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Lin S et al., The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.015 - Bi-allelic FSD1L variants cause retinitis pigmentosa; FSD1L localizes to the photoreceptor axoneme and a deep intronic deletion abolishes retina-enriched exon 10b inclusion. Key terms: FSD1L, retinitis pigmentosa, photoreceptor axoneme, exon 10b, minigene assay.

Study Highlights:
In human and mouse retinal tissues and six affected individuals from four families, exome/genome sequencing identified bi-allelic ultra-rare FSD1L variants associated with retinitis pigmentosa. Single-cell RNA-seq, immunofluorescence, and ultrastructure expansion microscopy show FSD1L is enriched in cones and rods and localizes along the photoreceptor microtubule axoneme including the connecting cilium and outer segment. Functional assays including ARPE-19 minigene splicing and long-read nanopore sequencing of patient lymphocytes demonstrate that a deep intronic 26-nt deletion abolishes inclusion of a retina-enriched exon (exon 10b). Together these data link isoform-specific mis-splicing and axonemal localization to a plausible disruption of intracellular trafficking leading to photoreceptor degeneration.

Conclusion:
Bi-allelic disruption of FSD1L is associated with retinitis pigmentosa, and retina-enriched exon 10b mis-splicing provides a plausible mechanism for isolated retinal disease.

Music:
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Article title:
Bi-allelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement

First author:
Lin S

Journal:
The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.015

DOI:
10.1016/j.ajhg.2026.01.015

Reference:
Lin S., Cancellieri F., Cao Y., et al. Bi-allelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement. The American Journal of Human Genetics 113, 1–11 (2026). https://doi.org/10.1016/j.ajhg.2026.01.015

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/fsd1l-retinitis-pigmentosa-axoneme

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive scientific content in the transcript: discovery of bi-allelic FSD1L variants in RP families; retina-enriched isoform with exon 10b; deep intronic deletion disrupting exon 10b; minigene splicing assays; FSD1L localization to photoreceptor axoneme/connecting cilium/outer segment; expression pattern in
- transcript topics: RP and inherited retinal disease overview; FSD1L as RP gene candidate; Retina-enriched isoform and exon 10b; Deep intronic deletion c.1025+624_1025+649del and exon 10b skipping; Minigene splicing assays in ARPE-19 cells; FSD1L localization to photoreceptor axoneme via U-ExM

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:
- Bi-allelic ultra-rare FSD1L variants identified in six individuals from four families
- FSD1L expression enriched in cone photoreceptors (and present in rods) in human retina
- FSD1L localizes along the photoreceptor microtubule axoneme, including the connecting cilium and outer segment
- Retina-enriched isoform includes exon 10b; deep intronic deletion disrupts exon 10b inclusion
- Minigene splicing assays show exon 10b skipping with the intronic deletion
- Clinical spectrum includes RP with variable neurological involvement; isoform- and allele-specific effects explain phenotypic variability

QC result: Pass.

Serpieri V et al., The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.014 - Bi-allelic FSD1L variants disrupt a microtubule-associated protein, causing hydrocephalus, corpus callosum defects and an L1 syndrome-like neurodevelopmental disorder in humans and models. Key terms: FSD1L, microtubules, ciliogenesis, hydrocephalus, iPSC neuronal differentiation.

Study Highlights:
Exome sequencing in eleven affected individuals (including five fetuses) identified bi-allelic FSD1L variants associated with hydrocephalus and corpus callosum defects. Using iPSC-derived neural progenitor differentiation, neurosphere assays, patient fibroblasts, immunohistochemistry, and in utero CRISPR-Cas9 mouse knockdown, the authors show that FSD1L localizes to mitotic spindle microtubules and to the transition zone/axoneme of the primary cilium. Patient NPCs fail to differentiate into premature neurons, undergo increased cell death, and form smaller disorganized neurospheres, while patient fibroblasts show abnormal spindles, reduced ciliogenesis and shorter cilia. Fsd1l repression in mouse embryos produced lateral ventricular dilation, functionally linking FSD1L to mitotic spindle assembly, ciliogenesis, neuronal differentiation and axon guidance.

