Base by Base

Cuddapah VA et al., Proceedings of the National Academy of Sciences (PNAS) - An international series of 10 individuals with ultrarare heterozygous BMAL1 variants present a syndromic neurodevelopmental phenotype (developmental delay, autism, variable sleep issues, seizures, marfanoid features). Functional assays in human cells and Drosophila show both loss- and gain-of-function effects on BMAL1 activity, PER2 expression, circadian rhythms, and memory, supporting BMAL1 disruption as a cause of neurodevelopmental disease. Key terms: BMAL1, neurodevelopmental disorder, circadian rhythms, developmental delay, Drosophila.

Study Highlights:
Through gene-matching the authors identified 10 individuals carrying ultrarare BMAL1 variants, many de novo, sharing developmental delay and autism spectrum disorder. CRISPR-edited U2OS Per2-dLuc reporter lines showed 8/9 tested variants altered PER2 transcription and circadian parameters, indicating loss- or gain-of-function effects. Two conserved variants modeled in Drosophila produced variant-dependent changes in locomotor rhythms and impaired short- and long-term memory. Together the cellular and in vivo data support pathogenicity of BMAL1 variants in a neurodevelopmental syndrome.

Conclusion:
Ultrarare heterozygous BMAL1 variants can disrupt molecular clock function and contribute to a syndromic neurodevelopmental disorder; these results motivate further study of circadian-targeted assessment and interventions in affected individuals.

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Article title:
Rare variants in BMAL1 are associated with a neurodevelopmental syndrome

First author:
Cuddapah VA

Journal:
Proceedings of the National Academy of Sciences (PNAS)

DOI:
10.1073/pnas.2427085122

Reference:
Cuddapah VA, Chen D, Cho B, et al. Rare variants in BMAL1 are associated with a neurodevelopmental syndrome. Proc Natl Acad Sci U S A. 2025;122(31):e2427085122. doi:10.1073/pnas.2427085122

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/rare-bmal1-variants-link-the-circadian-clock-to-neurodevelopment

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-28.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive auditing of sections describing BMAL1 clock mechanism, patient cohort and variants, cell-based PER2-dLuc assays, BMAL1 expression and CLOCK interaction, Drosophila cycle model and memory outcomes, and the clinical sleep phenotype discussion.
- transcript topics: BMAL1 clock mechanism overview; GeneMatcher cohort (10 individuals) and ultrarare BMAL1 variants; CRISPR-edited U2OS Per2-dLuc cell assays; BMAL1 expression and CLOCK interaction; Drosophila cycle ortholog modeling; Memory assays in flies (short-term and long-term)

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:
- Ten individuals with ultrarare BMAL1 variants identified in the cohort.
- Eight of nine tested BMAL1 variants disrupted BMAL1 function in cell-based assays.
- BMAL1 Ile201Thr variant showed gain-of-function, increasing signal magnitude and advancing rhythm.
- Drosophila ortholog cycle variants exhibited variant-dependent effects on behavioral rhythms.
- Memory impairment observed in flies expressing variant cycle (short-term and long-term).
- Clinical phenotype includes developmental delay and autism; seizures present in a subset; marfanoid habitus observed in subset.

QC result: Pass.

Waisertreiger I et al., PNAS - This study tests how stabilization of G-quadruplex (G4) DNA by ligands such as pyridostatin (PDS) affects genome stability in primary and malignant B cells. The authors map PDS-induced chromosomal breaks and fusions to ribosomal DNA (rDNA) and pericentromeric major satellite (MaSat) repeats and link G4 stabilization to tetraploidization in cells lacking G2/M arrest. Key terms: G-quadruplex, pyridostatin, pericentromeric, ribosomal DNA, tetraploidy.

Study Highlights:
Pyridostatin (PDS) treatment induces recurrent DNA breaks and chromosome fusions localized mainly to rDNA arrays and pericentromeric MaSat repeats in mouse primary B cells and B cell lymphoma lines. PDS causes high levels of tetraploid metaphases in primary mouse B cells (and in GM12878 cells) that correlate with abundant dicentric chromosomes and absence of a WEE1-dependent G2/M arrest, whereas CH12 cells arrest in G2/M and largely avoid tetraploid metaphases. Similar pericentromeric fragility is seen with the G4 ligand CX-5461 and in human lymphoma cell lines, supporting a role for G4 stabilization in driving pericentromeric instability.

Conclusion:
G4-stabilizing ligands provoke replication-associated breaks at rDNA and pericentromeric repeats, producing dicentric fusions and, when checkpoint arrest is absent, tetraploidization; this identifies both a vulnerability in B cell cancers and a potential therapeutic avenue with caution for off-target tetraploidization.

Music:
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Article title:
G- quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in B lymphocytes

First author:
Waisertreiger I

Journal:
PNAS

DOI:
10.1073/pnas.2506939122

Reference:
Waisertreiger I., Ayelea K., Elshaikha M.H., Barlow J.H. PNAS (2025) doi:10.1073/pnas.2506939122

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/gquadruplex-stabilization-triggers-pericentromeric-dna-breaks-in-b-cells

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-27.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of mechanistic and experimental results: G4 stabilization by PDS, localization of breaks to rDNA and pericentromeric MaSat repeats, tetraploidy in mouse primary B cells and GM12878, absence of tetraploidy in CH12 due to G2/M arrest (and its reversal by inhibitors), human B cell lines (GM12878 and Raji
- transcript topics: G-quadruplex structures and PDS mechanism; PDS-induced chromosomal breaks at rDNA and MaSat repeats; tetraploidy and cell-cycle checkpoint differences across cell types; CH12 cells: G2/M arrest, CDK1 inhibition, WEE1 interplay; human B cell lines GM12878 and Raji; PBMC safety; therapeutic implications, drug combinations, and safety considerations

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:
- PDS stabilizes G-quadruplexes and locks them, hindering helicase unwinding and triggering replication-associated DNA breaks
- PDS-induced damage localizes predominantly to rDNA repeats and pericentromeric MaSat repeats in mouse primary B cells
- Tetraploidy is observed in mouse primary B cells and in GM12878 human B cells after PDS treatment; CH12 cells display G2/M arrest preventing tetraploidy
- Healthy PBMCs show little to no chromosomal instability under PDS exposure, indicating a therapeutic window
- CX-5461 and Phen-DC3 also drive pericentromeric damage, supporting a G4-stabilization mechanism; WEE1 inhibition can modulate G2/M arrest and tetraploidy
- Combination strategies (e.g., PDS with WEE1 inhibitors) enhance chromosomal instability in CH12 cells, suggesting potential synergy

QC result: Pass.

️ Episode 118: Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B

In this episode of PaperCast Base by Base, we explore how cancer cells co-opt a primate-specific KRAB zinc finger protein, ZNF93, to fine-tune the mutagenic enzyme APOBEC3B and manage replication stress.

Study Highlights:
Using genome-wide KZFP binding maps, CUT&Tag, RNA-seq, and functional assays across multiple cancer cell lines, the authors identify ZNF93 as a proliferation-linked regulator enriched at promoters of young endonuclease-competent LINE-1 elements and as a direct repressor of APOBEC3B. ZNF93 knockdown consistently reduces proliferation, activates replication stress and DNA-damage checkpoints, and triggers inflammatory programs, while ZNF93 overexpression improves recovery from genotoxic insult similarly to APOBEC3B depletion. Mechanistically, ZNF93 binds the APOBEC3B promoter and suppresses its expression largely independent of TRIM28-mediated heterochromatin, with ZNF93 loss driving strong APOBEC3B upregulation and heightened stress signaling. Across human tumors, ZNF93 levels broadly correlate with proliferation and are elevated in many cancers, whereas HPV-positive cervical cancers show reduced ZNF93 alongside elevated APOBEC3B, suggesting tumors tune this axis to balance mutagenesis with tolerable replication stress.

