Music:
Enjoy the music based on this article at the end of the episode.

DOI:
10.1038/s41586-025-09521-x

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:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode:
201: 201: Sex, Smoking, and Somatic Selection in the Bladder

️ Season:
1

Article title:
Sex and smoking bias in the selection of somatic mutations in human bladder

Journal:
Nature

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited transcript sections describing the sequencing approach, gene panel, positive/negative selection signals, TERT promoter mutations linked to age and smoking, smoking as promoter, FGFR3 negative selection, natural saturation mutagenesis, TP53 site selection, sex differences, and sampling design (dome
- transcript topics: Ultradeep duplex sequencing of normal urothelium; Driver mutations in RBM10, CDKN1A, ARID1A; Positive/negative selection signals (dN/dS, clustering, functional bias); TERT promoter activating mutations and association with age and smoking; Smoking as promoter rather than global mutagenesis; FGFR3 truncating mutations under negative selection

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Ultradeep sequencing identified thousands of driver mutations across 16 genes in normal urothelium
- Men show higher truncating driver mutations in RBM10, CDKN1A, ARID1A than women
- Activating TERT promoter mutations detected in normal bladder tissue and associated with age and smoking
- TERT promoter mutations promote clonal expansions rather than globally increasing mutation density in smokers
- FGFR3 truncating mutations exhibit negative selection in normal urothelium
- Natural saturation mutagenesis observed in vivo via ultradeep sequencing, with TP53 site-specific positive selection

QC result: Pass.

Music:
Enjoy the music based on this article at the end of the episode.

DOI:
10.1038/s41586-025-09448-3

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:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode:
200: 200: Sperm Sequencing Reveals Extensive Positive Selection in the Male Germline

️ Season:
1

Article title:
Sperm sequencing reveals extensive positive selection in the male germline

Journal:
Nature

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing (i) mutation rates in sperm vs blood, (ii) NanoSeq/duplex sequencing methodology and error correction, (iii) positive selection in the male germline including gene count and LOF/activating mechanisms, (iv) RAS–MAPK pathway involvement, (v) disease risk implications and paternal ag
- transcript topics: Sperm mutation rates and somatic comparison; NanoSeq/duplex sequencing methodology and error correction; Positive selection in the male germline: gene count and mutation mechanisms; Loss-of-function vs activating mutations and RAS–MAPK pathway; Disease risk implications and paternal age effects; Study limitations and boundaries of NanoSeq (variant types detected)

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Baseline sperm mutation rate: 1.67 substitutions per year per haploid genome
- Sperm accumulate mutations ~8x slower than in blood
- Number of genes under significant positive selection: 40 (31 newly identified)
- Loss-of-function mutations are common among positively selected genes; many in the RAS–MAPK pathway
- Positive selection drives 2–3x increased risk of disease-causing mutations
- 3–5% of sperm from middle-aged to older individuals carry a pathogenic mutation across the exome

QC result: Pass.

PLD4 Deficiency and Lupus: When Nuclease Failure Ignites Autoimmunity

Music:
Enjoy the music based on this article at the end of the episode.

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:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/pld4-deficiency-and-lupus-when-nuclease-failure-ignites-autoimmunity

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the core scientific narrative in the transcript describing PLD4 mutations, endosomal nucleic acid sensing, exonuclease impairment, single-cell analyses (scRNA-seq and CyTOF), Pld4−/− mice, and baricitinib/JAK-STAT therapeutic implications.
- transcript topics: PLD4 mutations and monogenic lupus; Endosomal nucleic acid sensing: TLR7/9 pathways and IFN signaling; PLD4 exonuclease activity assays (in vitro and ex vivo); scRNA-seq of patient PBMCs (DCs/monocytes) and IFN/TLR signatures; CyTOF cytokine profiling in PBMCs; Pld4−/− mouse autoimmunity and nephritis with pDC/plasma cell expansion

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Five SLE patients carrying biallelic PLD4 mutations were identified.
- PLD4 functions as a 5′ exonuclease that cleaves ssDNA and ssRNA in endosomes to limit TLR7/9 signaling.
- Mutations in PLD4 impair exonuclease activity in vitro (loss of catalytic function observed for patient-derived variants).
- scRNA-seq and CyTOF show IFN/TLR pathway activation predominantly in dendritic cells and monocytes.
- Pld4−/− mice display autoimmunity and nephritis with expansion of plasmacytoid dendritic cells (pDCs) and plasma cells.
- Baricitinib (a JAK inhibitor) reduces type I IFN signaling and rescues phenotypes in PLD4-deficient models (mice and patient-derived cells).

QC result: Pass.

Mechanical Confinement and the Shape-Shifting Life of Melanoma Cells

Music:
Enjoy the music based on this article at the end of the episode.

