Moye AR et al., The American Journal of Human Genetics - Biallelic loss-of-function variants in SAXO6, a microtubule inner protein of photoreceptor cilia, cause late-onset retinal dystrophy by destabilizing axonemal microtubules. Key terms: SAXO6, microtubule inner protein, photoreceptor cilia, retinal dystrophy, iU-ExM.

Study Highlights:
The study analyzed human patients with late-onset recessive retinal dystrophy and combined genetic sequencing (WES/WGS and long-read RNA) with high-resolution imaging and proteomics. Iterative ultrastructure expansion microscopy and immuno-gold TEM localized SAXO6 to specific microtubule doublets in photoreceptor connecting cilia and outer segments and to motile cilia in airway models. Cross-linking mass spectrometry on isolated bovine tracheal cilia detected an interaction between SAXO6 Mn-motif regions and α-tubulin (Lys370), supporting SAXO6 as a microtubule inner protein. Functionally, predicted null SAXO6 genotypes segregate with late-onset RP or cone-rod dystrophy, implicating MIP dysfunction in long-term photoreceptor stability.

Conclusion:
Biallelic loss-of-function variants in SAXO6 cause late-onset retinal dystrophy, likely by disrupting a microtubule inner protein that stabilizes photoreceptor axonemes.

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

Article title:
Loss-of-function variants in SAXO6, encoding a microtubule inner protein of photoreceptor cilia, cause a late-onset retinal dystrophy

First author:
Moye AR

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.02.001

Reference:
Moye AR, McCafferty CL, Lin S, Han JH, Dudakova L, Rodenburg K, Szabó V, Nagy ZZ, Zur D, Vajter M, Kousal B, Moulin AP, Graff-Meyer A, Roosing S, Mahroo OA, Arno G, Webster AR, Ben-Yosef T, Liskova P, Engel BD, Zobor D, Quinodoz M, Rivolta C. Loss-of-function variants in SAXO6, encoding a microtubule inner protein of photoreceptor cilia, cause a late-onset retinal dystrophy. The American Journal of Human Genetics. 2026 Mar 5;113:1–18. https://doi.org/10.1016/j.ajhg.2026.02.001

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/saxo6-photoreceptor-mip-retina

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

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections covering SAXO6 gene discovery and renaming from MDM1; SAXO6 LOF variants and segregation; SAXO6 localization in photoreceptor cilia and motile cilia; imaging methods iU-ExM and Ig-TEM; cross-linking MS evidence for SAXO6–α-tubulin interaction; rod vs cone MT doublet occupancy; clinical impli
- transcript topics: SAXO6 gene discovery and renaming from MDM1; Bi-allelic SAXO6 LOF variants and family segregation; Subcellular localization of SAXO6 in photoreceptor cilia (CC/OS) and in motile cilia; Imaging methods: iterative ultrastructure expansion microscopy (iU-ExM); Immuno-gold TEM localization of SAXO6; Cross-linking mass spectrometry evidence for SAXO6–α-tubulin 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:
- Six individuals from five families carry bi-allelic SAXO6 loss-of-function variants associated with late-onset RP/CRD
- SAXO6 renamed from MDM1 to SAXO6 (stabilizer of axonemal microtubules 6)
- SAXO6 localizes inside the lumen of photoreceptor ciliary microtubules and in motile cilia
- Cross-linking MS identifies an interaction between SAXO6 (Lys201) and α-tubulin (Lys370) with ~30 Å separation
- Iterative ultrastructure expansion microscopy expanded tissue ~10×, revealing SAXO6 localization along microtubule doublets
- Rods show SAXO6 occupancy on 6–7 microtubule doublets; cones on all 9 doublets

QC result: Pass.

Siraj L et al., Nature, doi:10.1038/s41586-026-10121-6 - