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...

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...

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...

• (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