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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 HCoVs tested; primary focus on HCoV-229E
- 32 °C supports robust replication of HCoV-229E across all donor ages with apical release
- 37 °C largely restricts replication to fetal and some pediatric tissues; adults show resistance
- Enterocytes identified as main target cells for HCoV-229E
- Camostat markedly reduces HCoV-229E replication; serine protease dependence demonstrated

QC result: Pass.

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-PRDM9 hotspots are self-preserving.
- Symmetric binding increases crossovers; asymmetric binding reduces crossover probability.
- Model uses three loci: modifier M, targeting A, and target B; binding outcomes include symmetric, asymmetric, or none.
- When symmetric and asymmetric bindings are equally likely to resolve as crossovers, non-PRDM9 is the evolutionarily stable state.
- If symmetric binding has a crossover-resolution advantage (ρs > ρa), PRDM9 can be favored or coexist with non-PRDM9.

QC result: Pass.

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 vs extravesicular nucleic acids.
- Exosomes carry DNA on their outer surface; surface DNA abundance increases with PARP inhibitor treatment.
- Surface DNA drives uptake of exosomes by M2 macrophages via scavenger receptors.
- Uptake of surface-DNA–bearing exosomes shifts macrophages toward an M1-like pro-inflammatory state (IL-12, TNF-α, iNOS, CCL2 up; arginase-1 down).

QC result: Pass.

Schnaiter S et al., The American Journal of Human Genetics - Pooled analysis of four cohorts (4,943 tumors) using the Myriad MyChoice HRD+ CDx assay quantified how HRD-related genomic instability scores (HRD-GIS) predict BRCA1 and BRCA2 variant pathogenicity and mapped likelihood ratios to ACMG/AMP evidence strengths. Key terms: homologous recombination deficiency, HRD-GIS, BRCA1, BRCA2, ovarian cancer.

Study Highlights:
Schnaiter et al. pooled Myriad MyChoice HRD+ CDx results from four cohorts totaling 4,943 high-grade ovarian tumors to assess whether tumor HRD-GIS predicts BRCA1/2 variant pathogenicity. They observed 91.0% of BRCApv tumors were GIShigh versus 30.0% of BRCAwt tumors. The pooled likelihood ratio for a variant being pathogenic in a GIShigh tumor was 3.03 (95% CI 2.88–3.19), equivalent to supporting pathogenic evidence, while GISlow had a pooled LR of 0.13 (95% CI 0.10–0.16), equivalent to moderate benign evidence. Results apply to HGOC samples assessed with the MyChoice assay and may aid ACMG/AMP variant classification, with noted cohort and assay limitations.

Conclusion:
HRD-GIS determined by the MyChoice HRD+ CDx assay in HGOC provides supporting evidence for BRCA1/2 pathogenicity when GIShigh and moderate benign evidence when GISlow, supporting its integration into ACMG/AMP variant interpretation.

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 S

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.05.015

Reference:
Schnaiter S., Santer F.R., Csanaky K.A., et al. Homologous recombination deficiency-driven genomic instability in ovarian cancer as an indicator of BRCA1 and BRCA2 variant pathogenicity. The American Journal of Human Genetics. 113, 1–8 (2026). 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-classification

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 the transcript sections describing BRCA1/BRCA2 biology, genomic scars (LOH, TAI, LSTs), GIS scoring with MyChoice HRD+ CDx, Bayesian/ACMG interpretation, cohort details, and clinical implications, comparing them to the original article.
- transcript topics: BRCA1 and BRCA2 role in homologous recombination; Genomic scar signatures: LOH, telomeric allelic imbalance, large-scale state transitions; Genomic instability score (GIS) and Myriad MyChoice HRD+ CDx assay; Bayesian LR framework and ACMG/AMP variant interpretation; Cohort details: Marburg, NHS, Study 19, NOVA; limitations (germline vs somatic, HGOC focus); Clinical implications for BRCA variant classification and VUS

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 uses LOH, telomeric allelic imbalance (TAI), and large-scale state transitions (LSTs) to quantify genomic instability
- GIS threshold for HRD-GIS positivity is GIS >= 42; GIS < 42 is negative
- Cohorts analyzed: Marburg, NHS, Study 19, NOVA; total 4,943 tumor samples; 765 BRCApv and 4,178 BRCAwt
- BRCApv GIShigh proportion 91.0%; BRCApv GISlow proportion 9.0% (as reported); BRCAwt GIShigh 30.0%; BRCAwt GISlow 70.0%
- Likelihood ratios: LR for BRCA1/BRCA2 pathogenic in GIShigh HGOC = 3.03 (CI 2.88–3.19); LR for GISlow = 0.13 (CI 0.10–0.16)

QC result: Pass.

