Singh P et al., PNAS - This paper compares alternative splicing (AS) and gene expression (GE) across 200 transcriptomes from oral and pharyngeal jaws of 18 haplochromine cichlid species across Lakes Victoria, Malawi, and Tanganyika. The authors show that rapid changes in AS, often from low-frequency ancestral isoforms and some novel isoforms, contributed more to early trophic diversification than shifts in GE. Key terms: alternative splicing, adaptive radiation, cichlids, gene regulation, craniofacial development.

Study Highlights:
Using 200 jaw transcriptomes spanning three East African cichlid radiations, the authors found that alternative splicing (AS) diverged faster than gene expression (GE) and was enriched for craniofacial and jaw morphogenesis genes. Most adaptive isoforms were present at low levels in nonradiating ancestral lineages and increased in frequency in radiating lineages, consistent with standing splice variation fueling rapid adaptation. A subset of novel isoforms evolved rapidly, some within a few thousand years, and mapped to candidate craniofacial genes such as col21a1. Younger radiations (Victoria, Malawi) showed stronger AS divergence while the older Tanganyika radiation displayed more GE differences.

Conclusion:
Ancestral alternative splice variation, supplemented by rapidly evolved novel isoforms, provided a labile reservoir of protein-coding diversity that likely enabled the extremely rapid trophic diversification of African cichlid radiations; integrating splicing into regulatory perspectives is essential to understand rapid adaptive evolution.

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

Article title:
Ancestral splice variation is a key substrate for rapid diversification in African cichlids

First author:
Singh P

Journal:
PNAS

DOI:
10.1073/pnas.2516477123

Reference:
Singh P., Ahi E.P., Duenser A., Durdevic M., Gessl W., Schaeffer S., Gall J., Seehausen O., Sturmbauer C. Ancestral splice variation is a key substrate for rapid diversification in African cichlids. PNAS. 2026;123(20):e2516477123. doi:10.1073/pnas.2516477123

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/ancestral-splice-variation-african-cichlids

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing AS vs GE dynamics, ancestral standing variation, novel isoforms (col21a1), lake-by-lake evolutionary patterns, and convergent/trophic evolution; cross-checked against the original article.
- transcript topics: Adaptive radiation and jaw anatomy in African cichlids; Gene expression vs alternative splicing (GE vs AS); Ancestral standing variation and novel isoforms; Temporal patterns: young vs old radiations (Victoria/Malawi vs Tanganyika); Key genes: col21a1 and craniofacial pathways; Convergent vs divergent regulation across radiations

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...

Han YJ et al., Proceedings of the National Academy of Sciences (PNAS) - This episode examines a PNAS study showing that the BRCA1 pseudogene BRCA1P1 produces circular RNAs that suppress antiviral innate immunity in human cancers; depleting BRCA1P1 activates interferon-stimulated genes, increases apoptosis and chemosensitivity, and enhances immune clearance in preclinical models. Key terms: BRCA1P1, pseudogene, circular RNA, antiviral immunity, breast cancer.

Study Highlights:
BRCA1P1 is expressed broadly across human cancer cell lines and is elevated in breast tumors. The majority of BRCA1P1 transcripts are circular RNAs that bind the NF-κB subunit RelA to attenuate NF-κB–driven antiviral gene transcription. Loss of BRCA1P1 by ASO or CRISPR induces ISGs, IFNβ and TNF, increases apoptosis and sensitivity to chemotherapy, and enhances macrophage phagocytosis. In patient-derived organoids and humanized mouse xenografts BRCA1P1 depletion reduces tumor viability and increases T cell and M1 macrophage infiltration.

Conclusion:
BRCA1P1-derived circular RNAs act as immunosuppressive regulators of antiviral and antitumor immunity in human cancers, and targeting BRCA1P1 activates antiviral programs that reduce tumor growth and boost immune infiltration.

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

Article title:
Regulation of antiviral and antitumor immunity by the BRCA1 pseudogene in human cancers

First author:
Han YJ

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

DOI:
10.1073/pnas.2528911123

Reference:
Han YJ, Zhang J, Shariff M, Wu S, Khramtsova G, Nguyen LC, Peiffer DS, Li N, Lewicka A, Moore M, Piccirilli JA, Olopade OI. Regulation of antiviral and antitumor immunity by the BRCA1 pseudogene in human cancers. Proc Natl Acad Sci U S A. 2026;123(19):e2528911123. doi:10.1073/pnas.2528911123

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/brca1p1-pseudogene-antiviral-immunity

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing BRCA1P1 background, circular RNA nature, RelA/NF-κB interaction, depletion experiments (ASO/CRISPR), pancancer expression, antiviral gene upregulation, apoptosis, chemotherapy sensitivity, immune infiltration, PDOs, and humanized mouse models, plus clinical implications and de
- transcript topics: BRCA1P1 background and primate-specificity; BRCA1P1 circular RNA and RelA/NF-κB interaction; BRCA1P1 depletion methods (ASO, CRISPR) and pancancer scope; Antiviral gene induction and cytokine responses; Apoptosis and chemotherapy sensitivity after BRCA1P1 loss; Macrophage phagocytosis and T cell infiltration

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:
- BRCA1P1 is a primate-specific, chimeric BRCA1/RPLP1 pseudogene; majority of BRCA1P1 transcripts are circular RNAs (~70-80%).
- BRC...

Bourgeois et al., Nature Communications - This study used enhanced CRISPR base editor screens, structural biology, biochemical assays, and in vitro/in vivo selection to map MEN1 mutations that drive resistance to five clinical menin inhibitors and to explain their mechanisms. Key terms: MEN1, menin inhibitors, CRISPR base editing, drug resistance, KMT2A.

Study Highlights:
CRISPR base editor screens tiled MEN1 and profiled resistance to five clinical menin inhibitors, revealing shared (M327 I/V/T, G331D) and inhibitor-specific (C334R, E368K/V, V372A) substitutions. Co-crystal structures of mutant menin bound to each inhibitor explain resistance via steric clashes or disrupted interactions and correlate with measured Ki and cellular IC50 shifts. Orthogonal in vitro selection and PDX experiments show many predicted mutations arise spontaneously under drug pressure and that higher inhibitor potency or dosing can suppress or overcome some resistant clones. The particular amino acid substitution at a residue critically determines the magnitude and breadth of resistance.

Conclusion:
Enhanced CRISPR base editing combined with structural and biological validation maps a mutational landscape in MEN1 that can produce pan-class or drug-specific resistance to menin inhibitors; these data can guide clinical monitoring, choices between inhibitors, dosing strategies, and next-generation inhibitor design.

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

Article title:
CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials

First author:
Bourgeois

Journal:
Nature Communications

DOI:
10.1038/s41467-026-72685-1

Reference:
Bourgeois, W., Rice, H.E., Wenge, D.V. et al. CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72685-1

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/papercast-base-by-base-menin-mutations-365

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the CRISPR base editor screen identifying MEN1 mutations that affect five clinical menin inhibitors, including shared vs inhibitor-specific mutations, biochemical and structural validation, and in vivo PDX confirmation, as well as dose-related resistance dynamics and limitatio
- transcript topics: Menin-KMT2A interaction and menin inhibitors in leukemia; CRISPR base editor screen design and MV4;11 cells; Shared and inhibitor-specific MEN1 mutations (M327, G331, T349, C334R, E368K/V, V372A); Biochemical binding: TR-FRET and Ki shifts; Structural insights: co-crystal structures; In vivo validation: PDX models

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:
- Five inhibitors tested: DS-1594, JNJ-6617, KO-539...