Base by Base

Chick SL et al et al., Nature Communications - Largest exome-sequencing meta-analysis to date (28,898 cases, 103,041 controls, 3,444 trios) identifies STAG1 and ZNF136 at exome-wide significance and six additional genes at FDR<5%, highlighting roles for chromatin organisation and GABAergic signalling. Key terms: schizophrenia, rare coding variants, STAG1, SLC6A1, whole-exome sequencing.

Study Highlights:
The authors generated a new exome-sequenced case-control sample (4,650 cases, 5,719 controls) and meta-analysed published data for a total of 28,898 cases, 103,041 controls and 3,444 trios. They report exome-wide significant enrichment of rare PTVs and damaging missense variants in STAG1 and PTVs in ZNF136, plus six genes at FDR<5% including SLC6A1 and KLC1. SLC6A1 and KLC1 associations are driven by damaging missense variants, and STAG1 and KLC1 overlap loci from schizophrenia GWAS. Several implicated genes show pleiotropic rare-variant enrichment in developmental disorders, autism and epilepsy.

Conclusion:
STAG1 and ZNF136 are implicated in schizophrenia at exome-wide significance and six additional genes at FDR<5%, supporting disrupted chromatin organisation and altered GABAergic/neural transport pathways in disease etiology.

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

Article title:
Whole-exome sequencing analysis identifies risk genes for schizophrenia

First author:
Chick SL et al

Journal:
Nature Communications

DOI:
10.1038/s41467-025-62429-y

Reference:
Chick SL et al., Whole-exome sequencing analysis identifies risk genes for schizophrenia. Nature Communications (2025). DOI: 10.1038/s41467-025-62429-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:
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/whole-exome-sequencing-identifies-new-schizophrenia-risk-genes

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections covering study design and sample, gene discoveries (STAG1, ZNF136; six additional genes), mechanistic biology (cohesin/chromatin, GABA signaling), convergence with common-variant signals, NRXN1 CNV locus, pleiotropy, and limitations.
- transcript topics: Study design and new exome sequencing sample; Gene discovery: STAG1 and ZNF136 (exome-wide); Six additional genes at FDR<5%: SLC6A1, PCLO, ZMYND11, BSCL2, KLC1, CGREF1; Damaging missense variants driving SLC6A1 and KLC1 (MPC > 2); Convergence of rare- and common-variant signals at STAG1 and KLC1; NRXN1 PTV enrichment and CNV locus overlap

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:
- STAG1 exome-wide significance for rare PTVs and damaging missense (MPC>2)
- ZNF136 exome-wide significance for rare PTVs
- Six additional genes at FDR<5%: SLC6A1, PCLO, ZMYND11, BSCL2, KLC1, CGREF1
- SLC6A1 and KLC1 associations driven by damaging missense variants (MPC>2) alone
- NRXN1 PTV enrichment observed at a CNV locus
- Convergence of rare-variant and common-variant signals at STAG1 and KLC1

QC result: Pass.

️ Episode 109: Autocrine Interferon Poisoning: ADAR1–BRCA Synthetic Lethality

In this episode of PaperCast Base by Base, we explore how loss of the RNA editor ADAR1 becomes lethal to BRCA1/2‑mutant cancer cells through a tumor‑cell‑autonomous interferon response, outlining a biomarker‑guided path to ADAR1‑targeted therapy.

Study Highlights:
A focused PRR siRNA screen and multiple orthogonal validations revealed a robust synthetic lethality between BRCA1/2 mutations and ADAR1 loss across isogenic human and mouse models, non‑isogenic TNBC lines, and zebrafish, with the cytoplasmic ADAR1p150 isoform and its deaminase activity required for survival. ADAR1 depletion elevated R‑loops, replication stress, γ‑H2AX foci, micronuclei, and apoptosis in BRCA‑deficient cells, while RNase H1 overexpression partially rescued DNA‑damage phenotypes and viability, implicating R‑loop burden as a trigger. The knockout activated cytosolic nucleic‑acid sensing pathways—RIG‑I, MDA5, LGP2, PKR, and cGAS—driving type I interferon and integrated‑stress responses; co‑silencing these sensors or inhibiting JAK/STAT signaling abrogated lethality, whereas exogenous interferons enhanced it. Patient data showed higher cytoplasmic ADAR1p150 expression and increased A‑to‑I RNA editing activity in BRCA‑mutant tumors and PDX models, indicating an ADAR1 dependency that is detectable in clinical specimens.

