Base by Base

Gustavo Barra
  • 3.0 (2)
  • Life Sciences
  • Updated Daily

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. 3h ago

    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

  2. 15h ago

    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

  3. 5d ago

    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

  4. 5d ago

    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

  5. Jun 23

    401: LDB1 variants split neurodevelopmental outcomes by location and mechanism

    Fluri R et al., The American Journal of Human Genetics - This episode examines a cohort study of 16 individuals with de novo LDB1 variants that reveals two overlapping but distinct neurodevelopmental phenotypes tied to variant location. Functional assays and Drosophila models demonstrate loss-of-function effects for N-terminal variants and dominant-negative effects for C-terminal variants. Key terms: LDB1, neurodevelopmental disorder, ventriculomegaly, dominant-negative, haploinsufficiency. Study Highlights: The authors assembled 16 individuals with de novo LDB1 variants and mapped variants to the N-terminal dimerization domain or the C-terminal LIM interaction domain. In vitro assays showed N-terminal missense variants disrupt homodimerization leading to loss of function, while C-terminal variants impair LHX2 binding and act in a dominant-negative manner. Drosophila knockdown and overexpression corroborated dosage sensitivity and distinct in vivo effects, including rescue by wild-type LDB1 and worsening by C-terminal variants. Clinically, C-terminal LID-affecting variants associate with congenital ventriculomegaly and more frequent extra‑neural anomalies, whereas N-terminal variants tend to cause variable NDD without consistent brain malformations. Conclusion: Variant location in LDB1 predicts distinct pathomechanisms and overlapping clinical presentations: N-terminal variants cause haploinsufficiency/loss of function, while C-terminal LID variants act dominant-negatively and are linked to ventriculomegaly and broader organ involvement. Music: Enjoy the music based on this article at the end of the episode. Article title: De novo variants in LDB1 are linked to distinct neurodevelopmental phenotypes determined by variant location and differing pathomechanisms First author: Fluri R Journal: The American Journal of Human Genetics DOI: 10.1016/j.ajhg.2026.05.012 Reference: Fluri R., Coll-Tané M., Brunet T., et al. De novo variants in LDB1 are linked to distinct neurodevelopmental phenotypes determined by variant location and differing pathomechanisms. The American Journal of Human Genetics. 2026;113:1–15. doi:10.1016/j.ajhg.2026.05.012 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/ldb1-variant-location-pathomechanisms QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-23. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections describing LDB1 structure (DD and LID), variant spectrum (N-terminal vs C-terminal), two mechanisms (haploinsufficiency vs dominant-negative), cellular assays (protein levels, ubiquitination, aggregates), LDB1-LHX2 interactions, Drosophila chi model (dosage sensitivity, rescue/toxicity, sleep), and cli - transcript topics: LDB1 structure and domains (DD and LID); Variant spectrum across LDB1 (N-terminal vs C-terminal); Mechanisms: haploinsufficiency and dominant-negative effects; Cellular assays: protein stability, ubiquitination, aggregates; LDB1 interactions: dimerization and LHX2 binding; Drosophila model chi (chip) dosage sensitivity and experiments QC Summary: - factual score: 9/10 - metadata score: 10/10 - supported core claims: 7 - claims flagged for review: 1... Chapters (00:00:20) - Beyond the genetic blueprint of neurodevelopmental disorders(00:02:51) - Common mutations in the LDB1 gene cause congenital ventric(00:08:42) - Mutations in the LDB1 gene cause severe brain dysfunction(00:14:24) - C terminal variant causes sleep disorders in flies