Conclusion:
ZNF93 operates as a primate-specific rheostat that restrains APOBEC3B-driven replication stress and is exploited by tumors, highlighting a potential therapeutic lever to modulate genome instability in cancer.

Reference:
Forey R, Raclôt C, Pulver C, Rosspopoff O, Offner S, Duc J, Planet E, Martins F, Turelli P, Trono D. Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B. Proceedings of the National Academy of Sciences. 2025;122(34):e2505021122. https://doi.org/10.1073/pnas.2505021122

License:
This episode is based on an open-access article published under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0) – https://creativecommons.org/licenses/by-nc-nd/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/

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

Keywords: ZNF93; APOBEC3B; replication stress; KRAB zinc finger proteins; cancer epigenetics

Pol III–linked polyadenylation fuels SINE RNA accumulation during infection

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

DOI:
10.1073/pnas.2507186122

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/pol-iiilinked-polyadenylation-fuels-sine-rna-accumulation-during-infection

Lareau CA et al., PNAS - Single-cell multiomic profiling identifies a mosaic synonymous mtDNA variant (m.7076A>G) in MT-CO1 that is selectively depleted in CD8+ effector memory T cells. Mechanistic assays show the variant forces wobble decoding, stalls mitochondrial ribosomes, and impairs differentiation of high-demand effector T cells. Key terms: mitochondria, synonymous mutation, mtDNA, CD8+ T cells, translation.

Study Highlights:
The study identifies a mosaic synonymous mtDNA mutation m.7076A>G in MT-CO1 present at ~47% heteroplasmy in a healthy donor and shows selective depletion of the mutant allele specifically in CD8+ effector memory/short-lived effector T cells. MT-CO1 transcript abundance is unchanged by genotype, but mitochondrial ribosome profiling reveals enrichment of the mutant allele in ribosome-protected fragments, consistent with translational stalling. The effect is explained by the limited mitochondrial tRNA pool: the mutant GGG codon requires wobble/super-wobble decoding by the single mt-tRNAGly, reducing codon:anticodon affinity and slowing translation. Short-lived effector CD8+ T cells have elevated translational and metabolic demands that amplify dependence on efficient MT-CO1 translation, driving lineage-specific purifying selection.

Conclusion:
A synonymous mtDNA change can have cell type–specific functional consequences by altering codon syntax and translation efficiency; single-cell multiomics reveals purifying selection of such variants in metabolically demanding immune states. These results expand annotation of mitochondrial variation and motivate targeted studies of codon optimality in mtDNA.

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

Article title:
Cell type–specific purifying selection of synonymous mitochondrial DNA variation

First author:
Lareau CA

Journal:
PNAS

DOI:
10.1073/pnas.2505704122

Reference:
Lareau CA, Zielinski S, Stickels RR, et al. Cell type–specific purifying selection of synonymous mitochondrial DNA variation. PNAS. 2025;122(30):e2505704122. doi:10.1073/pnas.2505704122

License:
Creative Commons Attribution License 4.0 (CC BY)

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/cell-typespecific-purifying-selection-of-synonymous-mtdna-variation

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the scientific content describing (1) identification of the mosaic mtDNA variant m.7076A>G in MT-CO1, (2) CD8+ TEM–specific depletion of the mutant allele, (3) stable MT-CO1 mRNA across genotypes, (4) ribosome profiling showing translational stalling of the mutant codon, (5) wobble decoding due to mt-tRNA limit
- transcript topics: Identification of mosaic mtDNA variant m.7076A>G in MT-CO1; CD8+ TEM depletion of m.7076G allele; MT-CO1 transcript levels remain stable; Mitochondrial ribosome profiling and translation pausing; Glycine tRNA limitation and super-wobble decoding; SLEC metabolic dependence on OXPHOS and puromycin/SCENITH data