Conclusion:
Bi-allelic pathogenic variants in FSD1L cause a neurodevelopmental syndrome overlapping L1 syndrome by disrupting a microtubule-associated protein required for mitotic spindle assembly, ciliogenesis, and neuronal differentiation.

Music:
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Article title:
Bi-allelic variants in FSD1L cause a neurodevelopmental disorder overlapping with L1 syndrome

First author:
Serpieri V

Journal:
The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.014

DOI:
10.1016/j.ajhg.2026.01.014

Reference:
Serpieri V., Vezain-Mouchard M., Orsi A., et al. Bi-allelic variants in FSD1L cause a neurodevelopmental disorder overlapping with L1 syndrome. The American Journal of Human Genetics. 113, 1–16 (March 5, 2026). https://doi.org/10.1016/j.ajhg.2026.01.014

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/fsd1l-microtubule-ciliogenesis

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s presentation of the AJHG 2026 FSD1L study’s main claims, cellular mechanisms, experimental models, and clinical implications as described in the article.
- transcript topics: Clinical features resembling L1 syndrome; Gene discovery via exome sequencing and GeneMatcher; Autosomal recessive inheritance; FSD1L as a microtubule-associated protein localizing to mitotic spindle and primary cilium; iPSC-derived neural progenitor differentiation defects; Fibroblast spindle abnormalities and ciliogenesis defects

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:
- Bi-allelic FSD1L variants identified in 11 affected individuals from six unrelated families
- FSD1L localizes to mitotic spindle microtubules and to the primary cilium transition zone/axoneme
- iPSC-derived neural progenitor cells from affected individuals failed to differentiate into premature neurons and showed increased cell death
- Patient fibroblasts exhibited abnormal mitotic spindles and reduced ciliogenesis with shorter cilia
- Fsd1l repression in mouse embryos produced ventriculomegaly (lateral ventricular dilation)
- Phenotype closely resembles L1 syndrome; overlapping expression patterns with L1CAM in developing brain

QC result: Pass.

Zhou S et al., Nature Communications, doi:10.1038/s41467-025-65448-x - snaR-A noncoding RNA interacts with U2 snRNP subunit SF3B2 and nuclear speckles, increasing intron retention and promoting proliferation in human cancer-relevant cells. Key terms: snaR-A, SF3B2, intron retention, nuclear speckles, RNA polymerase III.

Study Highlights:
Using human cell lines (HEK293T, A549, THP-1) and tumor chromatin data, the authors combined biotinylated RNA pulldown mass spectrometry, PAR-CLIP/CLIP-qPCR, HCR-RNA-FISH, TSA-seq, and ultra-deep RNA-seq (IRFinder, rMATS) to map snaR-A interactions and splicing outcomes. snaR-A directly binds splicing factors and shows nucleotide-level crosslinking to the U2 snRNP protein SF3B2, and localizes to subnuclear foci adjacent to nuclear speckles and U6-containing sites. Functionally, snaR-A overexpression increases intron retention and selectively depletes SF3B2 protein, whereas snaR-A depletion reduces intron retention for transcripts with high U2 occupancy and speckle proximity. These splicing changes alter protein abundance for multiple targets and coincide with reduced proliferation after snaR-A depletion, consistent with tumor-level associations to growth.

Conclusion:
snaR-A acts as a molecular antagonist of U2-dependent splicing by interacting with SF3B2 and perturbing processing of specific mRNA subpopulations, promoting intron retention and proliferation in cancer-relevant contexts.