Conclusion:
These results establish a clinically actionable blueprint in which BRCA1/2 status predicts vulnerability to ADAR1 inhibition by exploiting autocrine interferon poisoning rather than DNA breaks, suggesting combinations and sequencing distinct from PARP inhibitor strategies.

Reference:
Autocrine interferon poisoning mediates ADAR1‑dependent synthetic lethality in BRCA1/2‑mutant cancers. Nature Communications. 2025;16:6972. https://doi.org/10.1038/s41467-025-62309-5

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/

 ADAR1; BRCA1/2; synthetic lethality; interferon; R-loops

Bell HW et al et al., Nature Communications - This study shows that CpG methylation at proximal HBG promoters causally enforces perinatal silencing and that targeted epigenome editing can reverse that silencing in cell models and primary erythroblasts. UHRF1 and the methyl-CpG reader MBD2 are key mediators of repression. Key terms: HBG, CpG methylation, UHRF1, MBD2, epigenome editing.

Study Highlights:
A CRISPR/Cas9 screen identified UHRF1 as a mediator of HBG repression; loss of UHRF1 causes global CpG demethylation and HBG activation. Targeted dCas9–TET1 (TETv4) demethylation of the HBG proximal promoters activates HBG in HUDEP2 cells and primary CD34+ erythroblasts, while targeted dCas9–DNMT3A–DNMT3L re-methylation restores repression. Mutation of the MBD2 methyl-CpG binding domain (Y178F) impairs methyl-CpG binding and derepresses HBG, supporting a model in which promoter CpG methylation recruits MBD2-NuRD to silence HBG.

Conclusion:
Localized CpG methylation at HBG proximal promoters is sufficient to silence the genes; targeted promoter demethylation reactivates HBG and offers a potential, more specific epigenomic strategy to induce therapeutic fetal hemoglobin for β-hemoglobinopathies.

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

Article title:
Removal of promoter CpG methylation by epigenome editing reverses HBG silencing

First author:
Bell HW et al

Journal:
Nature Communications

DOI:
10.1038/s41467-025-62177-z

Reference:
Bell HW et al., Removal of promoter CpG methylation by epigenome editing reverses HBG silencing. Nature Communications (2025). DOI: 10.1038/s41467-025-62177-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:
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/removal-promoter-cpg-methylation-hbg

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s coverage of promoter CpG methylation as a causal silencer of HBG, the role of UHRF1, targeted epigenome editing (TETv4 and D3AL), the MBD2-NuRD mechanism (including MBD2 Y178F), and validation in HUDEP2 and CD34+ erythroblasts, plus implications for HbF therapy.
- transcript topics: Promoter CpG methylation silences HBG; UHRF1 as maintenance methylation factor in HbF repression; Epigenome editing with TETv4 to demethylate HBG promoters; Durability of HBG activation in HUDEP2 cells; D3AL remethylation reverses activation; MBD2-NuRD complex and MBD2 Y178F mutation

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:
- UHRF1 maintains CpG methylation to repress HBG; disruption leads to demethylation and HBG activation
- Local promoter demethylation via targeted epigenome editing (TETv4) activates HBG in HUDEP2 and primary CD34+ erythroblasts, with robust expression (up to ~86% HbF/HBG)
- Remethylation of HBG promoters by D3AL reverses activation, reducing HBG expression (to ~23%)
- Activation requires demethylation across multiple CpG sites upstream of the TSS, not a single CpG
- MBD2 Y178F mutation impairs methyl-CpG binding and derepresses HBG, illustrating MBD2-NuRD’s key role
- MBD2-NuRD recruitment is linked to HBG silencing; BCL11A occupancy can persist even after demethylation

QC result: Pass.

Salminen A et al., Nature Communications - A large GWAS in 485,230 FinnGen participants (132,124 cases) identified genetic loci associated with pulpal and apical diseases. The study highlights strong signals near HORMAD2 on chromosome 22 and multiple signals in the HLA class II region, links top variants to immune and antigen-presentation pathways, and reports replication in independent cohorts. Key terms: GWAS, endodontic infections, HORMAD2, HLA, FinnGen.

Study Highlights:
A GWAS of 485,230 Finnish individuals with 132,124 cases of pulpal or apical disease identified 15 independent loci across 12 chromosomes, with strongest signals near HORMAD2 (chr22) and in the HLA class II region. Imputed HLA alleles, notably DRB1*04:01 and DQB1*03:01, were associated with endodontic infections, and many lead variants carried regulatory annotations tied to MHC class II, humoral immunity, and antigen processing. Most lead SNPs remained significant after adjusting for caries and several associations replicated in FinnGen subcohorts and the Estonian Biobank. Genetic correlations were observed with pain, caries, cardiometabolic traits and cardiovascular disease, and SNP heritability was modest (h2 ≈ 0.017–0.021).

