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. -17 h

    409: A systems-level atlas of carbon-response transcriptional states in Escherichia coli

    Shin J et al., PNAS - This episode examines a large transcriptome compendium (PRECISE-NP881) that profiles E. coli K-12 MG1655 across 43 carbon substrates. Independent component analysis resolved 137 iModulons, including 25 carbon-catabolism modules that organize substrates into four activity-defined groups tied to growth rate, substrate chemistry, metabolic entry routes, and proteome allocation. The study integrates growth phenotyping, FBA/ME-modeling, targeted knockouts, and reanalysis of a starvation/refeeding time course to connect transcriptional modules to physiological context. Key terms: carbon response, iModulon, Escherichia coli, carbon catabolite repression, transcriptional regulatory network. Study Highlights: The authors assembled PRECISE-NP881 (881 transcriptomes) and used ICA to define 137 iModulons, 25 of which are carbon-catabolism modules whose activities cluster substrates into four groups. Faster-growing sugars showed limited CRP-linked remodeling while slower-growth, non-glycolytic substrates activated CRP-linked, NtrC-1, Propionate, and SgcABCEQX iModulons. Targeted knockouts (e.g., ΔprpC) demonstrated conditional growth defects on Group C/D substrates supporting a role for methylcitrate-mediated propionyl-CoA processing. Proteome-allocation modeling and projection of an independent starvation/refeeding dataset corroborated links between carbon-response modules, growth/stress physiology, and metabolite dynamics. Conclusion: The paper provides a quantitative atlas of carbon-responsive transcriptional states in E. coli, decomposing CCR into separable CRP-linked and substrate-specific modules and linking these modules to growth rate, metabolic context, proteome allocation, and conditional physiological relevance. Music: Enjoy the music based on this article at the end of the episode. Article title: A systems-level atlas of carbon-response transcriptional states in Escherichia coli First author: Shin J Journal: PNAS DOI: 10.1073/pnas.2531884123 Reference: Shin J, Son HF, Krishnan J, Hefner Y, Szubin R, Sung J, Patel A, Lou XA, Catoiu EA, Palsson BØ, Zielinski DC. A systems-level atlas of carbon-response transcriptional states in Escherichia coli. PNAS. 2026;123(27):e2531884123. doi:10.1073/pnas.2531884123. 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/atlas-carbon-response-transcriptional-states-e-coli QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-07. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript sections describing PRECISE-NP881 atlas construction ( ICA/iModulons ), four substrate groups (A–D), CRP decomposition into Crp-1/Crp-2/Crp-3, NtrC-1 and Propionate iModulons linked to propionyl-CoA stress, methylcitrate pathway (prpC/astC), SgcABCEQX prophage iModulon, starvation/refeeding dynam - transcript topics: ICA-based iModulon analysis; CRP-linked iModulons decomposition (Crp-1, Crp-2, Crp-3); Four substrate groups (A–D) and growth phenotypes; NtrC-1 and Propiona...

    27 min

  2. -1 j

    408: Tau, mitochondria, and the fusion switch

    Tsakiria E et al., Proceedings of the National Academy of Sciences (PNAS) - Using Tau knockout mice and the C. elegans PTL-1 deletion, this study shows that loss of wild-type Tau promotes a conserved shift toward mitochondrial fusion, increases respiratory activity, membrane potential and mitophagy, raises ROS, and enhances stress resilience. The adaptive phenotypes depend on mitofusin/FZO-1 and are phenocopied by FZO-1 overexpression. Key terms: Tau protein, mitochondrial fusion, mitofusin (FZO-1), mitophagy, neurodegeneration. Study Highlights: Across mouse and nematode models, Tau/PTL-1 deficiency increased basal and ATP-linked respiration, mitochondrial membrane potential, and ROS while enhancing mitophagy. Loss of Tau shifted mitochondrial morphology toward a pro-fusion state with increased mitofusin (Mfn1/2/FZO-1) localization and reduced Drp1 recruitment. Genetic removal of the mitofusin FZO-1 abolished the enhanced bioenergetics, motility, longevity under stress, and stress resistance, whereas FZO-1 overexpression phenocopied key Tau-loss features. These results identify a conserved, mitofusin-dependent mechanism by which wild-type Tau restrains mitochondrial fusion and functional adaptation. Conclusion: Wild-type Tau acts as a conserved negative regulator of mitochondrial fusion and functional adaptation; its loss triggers FZO-1/mitofusin-dependent mitochondrial remodeling that elevates bioenergetics and stress resilience in a context-dependent manner. Music: Enjoy the music based on this article at the end of the episode. Article title: Tau protein as a regulator of mitochondrial function and dynamics First author: Tsakiria E Journal: Proceedings of the National Academy of Sciences (PNAS) DOI: 10.1073/pnas.2521642123 Reference: Tsakiria E., Campos-Marques C., Ferreira I.L., Trougakos I.P., Dioli C., Gianniou D.D., Silva J.M., Skourti K., Roussos A., Samiotaki M., Sotiropoulos I., Palikaras K., et al. Tau protein as a regulator of mitochondrial function and dynamics. Proc Natl Acad Sci U S A. 2026; doi:10.1073/pnas.2521642123. 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/tau-mitochondrial-fusion-episode-408 QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-06. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantively audited sections covering: WT Tau localization and baseline role; Tau/PTL-1 deficiency effects on respiration and mitophagy; pro-fusion shift and changes in fission/fusion proteins; ROS dynamics and hormetic effects; dependency on FZO-1 and rescue via FZO-1 overexpression; implications for Tau-lowering th - transcript topics: Tau deficiency and mitochondrial respiration (Seahorse data in Tau-KO mice and PTL-1 KO worms); Mitochondrial morphology and fusion/fission regulators (DRP-1, MFN1/MFN2, form factor); Mitophagy dynamics in Tau/PTL-1 deficiency; ROS production and membrane potential changes; ROS-mediated hormesis and antioxidant effects (NAC) across conditions; Genetic dissection...

    25 min

  3. -2 j

    407: SLC11A2 withholds metals from Salmonella in the gut epithelium

    Norberg ES et al., Proceedings of the National Academy of Sciences - Using metal‑responsive fluorescent Salmonella reporters, calf intestinal loops, and CRISPR edited epithelial cells, this study shows that the divalent metal transporter SLC11A2 is recruited to Salmonella‑containing vacuoles and restricts Fe2+ and Mn2+, limiting intracellular bacterial replication. Key terms: SLC11A2, nutritional immunity, Salmonella enterica, iron and manganese, intestinal epithelium. Study Highlights: The authors used metal‑sensing GFP reporters in Salmonella and a calf ligated ileal loop model to map metal availability and found a subpopulation of bacteria in IECs and lamina propria cells exposed to ≤0.1 µM Fe2+ and Zn2+, and possibly Mn2+, early in infection. SLC11A2 localized to the apical surface and endosomal network of IECs and was recruited to maturing Salmonella‑containing vacuoles; CRISPR knockout of SLC11A2 in HCT116 epithelial cells increased bacterial replication. Fluorescent reporters and ICP‑MS indicate vacuolar STm are less starved for Fe2+ and Mn2+ in the absence of SLC11A2, while Zn2+ and Mg2+ sensing was unchanged. Salmonella counters SLC11A2‑mediated restriction through the Mn2+/Fe2+ transporter MntH and siderophore production. Conclusion: SLC11A2 mediates epithelial nutritional immunity by sequestering Fe2+ and Mn2+ in Salmonella‑containing vacuoles, reducing vacuolar metal availability and limiting intracellular Salmonella replication. Music: Enjoy the music based on this article at the end of the episode. Article title: SLC11A2 withholds divalent metals from Salmonella in the gut epithelium First author: Norberg ES Journal: Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.2532675123 Reference: Norberg ES, Knodler LA, et al. SLC11A2 withholds divalent metals from Salmonella in the gut epithelium. PNAS. 2026;123:e2532675123. doi:10.1073/pnas.2532675123 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/slc11a2-withholds-divalent-metals-from-salmonella QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-05. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript sections covering nutritional immunity concepts, IEC-localized SLC11A2 function, calf ileal loop in vivo model, metal-responsive STm reporters, SLC11A2 recruitment to SCVs, SLC11A2 knockout effects in HCT116 cells, bacterial countermeasures (MntH and siderophores), intracellular niches (SCV vs cytoso - transcript topics: Nutritional immunity and trace metal tug-of-war; SLC11A2 (NRAMP2) in intestinal epithelial cells; Calf ligated ileal loop model and metal availability; Metal-responsive Salmonella reporters (iroN, sitA, zinT); SLC11A2 recruitment to Salmonella-containing vacuoles; SLC11A2 knockout in HCT116 cells and impact on Salmonella replication QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 6 - claims flagged for review: 0 - metadata chec...

    22 min

  4. -6 j

    406: Temperature & Age Shape Gut Susceptibility to HCoV-229E

    Synowiec A et al., Proceedings of the National Academy of Sciences (PNAS) - This episode examines a PNAS study using fetal, pediatric, and adult human intestinal enteroids to show that physiological temperature and developmental stage jointly determine susceptibility to HCoV-229E, with implications for extrapulmonary coronavirus infection and therapeutic testing. Key terms: HCoV-229E, intestinal enteroids, temperature sensitivity, age-dependent susceptibility, ANPEP/TMPRSS2. Study Highlights: The authors used age-stratified human intestinal enteroids (HIEs) and compared infection at 32 °C and 37 °C, finding temperature-dependent transcriptional reprogramming. HCoV-229E productively infected HIEs from all ages at 32 °C, but at 37 °C replication was largely restricted to fetal and some pediatric tissues. Enterocytes were identified as the primary target cells and viral progeny were released apically. Inhibition of serine proteases with camostat significantly reduced HCoV-229E replication, supporting a TMPRSS2-like entry dependency. Conclusion: Physiological temperature and developmental maturity create a dual barrier that limits intestinal replication of HCoV-229E in adults at 37 °C while permitting broader replication at cooler, upper-airway-like temperatures; HIEs provide a platform to probe host determinants and test entry-directed inhibitors such as camostat. Music: Enjoy the music based on this article at the end of the episode. Article title: Temperature and developmental stage govern intestinal susceptibility to human coronavirus 229E First author: Synowiec A Journal: Proceedings of the National Academy of Sciences (PNAS) DOI: 10.1073/pnas.2600632123 Reference: Synowiec A., Lie L.K., Szczepański A., et al. Temperature and developmental stage govern intestinal susceptibility to human coronavirus 229E. Proc. Natl. Acad. Sci. U.S.A. 2026;123(26):e2600632123. https://doi.org/10.1073/pnas.2600632123 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/temp-age-hcov-229e-ep406 QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-01. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the portions of the transcript describing: experimental design (age-stratified HIEs at 32°C vs 37°C), replication patterns of HCoV-229E (32°C broad permissivity; 37°C restricted), cell tropism (enterocytes as primary target), entry mechanism (ANPEP receptor, TMPRSS2 proteases), and protease inhibition (camostat - transcript topics: HCoV-229E infection in age-stratified human intestinal enteroids (HIEs); Temperature effects (32 °C vs 37 °C) on replication; Age dependence and donor variability; Cell type tropism and ANPEP/TMPRSS2 entry; Camostat inhibition and entry pathways; Limitations of the HIE model and translational implications QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 4 - 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: - Three age groups of HIEs used: fetal, pediatric, adult - Seasonal HCoV...

    20 min

  5. -6 j

    405: PRDM9 and the Hotspot Trade-off

    Úbeda F et al., Proceedings of the National Academy of Sciences (PNAS) - A population-genetic model explains why sequence-specific PRDM9-guided recombination hotspots can evolve and persist alongside non-PRDM9 hotspots by trading off reduced overall binding for increased symmetric binding that more often yields crossovers. Key terms: PRDM9, recombination hotspots, biased gene conversion, symmetric binding, population genetics. Study Highlights: The authors develop a three-locus population genetic model and run analytical and numerical simulations to compare PRDM9-like (specific) versus non-PRDM9 (unspecific) hotspot mechanisms. They find non-PRDM9 hotspots are generally favored because they yield higher overall binding and more crossovers, but PRDM9 can be favored when symmetric binding more often resolves as crossovers. Intermediate parameter regimes permit stable coexistence or cyclical oscillations in the relative use of both hotspot types. The model makes testable predictions linking chromosome architecture and fertility costs to the evolutionary distribution of hotspot mechanisms. Conclusion: PRDM9 persistence reflects a trade-off: sequence specificity reduces average binding but increases symmetric homolog binding that can disproportionately raise crossover success; when the crossover-resolution advantage of symmetric binding outweighs binding loss, PRDM9 is favored or can coexist with non-PRDM9 mechanisms. Music: Enjoy the music based on this article at the end of the episode. Article title: On the origin of PRDM9-guided recombination hotspots First author: Úbeda F Journal: Proceedings of the National Academy of Sciences (PNAS) DOI: 10.1073/pnas.2535682123 Reference: Úbeda F, Bürger R, Fyon F. On the origin of PRDM9-guided recombination hotspots. Proc Natl Acad Sci U S A. 2026;123(26):e2535682123. doi:10.1073/pnas.2535682123 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/405-prdm9-hotspots QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-01. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript portions describing hotspot mechanisms, symmetric vs asymmetric binding, the three-locus model (modifier M, targeting A, target B), key results (dominance of non-PRDM9, potential PRDM9 advantage with symmetric binding, coexistence and oscillations), phylogenetic patterns and chromosome-size impli - transcript topics: PRDM9-guided recombination vs non-PRDM9 hotspots; Symmetric vs asymmetric binding in recombination; Three-locus population-genetic model (modifier, targeting, target loci); Evolutionary outcomes: dominance, coexistence, oscillations; Phylogenetic distribution and chromosome-size effects QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 4 - 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 hotspot mechanisms exist: PRDM9-guided (specific) and non-PRDM9 (open chromatin, sequence-independent). - PRDM9 hotspots erode via biased gene conversion; non-P...

    24 min

  6. 30 juin

    404: RUNA Reveals Surface DNA on Exosomes

    Bošković F et al., Proceedings of the National Academy of Sciences - This study introduces RUNA, a reversible chemistry that selectively labels uridine/thymidine to map nucleic acids across membranes, and uses it to show that most exosomal DNA is surface-exposed, increases after PARP inhibitor treatment, and alters macrophage uptake and activation. Key terms: RUNA, exosomes, surface DNA, macrophage polarization, PARP inhibitor. Study Highlights: The authors developed Reversible Uridine Nitrilium-mediated Addition (RUNA), which selectively and reversibly modifies the N3 of uridine and thymidine via an in situ nitrilium ion. By varying aldehyde membrane permeability, RUNA distinguishes intra-vesicular from extravesicular nucleic acids. Applied to exosomes from MyC-CaP prostate cancer cells, RUNA shows most exosomal DNA is surface-exposed and nearly doubles after rucaparib (PARP inhibitor) treatment. Surface DNA promotes uptake by M2 macrophages through scavenger receptors and shifts them toward an M1-like proinflammatory profile. Conclusion: RUNA is a modular, reversible chemical tool to map nucleic acid accessibility across membranes; using it the authors reveal exosomal surface DNA as a dynamic, damage-responsive determinant of macrophage uptake and immune modulation with implications for tumor–immune interactions. Music: Enjoy the music based on this article at the end of the episode. Article title: A nucleic acid labeling chemistry reveals surface DNA on exosomes First author: Bošković F Journal: Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.2532281123 Reference: Bošković F, Dutta Gupta P, Zhang J, Szostak JW, Krishnan Y. A nucleic acid labeling chemistry reveals surface DNA on exosomes. Proc Natl Acad Sci U S A. 2026;123(27):e2532281123. doi:10.1073/pnas.2532281123 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/runa-surface-dna-on-exosomes QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-30. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections describing RUNA mechanism, membrane-permeability tuning, exosome surface DNA, PARP-inhibitor effects on surface DNA, exosome uptake by M2 macrophages, macrophage polarization to an M1-like state, and study limitations. - transcript topics: RUNA mechanism and reversibility; Membrane permeability tuning to distinguish exRNA vs vesicular RNA; Exosome DNA topology: surface-exposed vs luminal; PARP inhibitor (rucaparib) effects on surface DNA; Exosome uptake by M2 macrophages via scavenger receptors; Macrophage polarization to M1-like state and cytokine changes 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: - RUNA selectively labels uridine and thymidine at N3 to form a reversible covalent adduct. - The RUNA adduct is thermally reversible by heating (e.g., 95 C for 15 minutes). - Membrane-permeable vs membrane-impermeable aldehydes distinguish total...