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

Article title:
Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

First author:
Zhou S

Journal:
Nature Communications, doi:10.1038/s41467-025-65448-x

DOI:
10.1038/s41467-025-65448-x

Reference:
Zhou S., Lizarazo S., Chorghade S., Mouli L., Cheng R., Rajendra K. C., Kalsotra A., Van Bortle K. Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations. Nature Communications. 2025;16:10460. https://doi.org/10.1038/s41467-025-65448-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/snar-a-sf3b2-splicing

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-21.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s presentation of the snaR-A study: interaction with SF3B2 and U2 snRNP, localization to nuclear speckles, intron retention effects, SF3B2 protein depletion, depletion effects on splicing and protein abundance, proliferation/migration phenotypes, TCGA prognosis, and limitations.
- transcript topics: snaR-A interaction with SF3B2 and U2 snRNP; localization of snaR-A to nuclear speckles and proximity to U6; snaR-A-induced intron retention and splicing disruption; SF3B2 protein depletion upon snaR-A overexpression; snaR-A depletion reduces IR in U2-residency, speckle-proximal transcripts; OGFR and other targets affected by splicing changes

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:
- snaR-A ncRNA interacts with SF3B2, a core U2 snRNP component
- snaR-A localizes to subnuclear foci near nuclear speckles and U6
- overexpression of snaR-A increases intron retention (IR)
- snaR-A overexpression reduces SF3B2 protein levels
- snaR-A depletion reduces IR for transcripts with high U2 residency and speckle proximity
- splicing changes lead to altered protein abundance for targets including OGFR

QC result: Pass.

Yu M et al., Cell Genomics, 6 (2026) 101071. doi:10.1016/j.xgen.2025.101071 - Large-scale exome sequencing shows CFTR risk variants, including deltaF508, reduce susceptibility to inflammatory bowel disease, suggesting targeted CFTR modulation as a potential IBD therapy. Key terms: CFTR, deltaF508, inflammatory bowel disease, exome sequencing, rare-variant burden test.

Study Highlights:
The authors analyzed large-scale human exome and genome sequencing data (38,558 cases and 66,945 controls in European discovery; 42,475 cases and 192,050 controls in replication across ancestries) using single-variant tests and gene-based rare-variant burden tests. They report a protective single-variant association for CFTR deltaF508 with IBD (meta-analysis p = 8.96E-11, OR = 0.82) and a significant protective gene-level burden of clinically annotated CF-risk variants (meta-analysis p = 3.9E-7, OR = 0.85). The study also compared variant prioritization methods and found clinically curated CFTR2 annotations outperform in silico predictors such as AlphaMissense for powering burden tests. Replication signals were observed in non-European groups at nominal significance and the results support exploration of selective, tissue-targeted CFTR modulators as a potential therapeutic implication.

Conclusion:
Clinically annotated CFTR risk variants, including deltaF508, confer a reproducible protective effect against IBD in large sequencing cohorts, supporting investigation of selective tissue-targeted CFTR modulation while balancing cystic fibrosis risks.

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

Article title:
Cystic fibrosis risk variants confer protection against inflammatory bowel disease

First author:
Yu M

Journal:
Cell Genomics, 6 (2026) 101071. doi:10.1016/j.xgen.2025.101071

DOI:
10.1016/j.xgen.2025.101071

Reference:
Yu M., Zhang Q., Yuan K., Sazonovs A., Stevens C.R., Fachal L., et al. Cystic fibrosis risk variants confer protection against inflammatory bowel disease. Cell Genomics. 6 (2026) 101071. https://doi.org/10.1016/j.xgen.2025.101071

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/cftr-deltaf508-ibd-protection

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the Results and Discussion segments of the transcript, including the DeltaF508 association with IBD, CFTR2-based burden tests, replication across ancestries, AlphaMissense evaluation and mechanistic discussion about mucus and BEST4+ enterocytes, and therapeutic implications.
- transcript topics: CFTR deltaF508 single-variant association with IBD; CFTR2-based rare-variant burden test; negative control with non-CF-risk variants; ancestry-adjusted analysis and replication (EUR, AFR.AMR, EAS); CFTR variant prioritization: AlphaMissense vs CFTR2; mechanistic discussion: mucus hydration and BEST4+ enterocytes

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:
- CFTR deltaF508 single-variant protective effect against IBD (OR 0.82; p 8.96E-11)
- CF-risk variants burden test shows protective effect against IBD (OR 0.85; p 3.9E-07)
- CD/UC subtype effects: deltaF508 protective stronger for CD (OR ~0.79) than UC (OR ~0.87)
- Exclusion of homozygous deltaF508 to avoid CF misclassification
- Cross-ancestry replication across AFR.AMR and EAS groups
- CFTR2-based burden variants outperform AlphaMissense for burden tests

QC result: Pass.