Conclusion:
Genetic variation affecting immune regulation—particularly MHC class II/HLA alleles and regulatory variation near HORMAD2 and linked genes—contributes to susceptibility to pulpal and apical diseases and provides loci for mechanistic follow-up and risk evaluation.

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

Article title:
Genome-wide association study of pulpal and apical diseases

First author:
Salminen A

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61721-1

Reference:
Salminen A, Hyvärinen K, Ritari J, et al. Genome-wide association study of pulpal and apical diseases. Nature Communications (2025). DOI: 10.1038/s41467-025-61721-1

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/ep-107-gwas-pulpal-apical-diseases

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the main GWAS findings, mechanistic interpretation (MTMR3/autophagy, HLA region), HLA alleles, confounding adjustment (DMFS), genetic correlations, replication, and limitations described in the transcript.
- transcript topics: Scale and design of FinnGen GWAS; Genetic loci identified (HORMAD2, MTMR3, HLA region); Autophagy and MTMR3 as immune-modulating mechanism; Imputed HLA alleles DRB1*04:01 and DQB1*03:01; DMFS adjustment and independence from caries; Genetic correlations with pain, BMI, smoking, type 2 diabetes, cardiovascular disease

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:
- 15 independent loci associated with endodontic infections
- Strongest signal on chromosome 22 near HORMAD2/MTMR3
- Second locus in the HLA class II region with DRB1*04:01 and DQB1*03:01 associations
- MTMR3/autophagy link and its role in immune response
- Heritability estimate h2 ≈ 0.017–0.021
- DMFS adjustment shows many associations independent of caries

QC result: Pass.

Ecker C et al., Nature Communications - This episode reviews a study that develops a surface-based, vertex-level framework for genome-wide imaging transcriptomics using spatial interpolation of the Allen Human Brain Atlas, validates the approach against serotonergic PET maps, and applies it to dissect GABAA-receptor subunit expression and link transcriptomic signatures to cortical thickness patterns and anxiety/depression in N=279 individuals. Key terms: imaging transcriptomics, GABA_A receptor, cortical thickness, pharmacotranscriptomics, spatial transcriptomics.

Study Highlights:
The authors generated spatially-dense vertex-level expression maps for 15,633 genes using AHBA samples and Gaussian Process interpolation and reduced them to nine co-expression gradients capturing ~41% variance. They validated a gradient-based, spatial-autocorrelation-preserving decoding approach against high-resolution 5-HT PET atlases, showing good sensitivity and specificity compared with LME and GLS methods. Applying vertex-level decoding to a benzodiazepine GABAA PET atlas, they identified two distinct GABAA subunit co-expression clusters with limbic versus widespread cortical expression. Stratifying N=279 participants by alignment of cortical thickness deviations to these clusters revealed an adult subgroup whose limbic-aligned pattern was associated with higher self-reported anxiety and depression.

Conclusion:
Surface-based transcriptomic decoding at vertex resolution can map molecular target expression to imaging phenotypes, revealing two GABAA subunit classes with distinct cortical signatures and behavioral associations that may inform pharmacotranscriptomic stratification and targeted interventions.

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

Article title:
Transcriptomic decoding of surface-based imaging phenotypes and its application to pharmacotranscriptomics

First author:
Ecker C

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61927-3

Reference:
Ecker C., Pretzsch C. M., Leyhausen J., et al. Transcriptomic decoding of surface-based imaging phenotypes and its application to pharmacotranscriptomics. Nature Communications (2025) 16:6727. doi:10.1038/s41467-025-61927-3

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 link: https://basebybase.com/episodes/106-transcriptomic-decoding-gabaa

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-14.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of core methods (vertex-level decoding with spatial interpolation), validation (5-HT PET concordance), GABA A subunit clustering, in vivo imaging phenotypes and behavioral associations, and pharmacotranscriptomics implications, plus acknowledged study limitations.
- transcript topics: Imaging transcriptomics and vertex-level spatial interpolation; Validation against serotonergic PET maps (5-HT system); GABA A receptor subunit decoding and two-cluster structure; In vivo imaging phenotypes (cortical thickness) and subgroup associations with anxiety/depression; Pharmacotranscriptomics and personalized treatment implications; Caveats and need for longitudinal data