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).
- Among BRCApv, 91.0% were GIShigh; among BRCAwt, 30.0% were GIShigh.
- LR for BRCA1/BRCA2 variant pathogenicity in GIShigh HGOC: 3.03 (95% CI 2.88–3.19) → supporting pathogenic evidence.
- LR for BRCA1/BRCA2 variant pathogenicity in GISlow HGOC: 0.13 (95% CI 0.10–0.16) → moderate benign evidence.

QC result: Pass.

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 flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Misaligned individuals enriched for rare damaging variants in canonical genes for height/LDL-C (ACAN, IGF1; FBN1 for tall stature; LDLR/APOB/PCSK9 for LDL-C effects).
- Higher-than-expected vs lower-than-expected stature linked to pLoF in ACAN/IGF1 and damaging missense in FBN1, respectively.
- Dichotomous traits (T2D, CAD, OP) show enrichment patterns: T2D cases with low PRS enriched for pathogenic pLoF in HNF1A/HNF4A; CAD controls with protective ANGPTL3 pLoF enriched f
- Exome-wide scan identified 74 significant genes; KANK1 and ACSL6 highlighted among BMI-related findings; NPL linked to BMI; KANK1 linked to AAM.
- BMI lower-than-expected misalignment associated with NPL and ACSL6; AAM higher-than-expected associated with KANK1.
- Non-genetic factors (SES, cholesterol-lowering medication, smoking, exercise) correlate with misalignment; population ancestry limitation noted (European only).

QC result: Pass.

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
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Two distinct LDB1-related neurodevelopmental phenotypes based on variant location (N-terminal LoF/haploinsufficiency vs C-terminal dominant-negative)
- N-terminal DD missense variants Arg121Trp and Arg193Trp impair LDB1 homodimerization (loss of function)
- C-terminal LID-disrupting variants impair LDB1-LHX2 interaction and act in a dominant-negative manner
- C-terminal frameshift variants increase LDB1 protein levels and form nuclear aggregates via altered ubiquitination
- N-terminal DD variants can decrease protein stability in some contexts
- Co-expression assays show dominant-negative interference of C-terminal variants with wild-type LDB1/LHX2 interactions

QC Flagged Items (audited and not fully supported):
- Core claim uncertain: The Arg181Gln variant remains a VUS with uncertain functional effect.

QC result: Warning. Items above were flagged during automated QC; the editorial team reviewed them before release.

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:
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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 and 19.4-fold differences).
- Centromeric CpG methylation and CENP-A/CENP-C occupancy show no major epigenetic differences among haplotypes; CDRs map to kinetochore attachment sites.
- Africans ancestry centromeres show higher proportions of 4-mer α-satellite HOR sequences (p = 0.001).
- Phylogenetic analysis indicates rapid chr21 centromere evolution in the last ~17,000 years.

QC result: Pass.

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 observed scale
- Five independent genome-wide significant index SNPs: two at EYA4, two at EYA1, one near CYP26A1
- Two additional loci near LMO4 and ALDH1A2 are suggestive rather than genome-wide significant
- Developmental regulation of inner ear (EYA4/EYA1) and retinoic acid metabolism (CYP26A1/C1, ALDH1A2) as core pathways
- Genetic correlations between MD and vertigo, tinnitus, hearing loss, migraine, sleep apnea; additional overlap with glaucoma
- Functional follow-up suggested via human inner ear organoids and polygenic risk modeling

QC result: Pass.

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 the GESUS cohort followed longitudinally over ~10 years
- A Moran process with fixed carrying capacity N ≈ 100,000 and generation time Tg ≈ 200 days
- Selective advantage s inferred per subject using ABC-SMC; distribution: ~47/67 positive, ~12/67 negative, ~8/67 neutral
- 66 of 67 subjects' data fall within the central 95% of model trajectories
- 37 of 67 subjects progressed to overt MPN; higher average s associated with progression but not perfectly predictive
- Inflammation (CRP) differences between CH and MPN groups; statins may reduce systemic inflammation and modulate clonal advantage

QC result: Pass.