Hunter CE et al., The EMBO Journal, doi:10.1038/s44318-025-00666-z - Review shows how alternative splicing, via TE exonization and cis-regulatory changes and revealed by long-read RNA-seq, reshapes gene regulation and drives phenotypic evolution in mammals. Key terms: alternative splicing, exonization, long-read RNA-seq, microexons, comparative transcriptomics.

Study Highlights:
This review synthesizes comparative transcriptomic studies across multicellular eukaryotes with emphasis on vertebrates and mammals. It highlights methods including short- and long-read RNA-seq, single-cell transcriptomics, and MS proteomics to map isoform diversity. The authors emphasize that lineage-specific AS is often driven by cis-regulatory changes and exonization of transposable elements, with trans-factor innovations (e.g., SRRM3/4, PTBP1 isoforms) modulating microexons and isoform ratios. Functional examples linking AS to phenotypes include an Alu-derived IFNAR2 decoy receptor reducing JAK/STAT signaling, TNNI3 exon3 loss or skipping associated with extreme heart rates, and hominoid shifts in MAPT exon10 splicing altering tau isoform proportion.

Conclusion:
Alternative splicing, shaped largely by cis-sequence changes and TE exonization and illuminated by long-read and single-cell transcriptomics, is a flexible evolutionary mechanism that can produce lineage-specific regulatory and phenotypic innovations.

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

Article title:
The splice of life: how alternative splicing shapes regulatory and phenotypic evolution

First author:
Hunter CE

Journal:
The EMBO Journal, doi:10.1038/s44318-025-00666-z

DOI:
10.1038/s44318-025-00666-z

Reference:
Hunter CE, Xing Y. The splice of life: how alternative splicing shapes regulatory and phenotypic evolution. The EMBO Journal. 2026. https://doi.org/10.1038/s44318-025-00666-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/alternative-splicing-exonization-evolution

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited sections covering splicing mechanisms, exonization and TE-derived exons, three main evolutionary modes of AS, cis vs trans regulation, sequencing technologies (long-read, single-cell, proteomics), and case studies (TBXT tail loss, TNNI3, MAPT). Also reviewed Tc1 humanized mouse results and immune/
- transcript topics: Basics of alternative splicing and spliceosome regulation; Exon creation via TE exonization (Alu elements) and exonization examples (IFNAR2); Exon loss and splicing level changes as evolutionary modes; Three case studies: TBXT tail loss via exon skipping; TNNI3 exon 3 loss/skip for high heart rate; MAPT exon 10 splicing and tau isoforms; Cis-regulatory vs trans-acting factors in splicing evolution (Tc1 human chromosome 21 study); Splicing regulators and microexons (SRRM3/4, PTBP1) and their evolutionary implications

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:
- Exon creation via transposable elements (TE exonization) contributes new exons (e.g., Alu-derived exons in immune genes like IFNAR2)
- Exon loss or skipping (e.g., TBXT exon 6) can drive phenotypic changes such as tail loss in hominoids
- Splicing-level changes (altered inclusion of exons) can reshape isoform outputs without changing gene presence
- MAPT exon 10 splicing, modulated by MBNL, shifts tau isoform ratios (3R/4R) and is linked to lineage-specific brain features
- Cis-regulatory changes predominantly drive lineage-specific AS patterns; Tc1 mouse study shows human exon splicing is recapitulated by cis elements rather than trans factors

QC result: Pass.

Gracia Carmona O et al., Patterns, 7 (2026) 101425. doi:10.1016/j.patter.2025.101425 - IndeLLM uses protein language models (ESM2) to score in-frame indels and a compact Siamese transfer-learning model that achieves state-of-the-art pathogenicity prediction with MCC = 0.77. Key terms: IndeLLM, protein language models, in-frame indels, Siamese network, ESM2.

