Base by Base

Lassen F et al., The American Journal of Human Genetics - Meta-analysis of up to 948,690 exome- or whole-genome-sequenced individuals across six biobanks used statistical phasing to infer compound-heterozygous genotypes, increasing detectable bi-allelic damaging genotypes by 19% and identifying 58 significant gene-trait associations, 17 of which show stronger recessive effects. Key terms: recessive genetics, compound heterozygous, biobank meta-analysis, loss-of-function, statistical phasing.

Study Highlights:
The study combined data from UKB, All of Us, 100kGP, Genes & Health, BioMe, and BBJ totaling 948,690 samples and phased rare variants to detect compound-heterozygous genotypes. Phasing increased the number of bi-allelic damaging genotypes by 19% and identified 5,563 genes with bi-allelic pLoF genotypes. Gene-based recessive testing across 41 traits found 58 significant associations after meta-analysis and Cauchy combination, with 17 instances showing stronger recessive than additive effects, including HBB with heart failure and LECT2 with height. The federated, cross-biobank approach improved power and highlighted the value of diverse ancestries for discovering recessive effects.

Conclusion:
Federated meta-analysis across multiple biobanks combined with statistical phasing substantially increases discovery of rare recessive gene-trait associations and expands the catalog of human gene knockouts, demonstrating the importance of phasing and diverse cohorts for recessive-effect discovery.

Music:
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Article title:
Meta-analysis across six global biobanks identifies recessive coding associations with complex traits and diseases

First author:
Lassen F

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.04.005

Reference:
Lassen F.H. et al., 2026. Meta-analysis across six global biobanks identifies recessive coding associations with complex traits and diseases. The American Journal of Human Genetics 113, 1–17. https://doi.org/10.1016/j.ajhg.2026.04.005

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/recessive-coding-associations-six-biobanks

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-03.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing: the role of statistical phasing to identify compound-heterozygous genotypes, the scale across six biobanks (~950k individuals), the rise in bi-allelic genotypes, and key recessive gene–trait associations (HBB, LECT2, ENSG00000267561, PYGM, ODAD1), plus pleiotropy and conditional
- transcript topics: Introduction to human knockouts and biobank-scale data; Compound heterozygosity and the need for phasing; Statistical phasing across six biobanks and study scale; Gene-based recessive associations across 41 traits; Notable associations: HBB with heart failure and lipids; LECT2 with height; ENSG00000267561 with height; BTNL9 association with HDL-C and triglycerides

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:
- PHASED approach increased bi-allelic damaging genotypes by 19% (compound-heterozygous and homozygous) across biobanks
- Identified 5,563 genes harboring bi-allelic genotypes; 1,767 additional genes beyond previous studies; total 8,925 unique genes when accounting for overlaps
- CH variants increased testable genes by 8.9% to 1,253 genes (from 1,151)
- 58 significant gene–trait associations identified; 17 likely recessive (based on comparing recessive vs additive signals)
- Notable recessive associations include HBB with heart failure and lipid traits; LECT2 with height; ENSG00000267561 with height; PYGM with AST; ODAD1 with COPD
- Ancestry-diversity contribution: 1,371 of the new knockouts found in non-European ancestries, concentrated in SAS cohorts

QC result: Pass.

Sanders CG et al et al., PNAS - Surveillance-derived influenza D virus (IDV) isolates were tested across cell lines, primary airway cultures, and precision-cut lung slices to assess human compatibility. IDV replicated to high titers in human respiratory models while eliciting muted interferon responses, highlighting a potential zoonotic threat and the need for enhanced surveillance. Key terms: influenza D virus, zoonosis, human airway, interferon evasion, surveillance.

Study Highlights:
A panel of six genetically diverse IDV isolates replicated efficiently in MDCK and A549 cell lines, primary well-differentiated human bronchial epithelial cultures, porcine airway cultures, and precision-cut lung slices. IDV induced markedly reduced IRF activation and lower IFN-λ1 and ISG expression compared to human influenza A virus, indicating limited innate immune sensing. Pretreatment with IFN-β potently restricted IDV replication, showing the virus is sensitive to an established antiviral state. Active surveillance at US swine exhibitions recovered multiple genetically distinct IDV strains spanning several clades.