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:
- m.7076A>G mosaic synonymous mtDNA variant in MT-CO1 present at ~47% heteroplasmy in donor PBMCs
- Mutant m.7076G allele selectively depleted in CD8+ effector memory (TEM) cells, not in other T cell subsets
- MT-CO1 mRNA levels are unchanged by genotype
- Mutant allele enriched in ribosome-protected fragments, indicating translational stalling
- CD8+ T cells with high metabolic demands (SLECs) show increased translational/metabolic activity and selective pressure against the mutant allele
- Limited mitochondrial tRNA pool (22 tRNAs); glycine decoding relies on wobble; GGG codon necessitates super-wobble decoding

QC result: Pass.

Vasudevan HN et al., PNAS - CRISPRi, transcriptomic and proteomic profiling in peripheral nervous system cell models reveal how NF1 loss rewires Ras signaling, alters MEK inhibitor response, and nominates KRAS as a direct neurofibromin effector and therapeutic target. Key terms: neurofibromin, NF1 loss, KRAS, MEK inhibitor, SHP2 SOS2 compensation.

Study Highlights:
Repressing NF1 in immortalized peripheral nerve (iPN) cells increases Ras‑GTP and pERK, drives proliferation and dedifferentiation, and reduces biochemical sensitivity to the MEK inhibitor selumetinib through altered feedback. CRISPRi of PTPN11 produces the opposite transcriptomic program, lowers Ras activity, and sensitizes cells to selumetinib, while SOS1 inhibition is limited by SOS2 compensation. APEX proximity proteomics shows neurofibromin preferentially associates with KRAS (not HRAS/NRAS) in PNS cells, and pan‑KRAS inhibition suppresses ERK and CDK1/2 activity in NF1 mutant cells. Together these data map upstream inputs and downstream outputs of Ras after NF1 loss and identify KRAS as a key, druggable effector in PNS models.

Conclusion:
Systematic genetic, transcriptomic, and proteomic dissection in PNS cell models indicates NF1 loss drives KRAS-dependent RAF/MEK/ERK activation and altered MEK inhibitor feedback; targeting KRAS directly — or upstream SHP2 rather than SOS1 where SOS2 compensates — may offer improved therapeutic strategies for NF1-mutant peripheral nerve tumors.

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

Article title:
A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system

First author:
Vasudevan HN

Journal:
PNAS

DOI:
10.1073/pnas.2506823122

Reference:
Vasudevan HN, Arang N, Sacconi Nunez M, Kennedy P, Payne E, Mohabeer S, Chien J, Wright A, Sale MJ, Kroganc NJ, Forget A, McCormick F. A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system. Proc Natl Acad Sci U S A. 2025;122(27):e2506823122. doi:10.1073/pnas.2506823122

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/a-transcriptomic-proteomic-and-functional-genetic-atlas-dissects-neurofibromin-function-in-the-peripheral-nervous-system

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing NF1 loss, Ras signaling, MEK inhibitor resistance, upstream inputs (SOS1/SOS2, SHP2/PTPN11), KRAS as the neurofibromin effector, proximity labeling results, pan-KRAS inhibition, and clinical/translational implications.
- transcript topics: NF1 loss and Ras signaling in peripheral nervous system cells; MEK inhibitor resistance and feedback rewiring; Upstream Ras inputs: SOS1/SOS2 and SHP2 (PTPN11); SHP2 vs SOS1 inhibition and compensation by SOS2; APEX proximity labeling: KRAS as the NF1 effector; Pan-KRAS inhibition (BI-2865) effects on ERK and CDK1/2

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:
- NF1 loss increases Ras-GTP and pERK, promoting proliferation
- NF1 loss decreases sensitivity to MEK inhibitors via altered feedback
- PTPN11 (SHP2) perturbation reduces Ras activity and sensitizes to MEK inhibition
- SOS1 inhibition is limited by SOS2 compensation; SOS2 knockdown improves SOS1 inhibition response
- KRAS, not HRAS/NRAS, is enriched near neurofibromin; KRAS repression increases selumetinib sensitivity
- Pan-KRAS inhibitor BI-2865 suppresses ERK activation and CDK1/2 in NF1 mutant cells

QC result: Pass.

