Base by Base

Gustavo Barra
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Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time. Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.

  1. -31 MIN · BONUS

    302 SMN1-Exon-7-Deletionen p.Arg288AlafsTer5 entgehen dem PCR-Neugeborenenscreening und erzeugen dennoch eine funktionelle SMN-Isoform

    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 Episodenlink: https://basebybase.castos.com/episodes/smn1-exon7-frameshift-variants

    28 min

  2. -1 J

    301: Biobank Mendelian randomization prioritizes 6,447 genes and nominates ANXA2 for dyslipidemia

    Ferolito BR et al., Human Genetics and Genomics Advances. 7 ( - Meta-analysis of MVP, UK Biobank and FinnGen with Mendelian randomization using eQTL/pQTL instruments implicates 6,447 genes and 69,669 causal gene-trait links. Study Highlights: The authors meta-analyzed GWAS from MVP, UK Biobank, and FinnGen across 2,003 harmonized phenotypes and used cis-eQTLs and cis-pQTLs from GTEx, eQTLGen, ARIC, Fenland, and deCODE to perform two-sample Mendelian randomization. They identified 69,669 significant gene-trait pairs (p ≤ 1.6×10⁻⁹) representing 6,447 genes with strong causal evidence and performed colocalization and sensitivity analyses to assess concordance. An XGBoost classifier trained on ChEMBL-derived approved targets and engineered biological features achieved a precision-recall AUC of 0.79 to rank MR hits by likelihood of clinical success. The resource yields rediscoveries and repurposing leads (e.g., ANXA2 nominated for lipid regulation) and supplies a prioritized list for downstream target evaluation. Conclusion: Integrating >1.2 million individuals' GWAS from large biobanks with eQTL/pQTL Mendelian randomization and orthogonal annotations yields 69,669 candidate causal gene-trait links and a machine-learning ranking that prioritizes targets for drug development. Music: Enjoy the music based on this article at the end of the episode. Reference: Ferolito BR, Dashti H, Giambartolomei C, Peloso GM, Golden DJ, Gravel-Pucillo K, Rasooly D, Horimoto ARV R, Matty R, Gaziano L, Liu Y, Smit IA, Zdrazil B, Tsepilov Y, Costa L, Kosik N, Huffman JE, Tartaglia GG, Bini G, Proietti G, Ioannidis H, Karim MA, Hunter F, Hemani G, Butterworth AS, Di Angelantonio E, Langenberg C, Ghoussaini M, Leach AR, Liao KP, Damrauer S, Selva LE, Whitbourne S, Tsao PS, Moser J, Gaunt T, Cai T, Whittaker JC, Million Veteran Program, Casas JP, Muralidhar S, Gaziano JM, Cho K, Pereira AC. Leveraging large-scale biobanks for therapeutic target discovery. Human Genetics and Genomics Advances. 7 (2026) 100556. https://doi.org/10.1016/j.xhgg.2025.100556. 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/biobank-mendelian-randomization-targets Chapters (00:00:00) - Base by Bass(00:00:31) - Seeking the cause of disease with a single trial(00:03:01) - The Mendelian randomization study(00:07:51) - The Machine-Learning Drug Hunter(00:10:49) - Treasure Hunt for old drugs(00:12:07) - The New Way to Lower Cholesterol(00:16:19) - Finding the cures to diseases by sequencing their genomes

    21 min

  3. -2 J

    300: Population-scale WGS links MHC class II antigen presentation to persistent Epstein–Barr virus (EBV) DNA

    Nyeo SS et al., Nature - Population-scale WGS reanalysis quantifies persistent EBV DNA and shows MHC class II–mediated antigen presentation predicts EBV DNAemia and links to autoimmune and respiratory disease. Study Highlights: Using whole-genome sequencing from UK Biobank (n≈490,560) and All of Us (n≈245,394), the authors extracted chrEBV-mapping reads, masked low-mappability regions, and defined EBV DNAemia (>1.2 genomes per 10^4 cells) in 9.7–11.9% of donors. They performed PheWAS, GWAS and ExWAS and identified 22 genome-wide significant loci and 686 missense variants across 148 genes with heritability enrichment in immune regulatory regions and B cells/antigen-presenting cells. Single-cell module scoring, pathway analyses and NetMHCpan/NetMHCIIpan peptide-presentation modeling implicated variable antigen processing and MHC class II presentation as primary determinants of EBV persistence, with stronger predicted presentation linked to lower EBV DNAemia. EBV DNAemia was reproducibly associated with autoimmune, respiratory, neurological and cardiovascular phenotypes across cohorts. Conclusion: Reanalysis of population-scale WGS demonstrates that host genetic variation—predominantly in antigen processing and MHC class II peptide presentation—modulates persistent EBV DNA in blood and associates with multiple complex diseases. Music: Enjoy the music based on this article at the end of the episode. Reference: Nyeo SS, Cumming EM, Burren OS, Pagadala MS, Gutierrez JC, Ali TA, Kida LC, Chen Y, Chu H, Hu F, Zou XZ, Hollis B, Fabre MA, MacArthur S, Wang Q, Ludwig LS, Dey KK, Petrovski S, Dhindsa RS & Lareau CA. Population-scale sequencing resolves determinants of persistent EBV DNA. Nature. 2026 Feb 19;650:664–672. https://doi.org/10.1038/s41586-025-10020-2 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/ebv-mhc-class-ii Chapters (00:00:00) - Base by Base(00:00:28) - A viral ghost in my body(00:03:32) - Herpes virus: When it's active, how to spot it(00:05:42) - The Hidden EBVD Genome(00:08:45) - The smoking gun in chronic fatigue(00:14:01) - Does Your Genetic Lock Fit With EBV?(00:19:01) - Finding the Secret of the Immune Program