Conclusion:
IDV readily infects and replicates in human respiratory tissues while limiting innate sensing, supporting intensified surveillance and mechanistic studies to evaluate its zoonotic and pandemic potential.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Efficient replication of influenza D virus in the human airway underscores zoonotic potential

First author:
Sanders CG et al

Journal:
PNAS

DOI:
10.1073/pnas.2530325123

Reference:
Sanders CG et al., Efficient replication of influenza D virus in the human airway underscores zoonotic potential. PNAS (2026) Vol. 123 No. 17 e2530325123. doi:10.1073/pnas.2530325123

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/influenza-d-human-airway-zoonotic-potential

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-03.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited the transcript sections describing field surveillance, in vitro and tissue-level replication in human/porcine models, innate immune responses, receptor usage, and zoonotic implications as reported in the canonical article.
- transcript topics: Field surveillance and isolation of IDV from exhibition swine; IDV replication in MDCK cells and A549 cells; Primary human and porcine airway epithelial cultures (ALI); Precision-cut lung slices (PCLS) and tissue-level replication; Innate immune sensing and interferon responses (IRF, IFN-λ1, ISGs); Interferon-β pretreatment and antiviral state

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:
- IDV replicates to high titers in MDCK cells and in immortalized human lung cells (A549).
- IDV replicates efficiently in primary well-differentiated human airway epithelial cultures (ALI) and in porcine ALI cultures, with comparable replication kinetics across species.
- IDV replicates efficiently in human and swine precision-cut lung slices (PCLS).
- IDV elicits markedly weaker interferon signaling and lower IFN-λ1 and ISG induction compared with IAV.
- IDV replication is potently restricted by preactivation of antiviral state with IFN-β.
- Field surveillance at 422 swine exhibitions recovered three genetically distinct IDV strains from swine isolates (panel of six isolates used in downstream analyses).

QC result: Pass.

Costantino L et al., PNAS - Costantino et al. dissect how Eco1-mediated acetylation of Smc3 (K112, K113) and cohesin ATPase activity separately regulate chromatin loop size, loop positioning, and sister chromatid tethering in budding yeast using Micro-C XL, ChIP, and biochemical ATPase assays. Key terms: cohesin, acetylation, ATPase, chromatin loops, sister chromatid cohesion.

Study Highlights:
Using a panel of budding yeast mutants, the authors show that acetylation of either Smc3 K112 or K113 is sufficient to produce positioned chromatin loops, while loss of both (Eco1 depletion) leads to expanded, unpositioned loops despite normal cohesin binding. K113 acetylation is required for sister chromatid cohesion (tethering), but cohesion-defective K113R mutants still form positioned loops, indicating looping can occur without tethering. K112 acetyl-mimic reduces loader-stimulated ATPase yet retains wild-type loop architecture, whereas hyper-ATPase mutants convert random loops into more positioned loops. The DE (low-ATPase) mutant produces long, unpositioned loops despite normal cohesin binding and Pds5 recruitment, indicating separable mechanisms downstream of acetylation and Pds5.

Conclusion:
Acetylation and ATPase activity separately tune cohesin's functions: acetylation at Smc3 K112/K113 helps position loops and control ATPase responsiveness, K113 acetylation is essential for tethering, and ATPase level biases cohesin toward random versus positioned loops, supporting active loop extrusion as the primary loop-forming mechanism.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Cohesin acetylation and ATPase activity control cohesion and loop architecture through distinct mechanisms

First author:
Costantino L

Journal:
PNAS

DOI:
10.1073/pnas.2531218123

Reference:
Costantino L, Ye T, Boardman K, Xiang S, Luo J, Mu Y, Ma W, Koshland D. Cohesin acetylation and ATPase activity control cohesion and loop architecture through distinct mechanisms. PNAS. 2026;123(17):e2531218123. doi:10.1073/pnas.2531218123.

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/cohesin-acetylation-atpase-loop-architecture

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-30.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing cohesin functions (loop extrusion and tethering), Eco1-mediated Smc3 acetylation at K112/K113, ATPase regulation by Scc2/Scc4, mutations (K112R, K113R, K112Q, K113Q, DE, TI), Micro-C XL method and CARs, Pds5 involvement, and the active loop extrusion model versus loop capture.
- transcript topics: Cohesin functions: loop extrusion and sister chromatid tethering; Smc3 K112/K113 acetylation and Eco1; ATPase regulation by loader Scc2/Scc4 and acetylation; Mutant analyses: K112R, K113R, K112Q, K113Q, ECO1-AID, TI, DE; Micro-C XL methodology and CARs/positioned loops; Pds5 binding and loop regulation