    21 min

  7. 26 juin

    403: HRD-GIS Evidence for BRCA1/2 Variant Classification

    Schnaiter et al et al., The American Journal of Human Genetics - Schnaiter et al. pooled Myriad MyChoice HRD+ CDx results from four cohorts (4,943 HGOC tumors) to test whether tumor HRD-related genomic instability scores (HRD-GIS) provide evidence for BRCA1 and BRCA2 variant classification under ACMG/AMP criteria. Key terms: homologous recombination deficiency, genomic instability score (HRD-GIS), BRCA1, BRCA2, MyChoice HRD+ CDx. Study Highlights: The authors analyzed 4,943 tumors (765 BRCApv, 4,178 BRCAwt) assessed with the MyChoice HRD+ CDx assay and found 91.0% of BRCApv tumors were GIShigh (≥42) versus 30.0% of BRCAwt. The pooled likelihood ratio (LR) that a variant is pathogenic in a GIShigh HGOC was 3.03 (95% CI: 2.88–3.19), mapping to supporting pathogenic evidence. Conversely, the pooled LR for GISlow (42) was 0.13 (95% CI: 0.10–0.16), mapping to moderate benign evidence. Results were consistent across three cohorts but limited by assay type, cohort composition, and incomplete second-hit and germline/somatic data. Conclusion: HRD-GIS measured by the MyChoice HRD+ CDx assay in HGOC yields statistically robust evidence that can be applied within ACMG/AMP variant interpretation: GIShigh supports pathogenicity (supporting strength) and GISlow supports benign classification (moderate strength), potentially improving BRCA1/2 VUS resolution. Music: Enjoy the music based on this article at the end of the episode. Article title: Homologous recombination deficiency-driven genomic instability in ovarian cancer as an indicator of BRCA1 and BRCA2 variant pathogenicity First author: Schnaiter et al Journal: The American Journal of Human Genetics DOI: 10.1016/j.ajhg.2026.05.015 Reference: Schnaiter et al., 2026, The American Journal of Human Genetics 113, 1–8. https://doi.org/10.1016/j.ajhg.2026.05.015 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/hrd-gis-brca-variant-pathogenicity QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-26. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript's coverage of HRD-GIS mechanism, BRCA1/BRCA2 variant interpretation via ACMG/AMP LR framework, threshold 42 (GIShigh vs GISlow), cohort data (Marburg, NHS, Study 19, NOVA), the Myriad MyChoice HRD+ CDx assay, and discussed limitations (second hits, germline vs somatic, assay-specific validation). - transcript topics: HRD-GIS mechanism in HGOC; BRCA1/BRCA2 function and HRD; Genomic scar metrics: LOH, TAI, LST; GIS scoring threshold and GIShigh/GISlow; Likelihood ratio framework and ACMG/AMP evidence mapping; Cohort data and Myriad MyChoice HRD+ CDx validation 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: - HRD-GIS is a composite of LOH, telomeric allelic imbalance (TAI), and large-scale state transitions (LST). - GIS high is GIS ≥ 42; GIS low is GIS 42. - Dataset comprised 4,943 HGOC tumors (765 BRCApv, 4,178 BRCAwt...