Study Highlights:
Using human protein sequences and ESM2 embeddings, the authors develop IndeLLM, a zero-shot scoring function that sums overlapping-region probabilities to correct length bias in in-frame indels. They train a compact Siamese one-hidden-layer network on PLM embeddings with biologically guided embedding splitting and achieve MCC = 0.77 on the test set. Per-residue probability differences mapped onto structures (FGFR1, GLMN) identify local regions affected by indels and improve interpretability. The framework reduces insertion false negatives and is released with Colab and GitHub tools for indel annotation and disease-variant analysis.

Conclusion:
IndeLLM zero-shot scoring and a small Siamese transfer-learning model provide improved, interpretable indel pathogenicity prediction, with the Siamese model achieving MCC = 0.77.

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

Article title:
Leveraging protein language models and a scoring function for indel characterization and transfer learning

First author:
Gracia Carmona O

Journal:
Patterns, 7 (2026) 101425. doi:10.1016/j.patter.2025.101425

DOI:
10.1016/j.patter.2025.101425

Reference:
Gracia Carmona O, Leipart V, Amdam GV, Orengo C, Fraternali F. Leveraging protein language models and a scoring function for indel characterization and transfer learning. Patterns. 7 (2026) 101425. https://doi.org/10.1016/j.patter.2025.101425

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/indellm-indel-siamese-model

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the scientific content conveyed in the transcript: indel biology, IndeLLM zero-shot scoring, Siamese Model 4, performance metrics, interpretability via structure-mapped probability changes, structural validation with AlphaFold, and broad applicability including non-human systems and accessible tooling.
- transcript topics: Indel biology: in-frame indels vs frameshift indels; Protein language models and length bias; Indel scoring: IndeLLM zero-shot (overlapping regions); Probability scoring math: sum vs log-sum; Siamese network (Model 4) and transfer learning; Performance metrics: MCC 0.65 (zero-shot) and 0.77 (Siamese); comparison to Provean

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:
- IndeLLM zero-shot scoring uses overlapping regions to correct length bias
- Switch from log probability sums to sum of probabilities to reduce noise
- Model 4 Siamese network with embedding splitting achieves MCC 0.77
- Zero-shot MCC is 0.65 and outperforms Brandes scoring (0.58); comparable to supervised methods
- Per-residue probability differences mapped to FGFR1 and GLMN explain pathogenicity; AlphaFold used for validation
- Honeybee example demonstrates generalizability beyond humans

QC result: Pass.

Tong Y et al., EMBO Molecular Medicine, doi:10.1038/s44321-025-00362-9 - Patient data, population genetics and iPSC-derived βcell models show INS R6C impairs preproinsulin ER translocation and causes recessive insulin-deficient diabetes in homozygotes. Key terms: INS R6C, preproinsulin translocation, iPSC-derived beta cells, monogenic diabetes, population genetics.

Study Highlights:
The study integrates clinical pedigrees, large-scale population screens and patient-derived iPSC βcell models, plus in vivo transplantation and transcriptomics. AlphaFold 3 structural modeling suggested weakened SRP54 interaction and altered SEC61 orientation for the R6C signal peptide, and population data showed no enrichment of diabetes among heterozygotes. In homozygous R6C iPSC-βcells up to two-thirds of nascent preproinsulin failed to translocate, preproinsulin accumulated, and insulin content and secretion were reduced by roughly 50% with altered proinsulin processing. Functionally, homozygous R6C grafts produced minimal human C-peptide in mice and responded poorly to GLP-1 receptor agonists, while heterozygotes were largely compensated by a single wild-type allele.

Conclusion:
INS R6C is a recessive loss-of-function mutation that causes early-onset, insulin-deficient diabetes in homozygotes while heterozygous carriers show variable or absent glycemic phenotypes.

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

Article title:
A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data

First author:
Tong Y

Journal:
EMBO Molecular Medicine, doi:10.1038/s44321-025-00362-9

DOI:
10.1038/s44321-025-00362-9

Reference:
Tong Y, Becker M, Schierloh U, Natividade da Silva F, Haataja L, Cai Y, Patel KA, Kobaisi F, Mirshahi UL, Colclough K, Javed MS, Wakeling MN, Fantuzzi F, Lytrivi M, Sawatani T, Arroyo MN, Yi X, Vinci C, Montaser H, Pachera N, Otonkoski T, Igoillo-Esteve M, Scharfmann R, Hattersley AT, Arvan P, De Beaufort C, Cnop M. A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data. EMBO Molecular Medicine. 2026;18:620–645. https://doi.org/10.1038/s44321-025-00362-9

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/ins-r6c-recessive-diabetes

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the core scientific narrative conveyed in the transcript, focusing on: INS R6C zygosity-dependent diabetes; ER translocation defect caused by the signal peptide; SRP54 and SEC61 translocon involvement; heterozygous vs homozygous iPSC-derived β-cell phenotypes; population-genetic evidence; in vivo transplantatio
- transcript topics: INS R6C mutation and zygosity; ER translocation defect and signal peptide mechanism; SRP54 and SEC61 translocon interactions; iPSC-derived β-cell modeling (heterozygous and homozygous); In vivo transplantation and C-peptide outcomes; Population genetics data (UK Biobank, Geisinger) and penetrance

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:
- Homozygous INS R6C causes early-onset diabetes with greatly reduced insulin production; two bad INS alleles impair ER translocation of preproinsulin (≈66% translocation loss; ≈50%
- Heterozygous R6C carriers show limited cellular defects with insulin secretion near normal; modest preproinsulin accumulation and altered proinsulin processing but preserved overal
- ER translocation defect is driven by R6C’s effect on signal peptide properties; AlphaFold modeling suggests weakened SRP54 interaction and inverted SEC61 orientation, reducing ER t
- Population data indicate no strong enrichment of diabetes in heterozygous carriers (UK Biobank: no diabetes among heterozygotes; Geisinger: odds ratio ~1.4 with wide CI).
- GLP-1 receptor agonists improve glucose metrics in homozygotes only modestly and do not restore insulin secretion; insulin replacement remains the primary therapy for homozygous R6
- Clinical counseling implications: reclassify INS R6C from dominant to recessive; emphasize penetrance variability and environmental modifiers (e.g., obesity, pregnancy).

QC result: Pass.

Wirth B et al., The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.012 - Two SMN1 exon 7 4-bp deletions (p.Arg288AlafsTer5) evade standard PCR newborn screening but produce a low-abundance, thermostable SMN protein that functionally rescues smn1-deficient zebrafish and averted therapy. Key terms: SMN1, spinal muscular atrophy, newborn screening, p.Arg288AlafsTer5, zebrafish rescue.

Study Highlights:
In two clinically healthy newborns flagged as lacking SMN1 by PCR-based NBS, long-range SMN1-specific PCR, Sanger sequencing, MLPA and ddPCR identified distinct 4-bp exon 7 deletions producing the same frameshift p.Arg288AlafsTer5. Cellular assays showed preserved exon 7 splicing, markedly reduced SMN protein abundance, and unchanged protein thermostability, while AlphaFold3 predicted only mild C-terminal structural alteration. Functional complementation in smn1-deficient zebrafish—using both mRNA injection and a stable Tg(UBI-mKate_SMN1-861VUS) transgene—fully rescued morphology, motor behavior, and survival. Population gnomAD analysis indicates these variants are rare but present in Europeans at a carrier frequency that predicts hundreds of compound heterozygotes without reported SMA, informing diagnostic sequencing and avoidance of unnecessary therapy.

Conclusion:
Integrated genetic, functional, structural, and population-level evidence supports likely non-pathogenic reclassification of the SMN1 c.855_858delAGAA and c.861_864delAAGG alleles and shows that very low levels of the altered SMN protein can preserve normal motor development.