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:
- Either K112 or K113 acetylation suffices to position loops; Eco1 depletion (both acetylations removed) leads to loop expansion and loss of positioned loops
- K113 acetylation is essential for sister chromatid cohesion; K113R mutants are cohesion-defective but can form positioned loops
- K112 acetylation reduces loader-stimulated ATPase; K112Q partially reduces ATPase; K113Q strongly reduces/abolishes loader stimulation
- Hyper-ATPase mutants (TI) reduce random loops and increase positioned loops; DE mutant (low ATPase) yields long, unpositioned loops despite cohesin binding
- DE mutant shows cohesin binding and Pds5 recruitment similar to wild type, suggesting defects are downstream of Pds5 recruitment
- Three distinct ATPase states are proposed: unacetylated (fully inducible/loop-extruding), K112-acetylated (partially inducible), K113-acetylated (non-inducible/cohesion-promoting)

QC result: Pass.

Schubert HA et al., PNAS - This episode reviews a global analysis showing that shifts in population sex composition have reversed historical sex gaps in fertility. Using UN World Population Prospects 2024 data and regression and standardization methods, the authors estimate male total fertility rates and project widening differences through 2100 driven by masculinized reproductive-age populations. Key terms: male fertility, sex ratio, total fertility rate, sex-selective abortion, population structure.

Study Highlights:
The authors estimate male and female total fertility rates using UN WPP2024 data combined with a regression-based model and demographic standardization. They identify a global crossover in 2024 when female TFRs first exceeded male TFRs and project growing disparities through 2100, especially in East Asia. Key drivers are higher sex ratios at birth, declining mortality, and a narrowing male–female mortality gap, with sex-selective abortion amplifying effects in some countries. The analysis highlights social consequences such as rising male childlessness and offers policy recommendations to mitigate sex imbalances.

Conclusion:
Masculinization of reproductive-age populations has flipped historical fertility patterns so that female TFRs now often exceed male TFRs, a gap expected to widen in many regions and to carry social and policy implications related to childlessness and partnership markets.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Masculinization of populations reverses sex differences in fertility

First author:
Schubert HA

Journal:
PNAS

DOI:
10.1073/pnas.2533317123

Reference:
Schubert HA, Spoorenberg T, Dudel C, Skirbekk VF. Masculinization of populations reverses sex differences in fertility. Proc Natl Acad Sci U S A. 2026;123:e2533317123. doi:10.1073/pnas.2533317123

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/353-masculinization-populations-fertility

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-30.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing historical sex differences in fertility, the 2024 crossover, drivers (birth sex ratio, mortality decline, sex-selective abortion), the age-gap Model 3 estimation approach, regional variations (East Asia vs Sub-Saharan Africa), war shocks, and policy implications.
- transcript topics: Historical fertility gender gaps and denominator effects; Birth sex ratio and sex-selective abortion; Mortality decline and sex mortality gap; Model 3 age-gap estimation of male TFR; Global crossover year 2024 and 2100 projections; Regional variations: East Asia vs Sub-Saharan Africa

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:
- Global crossover year: 2024
- 2100 projection: <10% of countries have higher TFRm
- Three drivers of masculinization: birth sex ratio, mortality declines, sex-selective abortion
- Model 3 (age-gap) best fits male fertility estimation
- Sub-Saharan Africa not crossing before 2100 due to maternal mortality
- War mortality shocks (Guatemala, Rwanda) have lasting demographic effects

QC result: Pass.

Boumasmoud M et al., PNAS - Reciprocal transplant experiments in anaerobic microcosms show that resident human gut microbiome context alters growth of introduced Escherichia coli strains and that microbially mediated acidification, driven by a Clostridium butyricum strain, can reproducibly suppress E. coli and reshape community fermentation profiles. Key terms: gut microbiome, Escherichia coli, interspecies interaction, acidification, Clostridium butyricum.

Study Highlights:
Using six human stool-derived microbiome samples and six resident E. coli isolates in replicated anaerobic microcosms, the authors measured strain-level and species-level growth across 36 strain-by-microbiome combinations. Growth performance of E. coli strains varied with microbiome context and was constrained by intraspecific competition setting a finite E. coli abundance per microbiome. One microbiome (M6) acidified during cultivation, inhibiting E. coli growth; a Clostridium butyricum isolate from M6 reproduced this acidification when transplanted into other samples. Addition of C. butyricum lowered pH, increased butyrate and decreased acetate/lactate, suppressed E. coli and altered overall community composition.

Conclusion:
Interindividual gut-microbiome variation causes variable ecological interactions that affect colonization by incoming strains, and a single transferable taxon (C. butyricum) can act as an ecological control point by driving acidification and reshaping community growth and metabolites.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Interspecies interaction controls Escherichia coli growth in human gut microbiome samples

First author:
Boumasmoud M

Journal:
PNAS

DOI:
10.1073/pnas.2527793123

Reference:
Boumasmoud M., León-Sampedro R., Beusch V., Benza F., Arnoldini M., Hall A.R. Interspecies interaction controls Escherichia coli growth in human gut microbiome samples. PNAS. 2026;123(17):e2527793123. doi:10.1073/pnas.2527793123

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/interspecies-ecoli-growth-microbiome

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-27.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's discussion of experimental design, key results (strain performance variation, acidification, keystone C. butyricum), and ecological implications; compared to the original article's reported methods, results, and interpretations.
- transcript topics: Experimental design: reciprocal transplant in anaerobic microcosms (M2–M7) with six E. coli strains; Strain-level and species-level growth variation across microbiome samples; Intraspecific competition and microbiome-specific finite E. coli abundance; Acidification as a driver of growth suppression; pH measurements; Clostridium butyricum as a keystone species driving acidification and community shifts; Transplantation of C. butyricum into other microbiomes; effects on butyrate, acetate, lactate

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:
- Six donor microbiome samples (M2–M7) and six focal E. coli strains (S2–S7) tested in 36 strain–microbiome combinations; growth varied by microbiome context
- No average home-field adaptation detected; rank order of strains largely consistent across microbiomes with S3 and S7 often most abundant
- Microbiome sample M6 acidified during incubation (pH ~5.4) and suppressed E. coli growth; neutralization restored growth
- A Clostridium butyricum strain isolated from M6 acidified medium and, when transplanted into other microbiomes, reduced pH and altered fermentation products (increased butyrate, de
- Butyricum transplantation reduced E. coli and total bacterial growth and reshaped community composition
- Butyrate production increased by 14.8 mM on average after C. butyricum inoculation; acetate decreased by ~8.08 mM and lactate by ~6.45 mM

QC result: Pass.

Harris M et al., Proceedings of the National Academy of Sciences (PNAS) - This episode examines a PNAS study that uses a domain-adaptive neural network to detect and classify selective sweeps in over 800 ancient and modern Eurasian genomes spanning ~7,000 years. The work recovers known targets (HLA, LCT, OCA2/HERC2, KITLG), reports 32 novel ancient sweep candidates, finds hard sweeps predominate, and shows 14 sweeps persisted across a major admixture event, highlighting resilience of certain adaptations. Key terms: ancient DNA, selective sweeps, domain-adaptive neural network, hard sweeps, admixture.

Study Highlights:
The authors trained a domain-adaptive neural network on simulated and ancient DNA to distinguish hard sweeps, soft sweeps, and neutrality across 708 ancient and 99 modern Eurasian genomes. The DANN outperformed standard CNNs under demographic and missing-data misspecification and detected 48 ancient sweeps, including 16 overlapping prior reports and 32 novel candidates. All identified sweeps were classified as hard and, after accounting for misclassification rates, the majority remain best explained by hard sweeps. Fourteen sweeps at genes involved in neuronal, reproductive, pigmentation, and signaling functions persisted across a major admixture event, often retaining the same high-frequency haplotype.

Conclusion:
Domain-adaptive deep learning improves detection of selective sweeps in degraded ancient genomes; hard sweeps were the dominant mode of adaptation in these ancient Eurasian samples and several selective events persisted despite strong admixture, pointing to sustained functional importance of particular loci.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
The persistence and loss of hard selective sweeps amid admixture in ancient Eurasians

First author:
Harris M

Journal:
Proceedings of the National Academy of Sciences (PNAS)

DOI:
10.1073/pnas.2528672123

Reference:
Harris M., Mo Z., Siepel A., Garud N.R. The persistence and loss of hard selective sweeps amid admixture in ancient Eurasians. Proc. Natl. Acad. Sci. U.S.A. 2026;123(17):e2528672123. doi:10.1073/pnas.2528672123

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/hard-sweeps-admixture-ancient-eurasians

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-26.