    24 min

  6. Jun 23

    400: Complete chromosome 21 centromere sequencing and Down syndrome

    Mastrorosa F et al., The American Journal of Human Genetics - Long-read assemblies and epigenetic mapping of chromosome 21 centromeres in families with trisomy 21 reveal centromere size diversity, two cases of extreme maternal centromere size asymmetry, and no global enrichment of small centromeres in affected individuals. Key terms: trisomy 21, centromere, alpha-satellite, long-read sequencing, meiotic nondisjunction. Study Highlights: Using PacBio HiFi and ultra-long ONT reads with hybrid assembly and DiMeLo-seq, the authors fully resolved chr21 centromeres in eight T21 individuals and several parents and compared them to 287 population haplotypes. Small centromeres were not overall enriched in T21 cases, contradicting earlier reports, but two families showed extreme (>10-fold) maternal centromere size asymmetry. CDRs and CENP-A/CENP-C signals were present across haplotypes and methylation profiles were largely conserved between generations and sample types. Phylogenetic analysis indicates recent rapid evolution of chr21 centromere haplotypes that may facilitate such asymmetry. Conclusion: Centromere size alone does not explain trisomy 21 risk at the population level, but extreme maternal centromere size asymmetry appears in a minority of families and may contribute to nondisjunction in those cases. Music: Enjoy the music based on this article at the end of the episode. Article title: Complete chromosome 21 centromere sequencing of families with Down syndrome First author: Mastrorosa F Journal: The American Journal of Human Genetics DOI: 10.1016/j.ajhg.2026.05.010 Reference: Mastrorosa F.K., Daponte A., de Gennaro L., et al. Complete chromosome 21 centromere sequencing of families with Down syndrome. The American Journal of Human Genetics. 113, 1–18 (2026). https://doi.org/10.1016/j.ajhg.2026.05.010 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/chr21-centromere-sequencing-down-syndrome QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-23. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript sections covering centromere structure, long-read sequencing workflow, extreme centromere size asymmetry findings, CpG/epigenetic mapping (CDRs, CENP-A/CENP-C), and population/evolutionary context. - transcript topics: Centromere structure and alpha-satellite HOR arrays; Maternal nondisjunction and Down syndrome etiology; Long-read sequencing technologies and hybrid phasing; Epigenetic centromere mapping (CDRs, CENP-A/CENP-C, CpG methylation); Centromere size asymmetry in Down syndrome families; Population diversity of chr21 centromeres (African ancestry four-mer HOR) 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: - Small chr21 centromeres are not enriched in Down syndrome cases compared with controls (p = 0.72). - Extreme centromere size asymmetry (>10-fold) observed in two Down syndrome families (e.g., 10.7-fold... Chapters (00:00:20) - Down Syndrome: The mystery of the cell division(00:04:45) - Down Syndrome: The repetitive DNA handles(00:09:49) - Down Syndrome: The tug of war(00:14:16) - The genetics of trisomy 21(00:15:58) - Down Syndrome: The mystery of the genetic cause(00:20:13) - A Single Link in the Code

    23 min

  7. Jun 22

    399: Ménière disease: inner ear development and retinoic acid pathways

    Shi Z et al., The American Journal of Human Genetics - A large GWAS meta-analysis across five biobanks (8,969 cases, 1,962,542 controls) identifies five genome-wide significant loci for Ménière disease, implicating developmental regulators EYA1/EYA4 and retinoic acid metabolism genes including CYP26A1. Integrative fine-mapping, eQTL, and single-cell expression place these signals in inner ear cell types and link MD to related sensory and neurological traits. Key terms: Ménière disease, EYA1, EYA4, retinoic acid, GWAS. Study Highlights: A GWAS meta-analysis of 8,969 Ménière disease cases and 1,962,542 controls across five biobanks identified five independent genome-wide significant loci, including two signals each at EYA4 and EYA1 and one near CYP26A1. Observed-scale SNP heritability was estimated at 7% (SE 0.8%), indicating a modest contribution of common variation. Fine-mapping, eQTL and single-cell expression data implicate dysregulation of inner ear developmental regulators and retinoic acid metabolism. Phenome-wide and genetic-correlation analyses reveal shared architecture with vertigo, tinnitus, hearing loss, migraine, and sleep apnea. Conclusion: Regulatory common variants in genes governing inner ear development (EYA1, EYA4) and retinoic acid signaling (CYP26A1/C1, ALDH1A2) contribute to Ménière disease risk, providing a genetic framework for functional follow-up and polygenic risk modeling. Music: Enjoy the music based on this article at the end of the episode. Article title: Genome-wide analysis implicates inner ear development in Ménière disease First author: Shi Z Journal: The American Journal of Human Genetics DOI: 10.1016/j.ajhg.2026.05.011 Reference: Shi Z, Mandla R, Li J, et al. Genome-wide analysis implicates inner ear development in Ménière disease. The American Journal of Human Genetics. 2026;113:1–12. https://doi.org/10.1016/j.ajhg.2026.05.011 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/base-by-base-399-meniere-inner-ear QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-22. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantive audit of the transcript's representation of GWAS scale, loci and genes (EYA4, EYA1, CYP26A1, ALDH1A2, LMO4), developmental/retinoic acid pathways, genetic correlations, limitations, and future directions as reported in the canonical article. - transcript topics: Genome-wide association study scale and meta-analysis across five biobanks; Identification of five independent signals: two at EYA4, two at EYA1, one near CYP26A1; EYA4 and EYA1 as developmental regulators of inner ear; Regulatory vs coding variants and gene expression implications; Retinoic acid signaling pathway involvement: CYP26A1/C1 and ALDH1A2; LMO4 as a suggestive signal and its developmental context 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: - MD SNP-based heritability estimated at 7% (SE 0.8%) on the observ... Chapters (00:00:20) - The genetic basis of Meniere disease(00:02:04) - Scientists solve the genetic mystery of Meniere's disease(00:06:35) - The genetic heritability of Meniere's(00:10:18) - Genetics of Meniere's Disease and gl(00:15:35) - Genetic determinants of Meniere's