Barra MJ et al et al., Nature Communications (2025) 16:7295 - This study reports development and analytic evaluation of an extraction-free DARQ LAMP assay detecting HPV16, HPV18, and HPV45 plus a cellular control with a <1 hour sample-to-answer workflow on a low-cost benchtop heater/fluorimeter. Clinical testing in Houston (n=38) and Maputo (n=191) showed 100% and 93% concordance, respectively, with the GeneXpert reference test. Key terms: HPV16, HPV18, HPV45, LAMP, point-of-care.

Study Highlights:
The authors developed a multiplexed DARQ LAMP assay targeting HPV16, HPV18, HPV45 and a cellular control and implemented an extraction-free NaOH lysis allowing direct addition of lysate to the reaction. Limits of detection with extracted DNA were 57, 11.7, and 14.3 copies/reaction for HPV16, HPV18, and HPV45, respectively, and with crude lysate were ~30.4 SiHa, 11.7 HeLa, and <10 MS751 cells/reaction. The assay runs on a portable Axxin T8-ISO device in under one hour and achieved 100% concordance in Houston (n=38) and 93% concordance in Maputo (n=191) versus GeneXpert. Extraction-free workflow simplified specimen handling but contributed to reduced sensitivity for samples with low viral load.

Conclusion:
An extraction-free, multiplexed DARQ LAMP assay provides rapid (<1 h), sensitive detection of HPV16/18/45 with high concordance to a WHO-prequalified reference test and a simple workflow suitable for point-of-care use in resource-limited settings, while further clinical validation and expansion to additional HPV types are needed.

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

Article title:
One-hour extraction-free loop-mediated isothermal amplification HPV DNA assay for point-of-care testing in Maputo, Mozambique

First author:
Barra MJ et al

Journal:
Nature Communications (2025) 16:7295

DOI:
10.1038/s41467-025-62454-x

Reference:
Barra MJ et al. One-hour extraction-free loop-mediated isothermal amplification HPV DNA assay for point-of-care testing in Maputo, Mozambique. Nature Communications (2025) 16:7295. https://doi.org/10.1038/s41467-025-62454-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/one-hour-extraction-free-loop-mediated-isothermal-amplification-hpv-dna-assay-for-point-of-care-testing-in-maputo-mozambique

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-22.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s depiction of the DARQ LAMP extraction-free HPV assay, its workflow, device, clinical evaluations, and performance metrics.
- transcript topics: HPV biology and cervical cancer screening context; DARQ LAMP methodology and extraction-free lysate; Targets HPV16/HPV18/HPV45 and cellular control; Point-of-care device and workflow (65 C, T8-ISO); Clinical evaluation in Houston and Maputo; Performance metrics, concordance, and limitations

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:
- Targets HPV16/18/45 and cellular gDNA control
- Extraction-free lysate prep using NaOH
- Four-step protocol on the T8-ISO yielding results in under 1 hour
- Clinical concordance: Houston 100% (n=38) and Maputo 93% (n=191)
- LOD with extracted DNA: HPV16 57 copies/reaction; HPV18 11.7 copies/reaction; HPV45 14.3 copies/reaction
- LOD with crude lysate: HPV16 30.4 SiHa cells; HPV18 11.7 HeLa cells; HPV45 <10 MS751 cells

QC result: Pass.