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 DANN method (domain adaptation, GRL, haplotype image inputs), the major results (counts of ancient/modern sweeps, hard sweeps, persistence across admixture), and the highlighted loci (HLA, LCT, OCA2/HERC2, KITLG), plus the discussion of admixture timing (~4.5 kya) and impl
- transcript topics: Domain-adaptive neural networks (DANN) and gradient reversal layer; Ancient DNA data quality and missing data; Hard vs soft sweeps definitions; Sweep detection results (ancient vs modern) and total counts; Admixture event around 4.5 kya and sweep persistence; Loci of interest: HLA, LCT, OCA2/HERC2, KITLG

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- 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:
- 708 ancient Eurasian genomes analyzed; 99 modern European genomes used for comparison
- Ancient sweeps detected: 48; modern sweeps detected: 28; total across datasets: 58
- All identified sweeps classified as hard sweeps; estimated hard sweeps exceed soft sweeps (80+%)
- 14 sweeps persisted across a major admixture event (~4.5 thousand years ago)
- Loci repeatedly highlighted among sweeps include HLA, LCT, OCA2/HERC2, KITLG

QC result: Pass.

Jaggers TN et al et al., PNAS - A spontaneous OPA1 A8S missense mutation in rhesus macaques produces retinal ganglion cell loss, RNFL thinning, optic nerve atrophy, OPA1 mislocalization, and mitochondrial abnormalities, creating a nonhuman primate model that mirrors human autosomal dominant optic atrophy. Key terms: OPA1, autosomal dominant optic atrophy, rhesus macaque, retinal ganglion cell, mitochondria.

Study Highlights:
The authors identified an OPA1 NM_015560.2:c.22G>T (p.ala8ser, A8S) variant segregating dominantly in a rhesus colony. Heterozygous macaques showed significant peripapillary RNFL thinning, temporal optic nerve head pallor, and reduced PERG amplitudes consistent with RGC dysfunction. Histology and TEM revealed RGC loss, reduced axonal mitochondrial density, dysmorphic mitochondria, myelin disruption, and OPA1 mislocalization in RNFL axons. The model displays phenotypic variability similar to human ADOA and supports use for preclinical testing of mitochondrial- and gene-targeted therapies.

Conclusion:
A spontaneous OPA1 A8S mutation in rhesus macaques recapitulates key structural, functional, and ultrastructural features of human ADOA, providing a translational NHP model for testing therapies.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Rhesus macaques with an OPA1 mutation demonstrate features of autosomal dominant optic atrophy

First author:
Jaggers TN et al

Journal:
PNAS

DOI:
10.1073/pnas.2509165123

Reference:
Jaggers TN et al., Rhesus macaques with an OPA1 mutation demonstrate features of autosomal dominant optic atrophy. PNAS. 2026;123:e2509165123. https://doi.org/10.1073/pnas.2509165123

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/350-opa1-rhesus-adoa

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of the transcript sections describing the OPA1 A8S mutation, heterozygous phenotype (RNFL thinning, ONH pallor, PERG deficits), ultrastructural mitochondrial defects and OPA1 mislocalization, homozygous cases, and translational therapy implications.
- transcript topics: OPA1 A8S mutation and spontaneous nonhuman primate model; Autosomal dominant optic atrophy (ADOA) in rhesus macaques; RNFL thinning and optic nerve head pallor; PERG dysfunction in OPA1 heterozygotes; Mitochondrial abnormalities and OPA1 mislocalization; TEM findings: dysmorphic mitochondria and axon loss

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- 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:
- OPA1 A8S missense mutation identified in rhesus macaques in CNPRC colony
- Mutation is dominant and linked to autosomal dominant inheritance pattern
- Heterozygotes show RNFL thinning and temporal ONH pallor; PERG amplitudes reduced
- OPA1 mislocalization and reduced axonal mitochondrial density observed in retina
- Homozygous OPA1 macaques identified; survive to adulthood and reproduce
- Manual RNFL measurements emphasized due to automated segmentation errors in diseased tissue

QC result: Pass.

Hou P et al., PNAS - This study combines kinetic assays and X‑ray crystallography to show how 8‑oxo‑guanosine triphosphate (8‑oxo‑rGTP) is incorporated by RNA polymerase II and how its pairing geometry with template bases (dC vs dA) differentially alters incorporation efficiency, extension, and proofreading, thereby introducing transcription‑coupled RNA damage. Key terms: RNA damage, 8-oxo-rGTP, RNA polymerase II, transcription fidelity, oxidative stress.