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

Article title:
SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions

First author:
Wirth B

Journal:
The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.012

DOI:
10.1016/j.ajhg.2026.01.012

Reference:
Wirth B., Das J., Kölbel H., Goh S., Farrar M.A., Piano V., Zetzsche S., Fuhrmann N., Becker J., Karakaya M., Zhang Y., Cao Y., Taghipour-Sheshdeh A., Stringer B.W., Giacomotto J., et al. SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions. The American Journal of Human Genetics. 2026 Mar 5;113:1–9. https://doi.org/10.1016/j.ajhg.2026.01.012

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/smn1-exon7-frameshift-variants

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-15.

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 two SMN1 exon 7 4-bp deletions, their molecular consequences, splicing, protein abundance and thermostability, in vivo zebrafish rescue, and population-genetics data with implications for clinical practice.
- transcript topics: Identification of two SMN1 exon 7 4-bp deletions; Molecular confirmation and variant characterization; SMN1 exon 7 splicing preservation; SMN protein abundance and thermostability assessments; Zebrafish functional rescue experiments; Population genetics (gnomAD) data and carrier frequencies

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:
- Two SMN1 exon 7 4-bp deletions (c.855_858delAGAA and c.861_864delAAGG) produce p.Arg288AlafsTer5
- Deletions disrupt the NBS primer-binding site, explaining initial SMN1 signal loss in screening
- Exon 7 splicing is preserved; SMN1 transcripts are full-length with no exon 7 skipping
- SMN protein abundance is markedly reduced in carriers
- Mutant SMN1 proteins are thermostable and structurally similar to WT
- In vivo zebrafish experiments show functional rescue by SMN1-855VUS and SMN1-861VUS

QC result: Pass.

Kay CJ et al., Nature, doi:10.1038/s41586-025-09808-z - Relaxed-clock dating of pre-LECA gene duplications in Asgard archaeal and alphaproteobacterial lineages shows a complex archaeal host with cytoskeleton, endomembrane system and nucleus before mitochondrial acquisition around 2.2 Ga. Key terms: eukaryogenesis, Asgard archaea, mitochondrial endosymbiosis, gene duplication, molecular clock.

Study Highlights:
The study interrogates eukaryogenesis using a time-resolved species tree and a sequential Bayesian relaxed molecular clock applied to 135 gene family trees. Analyses with MCMCTree dated divergence nodes (nFECA 3.05–2.79 Ga, mFECA 2.37–2.13 Ga, LECA 1.80–1.67 Ga) and pre-LECA duplication events of archaeal and bacterial origin. Most archaeal-derived duplications (about 85% of those sampled) were fixed prior to inferred mitochondrial endosymbiosis, with archaeal duplications for actin, tubulin, vesicle trafficking and spliceosomal components dated between ~3.0 and ~2.25 Ga. Functionally, these timings indicate the host lineage had an elaborated cytoskeleton, endomembrane trafficking and nuclear compartmentalization before mitochondrial integration, while alphaproteobacterial duplications cluster near ~2.2 Ga consistent with mitochondrial establishment.

Conclusion:
Gene-duplication dating supports a complexified archaeal host with cytoskeleton, endomembrane system and nucleus preceding mitochondrial endosymbiosis, favoring a late-mitochondrion model of eukaryogenesis.

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

Article title:
Dated gene duplications elucidate the evolutionary assembly of eukaryotes

First author:
Kay CJ

Journal:
Nature, doi:10.1038/s41586-025-09808-z

DOI:
10.1038/s41586-025-09808-z

Reference:
Kay CJ, Spang A, Szöllősi GJ, Pisani D, Williams TA & Donoghue PCJ. Dated gene duplications elucidate the evolutionary assembly of eukaryotes. Nature 650, 129–140 (2026). https://doi.org/10.1038/s41586-025-09808-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/asgard-archaea-duplication-timeline