Nadimpalli Kobren S et al., Nature Communications - The Undiagnosed Diseases Network (UDN) applied joint whole‑genome analysis across 4,236 individuals and introduced RaMeDiES, an analytical framework to prioritize genes by de novo recurrence and compound heterozygosity while integrating intronic splice predictions and experimental validation. The work recapitulated known diagnoses, identified new diagnoses and candidates, and released software and a public browser to enable cross‑cohort, deidentified discovery. Key terms: rare disease, whole genome sequencing, de novo mutations, compound heterozygosity, RaMeDiES.

Study Highlights:
The authors jointly called SNVs and indels across the UDN whole‑genome cohort and developed RaMeDiES statistical methods to detect genes enriched for deleterious de novo mutations and for recurrent compound heterozygous events. They extended analyses to deep intronic splice‑altering variants using SpliceAI and validated predictions with a massively parallel splicing reporter assay (MPSA). RaMeDiES recovered known diagnoses, produced five new diagnoses and multiple strong candidates, and runs fast on summary-level mutational targets enabling cross-cohort meta-analysis. A public browser and open-source RaMeDiES package were released to support automated, deidentified joint analyses.

Conclusion:
Well‑calibrated, cohort‑level statistical analyses of whole genomes can complement per‑case evaluation to reveal diagnoses and candidate genes in diverse ultra‑rare disease presentations, and RaMeDiES enables scalable, shareable discovery across sequenced cohorts.

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

Article title:
Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations

First author:
Nadimpalli Kobren S

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61712-2

Reference:
Nadimpalli Kobren S, Moldovan MA, Reimers R, et al. Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations. Nat Commun (2025) 16:7267. doi:10.1038/s41467-025-61712-2

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/joint-multifaceted-genomic-analysis-enables-diagnosis-of-ultra-rare-monogenic-presentations

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-21.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing RaMeDiES (joint genomic analysis), RaMeDiES-DN (de novo recurrence), RaMeDiES-CH (compound heterozygosity), intronic/splice-variant incorporation (SpliceAI, MPSA), pathway clustering, privacy-preserving data sharing, and study limitations.
- transcript topics: RaMeDiES overview and genotype-first analysis; RaMeDiES-DN de novo recurrence and mutation-rate modeling (Roulette); RaMeDiES-CH compound heterozygosity analysis and trio-based conditioning; Intron-splice variant integration (SpliceAI) and MPSA validation; Pathway analysis and phenotype clustering across cohorts; Privacy-preserving cross-cohort sharing via summary statistics

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:
- RaMeDiES identified five new diagnoses and three putative diagnoses in the UDN dataset
- MED11 intronic variants cause cryptic splicing resolved by RNA sequencing showing first-intron retention
- LRRC7 de novo variants detected in two patients with overlapping hypotonia/developmental delay phenotypes
- H4C5 histone gene variants detected with infantile-onset motor delays in de novo analyses
- Incorporation of intronic/splice variants via SpliceAI and validation with MPSA
- Taste transduction pathway enrichment linked to CACNA1C, GABRA3, HCN4 within patient clusters

QC result: Pass.

️ Episode 112: Local Genetic Sex Differences in Quantitative Traits

In this episode of PaperCast Base by Base, we explore how genetic differences between males and females are distributed across the genome, moving beyond global averages of heritability and correlation. The study introduces a fine-scale approach using LAVA to examine local genetic sex differences across 157 quantitative traits in the UK Biobank.

Study Highlights:
The researchers analyzed sex-stratified GWAS summary statistics and partitioned the genome into nearly 2,500 loci. They estimated local heritabilities, genetic correlations, and equality of genetic effects, finding that nearly every trait had at least one locus with sex-specific genetic architecture. Many differences appeared in blood biomarkers, with testosterone, urate, and lipoprotein traits showing strong local divergence. The study also demonstrated how interpretations vary depending on whether genetic effect sizes are assessed on raw or standardized scales, with standardized scales being more informative for heritability comparisons. Moreover, loci such as APOE and AKR1C genes revealed clear biological differences between the sexes, highlighting how local analyses can uncover dimorphic mechanisms missed in global assessments.