    22 min

  4. -3 J

    299: UFM1 loss and R81C mutation disrupt neuronal translation, ER stress, and synaptogenesis

    Perdigão C et al., EMBO Molecular Medicine - In mouse neurons, UFM1 loss or UFM1-R81C expression reduces protein translation, triggers ER stress and PERK activation, impairing dendrite and synapse development. Study Highlights: Using murine UFM1-deficient neurons generated by conditional knockout and CRISPR/Cas9 in vivo manipulations and lentiviral rescue, the study combined FUNCAT, puromycin labeling, patch-clamp electrophysiology, RNA-seq, mass spectrometry, TEM tomography, and in vitro UFMylation assays. UFM1 loss caused reduced dendrite complexity, a ~70% drop in colocalized synaptic puncta, decreased EPSC amplitudes and RRP size, induction of ER stress and PERK-UPR activation, and a substantial reduction in global protein translation. The UFM1-R81C variant was hypomorphic: it partially rescued morphology and function but showed drastically impaired activation by the E1 enzyme UBA5 and an aggravated ER-stress response to thapsigargin. Pharmacologically, Trazodone normalized translation in UFM1-R81C neurons and increased synapse numbers in both UFM1-KO and UFM1-R81C conditions, linking UPR/translation modulation to phenotypic rescue. Conclusion: UFMylation is required for neuronal development and function: UFM1 loss and the UFM1-R81C variant impair protein translation and ER homeostasis, and Trazodone restores translation in UFM1-R81C neurons while increasing synapse numbers. Music: Enjoy the music based on this article at the end of the episode. Reference: Perdigão C, Torres J, Magnussen HM, Koch J, Rudashevskaya E, Moschref F, Fiosins M, Benseler F, Wenger S, Nilsson T, Beuermann S, Bonn S, Rizzoli SO, Kulathu Y, Jahn O, Cooper BH, Ambrozkiewicz MC, Rhee JS, Brose N & Tirard M (2026) Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function. EMBO Molecular Medicine. https://doi.org/10.1038/s44321-026-00389-6 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/ 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/ufm1-r81c-neuronal-translation Chapters (00:00:20) - Genetics of encephalopathy: the mystery behind the disease(00:03:40) - UFM1 defects in the brain(00:08:08) - What Happened to Myelation in Tertiary neurons?(00:10:49) - Fixing the RA1C mutation in the brain(00:15:42) - UFM1 regulates synaptic firing in the brain(00:16:41) - A Small Voice for the Cell

    21 min

  5. -4 J

    298: Bi-allelic FSD1L variants in retinitis pigmentosa implicate photoreceptor axoneme

    Lin S et al., The American Journal of Human Genetics 113, 1–11 ( - Bi-allelic FSD1L variants cause retinitis pigmentosa; FSD1L localizes to the photoreceptor axoneme and a deep intronic deletion abolishes retina-enriched exon 10b inclusion. 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: Enjoy the music based on this article at the end of the episode. 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 Chapters (00:00:11) - The missing heritability of inherited retinal diseases(00:03:00) - Globally, retinal disease 1, Introduction(00:04:14) - The genetic cause of blindness(00:08:28) - The secret to retinitis pigmentosa(00:13:54) - Deep Dive into the dark corners of the genome(00:17:21) - Follow the Light Along the Axle

    20 min

  6. -5 J

    297: Bi-allelic FSD1L variants disrupt mitotic spindle and ciliogenesis in an L1-like neurodevelopmental disorder

    Serpieri V et al., The American Journal of Human Genetics. 113, 1–16 (March 5 - 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. 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: Enjoy the music based on this article at the end of the episode. 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 Chapters (00:00:20) - The genetic sleuths who solved a brain disease(00:03:50) - GeneMatch: The L1 Syndrome match(00:08:57) - FSD1L protein deficiency in the brain(00:11:26) - Why does L1 syndrome look so much like FSD1L(00:16:41) - Many single diseases are actually clusters of lookalikes, according to Bass(00:18:25) - A Story of Connections

    21 min

  7. -6 J

    296: snaR-A ncRNA antagonizes U2 snRNP SF3B2 to drive intron retention in human cells

    Zhou S et al., Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations. Nature Communications - snaR-A noncoding RNA interacts with U2 snRNP subunit SF3B2 and nuclear speckles, increasing intron retention and promoting proliferation in human cancer-relevant cells. 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. 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 Chapters (00:00:20) - Cancer's editing room: The heist(00:03:27) - The SNAR A saboteur(00:07:14) - Snarra disrupts the splicing machinery(00:11:53) - Snare A in lung cancer(00:16:50) - A whisper in the dark

    21 min

  8. -6 J

    295: CFTR deltaF508 and CF-risk variants protect against IBD in large exome study

    Yu M et al., Cell Genomics. 6 ( - 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. 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. 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

    28 min
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Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time. Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.

Informations

  • Création
    Gustavo Barra
  • Années d’activité
    2025 - 2026
  • Épisodes
    302
  • Classification
    Tous publics
  • Copyright
    © Gustavo Barra
  • Site web de l’émission
    Base by Base