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections that describe the eukaryogenesis timeline, gene duplication events, and the CALM model, including specific date ranges and functional system developments (cytoskeleton, endomembrane system, nucleus, mitochondrion).
- transcript topics: Eukaryogenesis timeline and debate (mitochondria early vs late); Relaxed molecular clock and cross-bracing dating approach; Pre-LECA duplications in archaeal origin (cytoskeleton, nucleus, trafficking); Endomembrane system and vesicle trafficking gene duplications; Nuclear components and RNA polymerase duplications; Mitochondrial endosymbiosis timing and alphaproteobacterial duplications

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:
- Pre-LECA host features (cytoskeleton, endomembrane system, nucleus) existed before mitochondrial endosymbiosis
- nFECA divergence 3.05–2.79 Ga
- mFECA divergence 2.37–2.13 Ga
- LECA divergence 1.80–1.67 Ga
- Alphaproteobacterial duplications associated with mitochondrial endosymbiosis (~2.2 Ga)
- 85% of pre-LECA archaeal-origin duplicates fixed before mitochondrial endosymbiosis

QC result: Pass.

Wirth B et al. (The American Journal of Human Genetics, 2026) — Zwei 4-bp-Deletionen in Exon 7 von SMN1 (p.Arg288AlafsTer5) entgehen dem Standard-PCR-Neugeborenenscreening, erzeugen jedoch ein SMN-Protein in sehr geringer Menge, das thermostabil ist, smn1-defiziente Zebrafische funktionell rettet und eine Therapie vermeiden half.

Studien-Highlights:
• Zwei klinisch gesunde Neugeborene wurden im PCR-basierten Neugeborenenscreening (NBS) fälschlich als „ohne SMN1“ auffällig.
• In der Bestätigungsdiagnostik (SMN1-spezifische Long-Range-PCR + Sanger-Sequenzierung + MLPA + ddPCR) wurden zwei unterschiedliche 4-bp-Deletionen in Exon 7 identifiziert, die denselben Frameshift erzeugen: p.Arg288AlafsTer5.
• Zellbasierte Assays zeigten erhaltenes Exon-7-Spleißen, eine deutlich reduzierte SMN-Proteinmenge und eine unveränderte Protein-Thermostabilität.
• AlphaFold3 sagte nur eine milde strukturelle Veränderung am C-Terminus voraus.
• In-vivo-funktionelle Komplementation im smn1-defizienten Zebrafisch (mRNA-Injektion + stabile Tg(UBI-mKate_SMN1-861VUS)-Transgenlinie) rettete Morphologie, Motorik und Überleben vollständig.
• Populationsanalyse (gnomAD) legt nahe, dass diese Varianten in Europäern selten, aber vorhanden sind, mit einer Trägerfrequenz, die mit Hunderten von Compound-Heterozygoten ohne registrierte SMA vereinbar ist — ein Argument für diagnostische Sequenzierung und die Vermeidung unnötiger Therapie.

Schlussfolgerung:
Integrierte genetische, funktionelle, strukturelle und populationsbasierte Evidenz unterstützt eine wahrscheinlich nicht-pathogene Reklassifizierung der SMN1-Allele c.855_858delAGAA und c.861_864delAAGG und zeigt, dass sehr niedrige Mengen des veränderten SMN-Proteins eine normale motorische Entwicklung erhalten können.

Musik:
Genieße am Ende der Episode die Musik, die auf diesem Artikel basiert.

Referenz:
Wirth B., Das J., Kölbel H., Goh S., Farrar M.A., Piano V., Zetzsche S., Fuhrmann N., Becker J., Karakaya M., Zhang Y., Cao Y., Taghipour-Sheshdeh A., Stringer B.W., Giacomotto J., et al.
SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions.
The American Journal of Human Genetics. 2026 Mar 5;113:1–9. https://doi.org/10.1016/j.ajhg.2026.01.012

Lizenz:
Diese Episode basiert auf einem Open-Access-Artikel, der unter der Creative Commons Attribution 4.0 International License (CC BY 4.0) veröffentlicht wurde:
https://creativecommons.org/licenses/by/4.0/

Unterstützung:
Base by Base – Stripe-Spenden:
https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Offizielle Website:
https://basebybase.com