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- 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:
- Gradient-based decoding uses spatial autocorrelation-preserving null models and gradient subsampling for robust gene-imaging associations
- Validation against 5-HT PET atlas shows strongest associations for HTR1A, HTR2A, and HTR4
- GABA A receptor subunits split into two clusters: Cluster 1 limbic-leaning (α2, α3, α5, β1, β3, ε, γ1) and Cluster 2 cortical/widespread (α1, α4, β2, γ2, γ3, δ)
- In LEAP cohort (N=279, ages 7–31), adults with limbic-aligned CT deviations show higher anxiety and depression
- Cross-sectional design acknowledged; longitudinal data are needed for causal inferences

QC result: Pass.

Persi E et al., Nature Communications - This episode unpacks a multi-cohort study showing that tumors evolving toward neutral genome-level selection (dN/dS ≈ 1) during or after therapy are associated with treatment resistance and poorer outcomes. Key terms: tumor evolution, dN/dS, neutral evolution, treatment resistance, whole-exome sequencing.

Study Highlights:
The authors analyzed paired whole-exome data from multiple untreated and treated cancer cohorts and an original 624-patient multiple myeloma cohort to estimate genome-level dN/dS and track evolution. In untreated primary progression dN/dS is largely stable per patient, with some cancer-specific shifts during metastasis. In diverse treated, resistant tumors there is a near-universal shift toward neutral evolution (dN/dS ≈ 1), and this shift correlates with worse clinical outcomes. Phylogenetic analysis shows positive selection on trunk/clonal mutations and purifying selection on branch/subclonal mutations, producing an overall neutral regime in late stages.

Conclusion:
Serial measurement of genome-level dN/dS can flag emerging treatment resistance: a shift toward neutrality indicates higher tumor fitness and poorer prognosis and may prompt therapy reassessment.

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

Article title:
Genome-level selection in tumors as a universal marker of resistance to therapy

First author:
Persi E

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61709-x

Reference:
Persi E., Sudalagunta P.R., Wolf Y.I., Canevarolo R.R., Damaghi M., Shain K.H., Silva A.S., Koonin E.V., Genome-level selection in tumors as a universal marker of resistance to therapy. Nature Communications (2025). DOI: 10.1038/s41467-025-61709-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 link: https://basebybase.com/episodes/genome-level-selection-resistance-therapy

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-13.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's core scientific claims about genome-wide dN/dS, treatment effects, neutral evolution, trunk vs. branch selection, datasets and methods, and clinical implications, plus acknowledged limitations and potential mechanisms (epigenetics, hypermutators).
- transcript topics: Genome-wide dN/dS metric; Untreated cancer evolution; Treated cancer evolution and neutrality; Trunk vs branch selection in tumor phylogenies; Cohorts and methods (WES, MM cohort); Clinical implications and prognosis

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:
- dN/dS is used as a genome-wide measure of selection strength in tumor genomes.
- In untreated cancers, dN/dS within a patient remains stable during primary progression, with cancer-specific signatures emerging in metastasis.
- In diverse treated cancers, there is a universal shift toward neutral evolution (dN/dS approximately 1).
- Post-treatment neutrality is associated with worse clinical outcomes (e.g., relapse risk and survival).
- Trunk (clonal) mutations show positive selection (dN/dS > 1) while branch (subclonal) mutations show purifying selection (dN/dS < 1); overall late-stage evolution tends toward neut
- The study analyzes multiple cohorts (ALL, CLL, ER-positive breast cancer, urothelial bladder cancer, glioblastoma) and validates with an original multiple myeloma cohort (624 patie

QC result: Pass.

Cross-population GWAS and proteomics improve risk prediction and reveal mechanisms in atrial fibrillation

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Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
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☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at 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/cross-population-gwas-and-proteomics-improve-risk-prediction-and-reveal-mechanisms-in-atrial-fibrillation

Genome Sequencing Forecasts Outcomes After Congenital Cardiac Surgery

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☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at 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/genome-sequencing-forecasts-outcomes-after-congenital-cardiac-surgery

Clinical Impact of Pharmacogenetic Risk Variants in a Large Chinese Cohort

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❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at 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/clinical-impact-of-pharmacogenetic-risk-variants-in-a-large-chinese-cohort

JAK2 Inhibition Selects RAS-Mutant Clones in Myelofibrosis

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

Support:
Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
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Episode link: https://basebybase.com/episodes/jak2-inhibition-selects-ras-mutant-clones-in-myelofibrosis