    23 min

  8. 25 juin

    402: When Polygenic Scores Miss: Rare Variants in Misaligned Individuals

    Baya N et al., The American Journal of Human Genetics 113, 1–19 (2026) - Baya et al. applied a misalignment framework to UK Biobank polygenic scores and exomes and found that individuals whose observed phenotypes deviate from polygenic expectation are enriched for rare damaging variants across multiple traits and diseases. Key terms: polygenic scores, rare variants, misalignment, liability threshold, UK Biobank. Study Highlights: The authors define 'misaligned' individuals whose covariate-residualized phenotypes differ markedly from PGS expectation and test enrichment for rare (MAF 0.1%) pLoF and damaging missense variants. In UK Biobank Europeans they replicate enrichments for canonical genes (e.g., ACAN, IGF1, APOB, LDLR) and identify novel exome-wide associations including COPB2, GORAB, KANK1, and ACSL6. Disease analyses support a liability-threshold model: T2D cases with HNF1A/HNF4A pLoFs had lower PRS, and CAD controls with protective ANGPTL3 variants had higher PRS. Misalignment classification helps prioritize individuals for rare-variant screening and can reveal pathogenic or protective genetic contributors. Conclusion: Deviation from polygenic expectation highlights individuals enriched for rare damaging variants, supporting a liability-threshold model where rare and common variants counteract or augment each other and offering a strategy to prioritize rare-disease genetic discovery. Music: Enjoy the music based on this article at the end of the episode. Article title: Individuals who deviate from polygenic expectation are enriched for damaging variants in genes linked to rare disease First author: Baya N Journal: The American Journal of Human Genetics 113, 1–19 (2026) DOI: 10.1016/j.ajhg.2026.05.013 Reference: Baya N.A., Lassen F.H., Hill B., Venkatesh S.S., Currant H., Lindgren C.M., Palmer D.S., Individuals who deviate from polygenic expectation are enriched for damaging variants in genes linked to rare disease, The American Journal of Human Genetics 113, 1–19 (2026). doi:10.1016/j.ajhg.2026.05.013 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/polygenic-misalignment-rare-variants QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-25. 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 misalignment framework, continuous-trait enrichments (height-related ACAN/IGF1, FBN1 for tall stature, LDL-C genes), BMD findings (COPB2/GORAB), LDL-C/HDL gene burdens (LDLR/APOB/PCSK9), dichotomous-trait results (T2D with HNF1A/HNF4A, CAD ANGPTL3), exome-wide discovery (7 - transcript topics: Phenotypic misalignment framework and liability-threshold model; Continuous-trait misalignment analyses (height, LDL-C, BMI, BMD, HbA1c, IOP, age at menopause); Canonical gene enrichment for height and LDL-C (ACAN, IGF1, SHOX; LDLR, APOB, PCSK9); Damaging variant enrichment in FBN1 for height misalignment (taller-than-expected); Exome-wide discovery of misalignment genes (KANK1, ACSL6, NPL, COPB2, GORAB); Dichotomous-trait misalignment (T2D/HNF1A/HNF4A; CAD/ANGPTL3; OP) QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 6 - claims flagge... Chapters (00:00:20) - What happens when your genetic destiny defies the odds?(00:02:51) - Polygenic scores: The financial(00:05:21) - Seeking rare genetic mutations in heart disease(00:09:48) - The genetic risk of heart disease(00:13:14) - Genetic misalignment: The future of disease triage

    20 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
    411
  • Classification
    Tous publics
  • Copyright
    © Gustavo Barra
  • Site web de l’émission
    Base by Base

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