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:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/mechanical-confinement-and-the-shape-shifting-life-of-melanoma-cells

️ Episode:
198: Mechanical Confinement and the Shape-Shifting Life of Melanoma Cells

️ Season:
1

Article title:
Mechanical confinement governs phenotypic plasticity in melanoma

Journal:
Nature

DOI:
10.1038/s41586-025-09445-6

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-14.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core scientific claims and themes described in the transcript: confinement-driven phenotype switching (go-or-grow), HMGB2-mediated chromatin remodeling, cytoskeletal (acetylated tubulin cage) remodeling, Nesprin2/LINC association, Notch/BRN2 axis in invasion, and drug-tolerance implications.
- transcript topics: Confinement-driven phenotype switching (go-or-grow); Neuronal invasion gene program and MITF suppression; HMGB2 upregulation and chromatin remodeling; Perinuclear acetylated tubulin cage and ATAT1 involvement; Nesprin2 (SYNE2) and LINC complex in HMGB2 enrichment; Nuclear stiffening via Lamin A/C

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Confinement induces neuronal invasion program and MITF downregulation (SOX11, NEUROD1, NNAT, NEFM upregulation; MITF downregulation)
- HMGB2 upregulation is induced by confinement and HMGB2 concentration increases (approximately doubles) under confinement
- Confinement triggers assembly of a perinuclear acetylated tubulin cage; ATAT1 mediates tubulin acetylation
- Nesprin2 (SYNE2) is required for HMGB2 enrichment and for perinuclear cage assembly
- HMGB2 increases chromatin accessibility at neural crest/neuronal loci; AP-1 and SOX9 motifs enriched
- Notch signaling and BRN2 axis mediate HMGB2-driven invasion

QC result: Pass.

Somatic Mutation and Selection at Population Scale

Music:
Enjoy the music based on this article at the end of the episode.

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:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/somatic-mutation-and-selection-at-population-scale

️ Episode:
197: Somatic Mutation and Selection at Population Scale

️ Season:
1

Article title:
Somatic mutation and selection at population scale

Journal:
Nature

DOI:
10.1038/s41586-025-09584-w

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-13.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited spoken content for alignment with the article's main findings: NanoSeq methodology and ultra-low error sequencing; age-related somatic mutation accumulation in oral epithelium; driver landscape (NOTCH1, TP53, FAT1); in vivo saturation mutagenesis and hotspots (TP53 DNA-binding domain; RAC1); clonal growth dynam
- transcript topics: NanoSeq methodology and ultra-low error sequencing; Age-related somatic mutation accumulation in oral epithelium; Driver landscape and positive selection in oral epithelium; In vivo saturation mutagenesis and hotspot mapping (TP53 DNA-binding domain; RAC1 GTP-binding pocket); Clonal growth dynamics and tissue architectural plateau; Alcohol-related mutational signatures and ALDH2 genetics

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- NanoSeq achieves error rate below five errors per billion base pairs
- Age-related somatic mutation accumulation in oral epithelium ~18 SNVs per cell per year
- Driver landscape includes 46 genes under positive selection and >62,000 driver mutations in oral epithelium
- NOTCH1, TP53 and FAT1 are among strongest driver genes in oral epithelium
- Approximately 10–20% of cheek cells carry a driver mutation in older individuals
- In vivo saturation mutagenesis identifies hotspots in TP53 DNA-binding domain and RAC1 GTP-binding pocket

QC result: Pass.

Impact of Chromatin Accessibility QTLs Across Immune Contexts

Music:
Enjoy the music based on this article at the end of the episode.

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:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/impact-of-chromatin-accessibility-qtls-across-immune-contexts

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-12.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core caQTL biology and context: PBMC-wide caQTL mapping; dynamic caQTLs along cell trajectories; COVID-19 contexts and heritability enrichment; caQTL–eQTL–GWAS integration; ABC-based distal linking; CARD9 case in monocytes; emphasis on triple convergence for causal inference.
- transcript topics: Single-cell caQTL mapping in PBMCs across healthy, COVID-19, convalescent; caQTL–eQTL–GWAS integration and interpretability; Topic modeling and cell-state trajectories of caQTLs; Dynamic caQTLs during activation (k17 CD8 TEM); COVID-19 cellular context and heritability enrichment; Distal caQTLs and ABC-based enhancer–gene linking

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- caQTL count across PBMCs: 37,390
- dynamic caQTLs identified: 4,200
- caQTL sharing: less than 20% confined to a single context
- increase in GWAS-loci explainable when incorporating caQTLs (from ~32.9% to ~57.3%)
- COVID-19 cell-state k17 enriched for disease-relevant heritability (severe COVID-19)
- triple convergence (GWAS locus + caQTL + eQTL) in the same cellular context

QC result: Pass.

️ 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/