Conclusion:
This work shows that local analyses provide crucial insights into sex-specific genetic effects, revealing subtle but biologically meaningful differences that global metrics can obscure.

Reference:
Uffelmann, E., de Leeuw, C., Schipper, M., & Posthuma, D. (2025). Local genetic sex differences in quantitative traits. *Nature Communications, 16*(7232). https://doi.org/10.1038/s41467-025-62504-4

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/

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 Keywords: sex differences, local heritability, genetic correlation, GWAS, quantitative traits

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

Dörrich M et al., Nature Communications - This episode summarizes HANCOCK, a monocentric multimodal dataset of 763 head and neck cancer patients combining demographics, structured pathology and blood data, surgery reports, whole-slide images (WSIs) and tissue microarrays (TMAs). The paper demonstrates that multimodal machine learning and multiple instance learning with histopathology foundation models improve prediction of recurrence and survival and that the dataset is publicly available for research. Key terms: multimodal dataset, head and neck cancer, histopathology, machine learning, precision oncology.

Study Highlights:
The authors assembled HANCOCK, a harmonized multimodal cohort of 763 head and neck cancer patients including 701 primary tumor WSIs and 368 TMAs alongside clinical, laboratory, and surgery-report data. They encoded each modality into multimodal patient vectors, used UMAP to explore patient clusters, and trained Random Forests to predict recurrence and survival with a maximum average AUC of 0.79. Multiple instance learning (CLAM) with self-supervised histology encoders (e.g., UNI, ResNet18) produced high localization AUCs and combining WSI and TMA inputs improved survival prediction (test AUC ~0.69 vs 0.65 and 0.52). The dataset and code are publicly released to enable reproducible multimodal research in precision oncology.

Conclusion:
HANCOCK is a large, publicly available multimodal resource that enables development and validation of multimodal ML and MIL approaches in head and neck oncology and is positioned to accelerate biomarker discovery and precision treatment research.

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

Article title:
A multimodal dataset for precision oncology in head and neck cancer

First author:
Dörrich M

Journal:
Nature Communications

DOI:
10.1038/s41467-025-62386-6

Reference:
Dörrich M., Balk M., Heusinger T., et al. A multimodal dataset for precision oncology in head and neck cancer. Nature Communications (2025) 16:7163. doi:10.1038/s41467-025-62386-6

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/

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

Episode link: https://basebybase.com/episodes/a-multimodal-dataset-for-precision-oncology-in-head-and-neck-cancer

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Evaluated the transcript sections describing HANCOCK dataset composition, multimodal fusion strategy, imaging-based MIL using CLAM and UNI, data-split strategy with genetic algorithm, performance outcomes (AUCs), biomarker context (HPV/PD-L1), and dataset availability/future directions.
- transcript topics: HANCOCK dataset overview and modalities; Multimodal data integration and early fusion; Imaging data: MIL/CLAM and histology foundation models (UNI); Genetic algorithm-based data splits for training/testing; Performance outcomes: recurrence and survival AUCs; Biomarkers and biology: HPV status and PD-L1

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:
- HANCOCK contains real-world data from 763 head and neck cancer patients with multimodal data (demographics, blood data, pathology/surgery reports, histologic images).
- WSIs: 701 primary-tumor WSIs; 396 lymph-node WSIs; 368 TMAs with HE/IHC staining.
- Multimodal integration uses early fusion; maximum average AUC ~0.79 for recurrence and survival.
- MIL (CLAM) with histology foundation models (UNI) yields high localization AUCs (~0.94–0.96).
- Combining WSIs and TMAs improves survival prediction (average AUC ~0.69) versus WSIs alone (0.65) or TMAs alone (0.52).
- Reproduction of known biomarkers: HPV status and PD-L1 have predictive value for outcomes; dataset public availability is highlighted.

QC result: Pass.