - LDpred2: Multi-Source Analysis(00:11:30) - EUR vs AFR GWAS: The Size Paradox(00:13:03) - The Best Multi-Source PGS(00:17:09) - The Fight for Equitable Genomic Prediction(00:21:14) - Personalized medicine in the cloud

️ Episode 179: Mosaicism for Autosomal Trisomies: Maternal Age, UPD, and Reproductive History in 1,266 Cases In this episode of PaperCast Base by Base, we explore a comprehensive literature analysis of 1,266 reported cases of autosomal trisomy mosaicism, contrasting prenatal cohorts—true fetal mosaicism and confined placental mosaicism—with postnatal diagnoses to clarify how maternal age and reproductive history relate to outcomes and uniparental disomy. Study Highlights:The authors screened 596 publications and assembled 948 prenatal and 318 postnatal mosaicism cases to compare outcome patterns and demographics. They found that advanced maternal age was more common in pregnancies with normal outcomes than in those with abnormal outcomes (73% vs 56%), while pregnancies ending in fetal loss showed a 50% advanced maternal age rate. Mosaic carriers with concomitant uniparental disomy of chromosomes 7, 14, 15, or 16 had markedly higher advanced maternal age than those with biparental disomy overall (78% vs 48%), suggesting age-associated biases in trisomy rescue. Reporting of reproductive history was limited, but prior fetal loss was nearly twice as frequent among mothers in the postnatal cohort compared with the prenatal cohort (30% vs 16%), and prior chromosomal abnormalities in earlier pregnancies appeared substantially enriched relative to non-mosaic series. Conclusion:These findings challenge assumptions drawn from non-mosaic trisomies and indicate that maternal age and reproductive history shape both outcomes and the likelihood of uniparental disomy in autosomal trisomy mosaicism, motivating better standardized reporting and registry-based studies. Reference:Kovaleva, N. V.; Cotter, P. D. Mosaicism for Autosomal Trisomies: A Comprehensive Analysis of 1266 Published Cases Focusing on Maternal Age and Reproductive History. Genes 2024, 15, 778. https://doi.org/10.3390/genes15060778 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Chapters (00:00:00) - Causes of Trisomy 21 in maternal age(00:01:59) - The Case of Mosaicism in America(00:02:38) - Common Trisomy 4, Non-Moist mosaic cases(00:03:09) - Autosomal mosaicism: The science, methodology, and impact(00:07:57) - The mosaic trisomies in babies(00:08:52) - Maternal age and mosaicism(00:12:26) - Mosaic Trisomy Recurrence Risk

️ Episode 178: TP53 Reduced Penetrance: Predictive Features and Clinical Implications In this episode of PaperCast Base by Base, we explore how a large ClinVar-anchored analysis integrates functional assays, computational predictors, immunogenicity estimates, allele frequencies, and clinical presentation to identify TP53 variants with reduced penetrance relative to classic Li-Fraumeni syndrome. Study Highlights:The authors reviewed ClinVar to assemble a set of TP53 variants flagged by diagnostic labs as reduced penetrance and compared them with benign and standard pathogenic reference sets using four independent functional assays and multiple in silico tools. Reduced penetrance variants tended to show intermediate activity in functional assays—most prominently in the Kato yeast transactivation readout—and had deleterious predictions by BayesDel and AlphaMissense, but with lower scores than standard pathogenic variants. These variants occurred at higher population frequencies than standard pathogenic variants, and carriers presented with cancer at later ages and with attenuated enrichment for classic Li-Fraumeni core cancers, although early-onset breast cancer and pediatric sarcomas remained associated. A random forest model using functional scores, predictors, immune fitness, and allele frequency prioritized 106 additional TP53 variants of uncertain or conflicting significance as potential reduced penetrance candidates for future study. Conclusion:The work outlines measurable features that distinguish reduced penetrance TP53 variants from both benign and standard high-penetrance variants, supporting refined classification and personalized surveillance strategies for carriers. Reference:Fortuno, C., Richardson, M. E., Pesaran, T., McGoldrick, K., James, P. A., & Spurdle, A. B. (2025). Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53. *Human Genetics and Genomics Advances*, 6, 100484. https://doi.org/10.1016/j.xhgg.2025.100484 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Chapters (00:00:00) - The challenge of classifying TP53 variants(00:03:52) - The pathogenicity of TP53(00:08:46) - The RP variants and their pathogenicity(00:10:11) - RP variants and the cancer screening debate(00:14:15) - Lessened penetrance TP53 variants