    22 min

  8. Jun 21

    398: Modeling JAK2V617F Clonal Expansion in the General Population

    Snyder J et al., Proceedings of the National Academy of Sciences (PNAS) - Longitudinal VAF measurements from 67 JAK2V617F-positive participants in the Danish GESUS study were analyzed with a Moran-process stem cell model and ABC-SMC to infer per-individual self-renewal advantages and assess prognostic value for MPN progression. Key terms: JAK2V617F, clonal hematopoiesis, Moran model, myeloproliferative neoplasms, mathematical modeling. Study Highlights: The study follows 67 individuals from the GESUS cohort with >1% JAK2V617F VAF and multiple follow-up measurements over >10 years. A Moran-process model at the HSC level fitted by ABC-SMC reproduced longitudinal VAF trajectories for 66 of 67 subjects and yielded per-individual estimates of the mutant self-renewal advantage s. Results show heterogeneity: ~70% of subjects had a statistically positive s, ~18% had a negative s, and ~12% were neutral, indicating many carriers show no expansion or even contraction. The fitted model can predict future VAF evolution for most subjects but s alone is not a perfect predictor of MPN diagnosis. Conclusion: A stem-cell Moran-process model explains longitudinal JAK2V617F VAF dynamics in most GESUS participants; inferred selective advantage varies widely, correlates with—but does not fully predict—MPN diagnosis, supporting individualized monitoring and further study of non-VAF risk factors. Music: Enjoy the music based on this article at the end of the episode. Article title: Mathematical modeling of JAK2V617F clonal expansion in a general population cohort First author: Snyder J Journal: Proceedings of the National Academy of Sciences (PNAS) DOI: 10.1073/pnas.2507773123 Reference: Snyder J, Andersen M, Gudmand-Høyer J, et al. Mathematical modeling of JAK2V617F clonal expansion in a general population cohort. Proc Natl Acad Sci U.S.A. 2026;123:e2507773123. doi:10.1073/pnas.2507773123 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/base398-jak2v617f-moran QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-21. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantively audited sections include background on JAK2V617F and MPN, Moran process model with carrying capacity and generation time, ABC-SMC inference of per-subject s, results breakdown (positive/neutral/negative s and 66/67 fit), link between s and MPN progression, inflammation/CRP and statin discussion, and limit - transcript topics: JAK2V617F mutation and myeloproliferative neoplasms biology; Moran process model and stem cell carrying capacity; Inference of per-individual selective advantage (s) via ABC-SMC; VAF trajectories across individuals and fit to the model; Association between s and progression to MPN; imperfect prediction; Inflammation (CRP) and statins as modifiers of clonal dynamics 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: - 67 individuals with >1% JAK2V617F VAF in... Chapters (00:00:00) - Can Your Body Naturally Suppress a Cancer Mutation?(00:05:30) - The genetics of JAK2 cancer(00:10:47) - The Stochastic Selection of MPN(00:16:05) - JAK2 mutation and the immune system

    25 min
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2 Ratings

About

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.

Information

  • Creator
    Gustavo Barra
  • Years Active
    2025 - 2026
  • Episodes
    407
  • Rating
    Clean
  • Copyright
    © Gustavo Barra
  • Show Website
    Base by Base

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