Study Highlights:
Pol II incorporates 8‑oxo‑rGTP efficiently opposite dC with kinetics comparable to GTP, whereas incorporation opposite dA is much slower but ~150‑fold more efficient than misincorporation of undamaged rGTP. Extension proceeds rapidly from a 3′‑r8OG:dC pair but is markedly slower from a 3′‑r8OG:dA pair. TFIIS‑stimulated proofreading cleaves r8OG:dC robustly but r8OG:dA is resistant to backtracking and cleavage. Crystal structures reveal 8‑oxo‑rG adopts anti Watson–Crick geometry with dC in the A‑site but flips to syn Hoogsteen geometry with dA, where an interaction with Rpb2 E529 stabilizes a pretranslocation state.

Conclusion:
Oxidation of the nucleotide pool can directly undermine Pol II fidelity by enabling efficient incorporation and differential handling of 8‑oxo‑rGTP, producing transcription‑coupled RNA damage with potential consequences for RNA processing, translation, and disease.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Structural basis of transcription -coupled RNA damage by incorporation of oxidized ribonucleotides

First author:
Hou P

Journal:
PNAS

DOI:
10.1073/pnas.2602266123

Reference:
Hou P, Lee C, Chong J, Oh J, Wang D. Structural basis of transcription-coupled RNA damage by incorporation of oxidized ribonucleotides. PNAS. 2026;123(16):e2602266123. doi:10.1073/pnas.2602266123

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/8oxo-rgpt-transcription-rna-damage

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections on background, kinetic experiments, structural determinations, proofreading, translocation mechanics, and disease relevance; aligned with the canonical article.
- transcript topics: Oxidative stress and oxidized ribonucleotides; 8-oxo-rGTP incorporation opposite dC and dA templates; Presteady-state kinetics and incorporation efficiency; Extension after 8-oxo-rGTP incorporation; TFIIS proofreading and backtracking with oxidized nucleotides; Structural basis: A-site anti conformation with dC; syn Hoogsteen with dA; E529 fork loop 2 interaction

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:
- 8-oxo-rGTP can be efficiently incorporated opposite dC, with efficiency comparable to GTP
- 8-oxo-rGTP opposite dA is misincorporated ~150-fold more efficiently than rGTP misincorporation
- Pol II extends more efficiently from 8-oxo-rG:dC than from 8-oxo-rG:dA
- TFIIS-stimulated cleavage occurs for 8-oxo-rGTP:dC (~70% cleavage after 30 minutes) but is limited for 8-oxo-rGTP:dA (<10%)
- 8-oxo-rGTP binds at the A-site opposite dC in anti conformation; opposite dA it adopts syn conformation forming Hoogsteen pairing
- Syn-8-oxo-rG:dA forms a hydrogen bond with Rpb2 E529 in fork loop 2, stabilizing a pretranslocation state and impeding translocation/backtracking

QC result: Pass.

Wang Y et al et al., PNAS - This episode covers a PNAS study describing v96, a personalized plasma cell-free DNA assay that tracks up to 96 patient-specific mutations to sensitively quantify measurable residual disease (MRD) in AML patients before and after allogeneic hematopoietic cell transplantation. Key terms: cell-free DNA, measurable residual disease, acute myeloid leukemia, hematopoietic cell transplantation, duplex sequencing.

Study Highlights:
The personalized v96 assay detected residual leukemia in 100% of 30 AML patients at clinical remission, compared with 20% by flow cytometry. Plasma cfDNA was more informative and sensitive than bone marrow DNA and driver mutation assays, with 90% of patients positive at 2 months posttransplant. Higher pretransplant mutant molecule counts correlated with relapse risk, and leukemic burden typically fell only after immunosuppression was discontinued, consistent with a graft-versus-leukemia effect.

Conclusion:
A plasma-based multiplexed assay (v96) enables highly sensitive, noninvasive MRD monitoring in AML patients undergoing transplantation and may inform timing of immunosuppression and posttransplant interventions, though larger studies are needed to confirm clinical utility.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
A plasma - based DNA test for quantification of disease burden in acute myeloid leukemia patients undergoing bone marrow transplantation

First author:
Wang Y et al

Journal:
PNAS

DOI:
10.1073/pnas.2537987123

Reference:
Wang Y et al., A plasma-based DNA test for quantification of disease burden in acute myeloid leukemia patients undergoing bone marrow transplantation. PNAS. 2026;123(16):e2537987123. doi:10.1073/pnas.2537987123

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/v96-plasma-ctdna-aml-transplant

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-21.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s presentation of the v96 methodology, passenger vs driver mutations, plasma vs marrow MRD detection, relapse prediction, and posttransplant immunosuppression dynamics against the original article.
- transcript topics: v96 workflow and passenger mutation panel; duplex sequencing (SaferSeqS) and error suppression; plasma vs bone marrow cell-free DNA for MRD detection; driver vs passenger mutations for MRD assessment; predictive power for relapse (352-fold difference pre-transplant); graft-versus-leukemia (GvL) dynamics and immunosuppression

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- 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:
- v96 assay tracks up to 96 leukemia-specific passenger mutations in plasma cfDNA and detects residual leukemia in all patients at complete remission (CR) by v96, vs 20% by flow cyto
- plasma cfDNA mutant-allele fractions (MAF) are higher than bone marrow DNA (2.9% vs 0.42%) at CR
- pre-transplant plasma mutant molecule counts are 352-fold higher in patients who relapse compared with those who do not relapse
- post-transplant residual disease declines more rapidly after immunosuppressive therapy is discontinued, indicating graft-versus-leukemia (GvL) activity
- v96 detects MRD in 100% of patients prior to transplant, whereas driver mutations detected by SaferSeqS are found in about 48% (10/21) at the same time point; at 2 months posttrans

QC result: Pass.

Holta KB et al., Proceedings of the National Academy of Sciences (PNAS) - This episode explains a quantitative framework for diffusion on spatially embedded dynamic mitochondrial networks. The study combines analytic theory, agent-based simulations, and live-cell imaging to show how connectivity, fusion/fission, and mobility set biomolecular mixing on mitochondrial populations. Key terms: mitochondria, diffusion, intracellular transport, temporal networks, fusion-fission.

Study Highlights:
The authors develop an analytic and simulation framework for diffusive spreading on spatially embedded dynamic networks formed by mitochondrial fusion and fission. They identify a connectivity-driven transition from three-dimensional dispersion across transiently interacting clusters (social regime) to low-dimensional transport along largely stationary interconnected tubules (physical regime). The steady-state distribution is determined by competing timescales for cluster filling, encounter, fusion/fission, and material decay. Application to three human cell lines reveals cell-type variability in predicted spreading times, with hyperfused networks limited by intracluster diffusion and fragmented networks limited by encounters.

Conclusion:
Network connectivity and the balance of diffusion, encounter, and fusion/fission timescales quantitatively determine mitochondrial material homogenization, producing distinct scaling regimes with measurable predictions across cell types.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Diffusive spreading across dynamic mitochondrial network architectures

First author:
Holta KB

Journal:
Proceedings of the National Academy of Sciences (PNAS)

DOI:
10.1073/pnas.2523913123

Reference:
Holta KB, Zurita C, Teryoshin L, Lewis SC, Koslover EF. Diffusive spreading across dynamic mitochondrial network architectures. Proc Natl Acad Sci U S A. 2026;123(15):e2523913123. doi:10.1073/pnas.2523913123

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/diffusive-spreading-mitochondrial-networks

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive auditing of the transcript’s representation of the article’s core framework, regimes, timescales, cell-type predictions, modeling approach, and acknowledged limitations, with cross-checks against the original article text and the facts pack.
- transcript topics: Temporal networks framework for diffusion on dynamic mitochondrial networks; Physical vs social mitochondrial network regimes; Four timescales governing diffusion: decay, cluster filling, encounter, fission; Agent-based spherocylindrical model and finite-volume diffusion; Time-resolved imaging and cell-type parameterization (SH-SY5Y, IMR90, U2OS); Predictions of spreading times across cell types

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:
- Connectivity-driven transition between low-dimensional (physical) and three-dimensional (social) network regimes
- Four timescales govern spreading: decay, cluster filling, encounter, and fission
- Spreading times: SH-SY5Y ~6 minutes; IMR90/U2OS ~45 minutes for Dp = 20 μm2/s
- Mobility of mitochondria can bottleneck spreading in fragmented networks
- Active transport increases encounter rates; model primarily assumes diffusion
- Three-cell-line analysis (SH-SY5Y, IMR90, U2OS) used to parameterize the model

QC result: Pass.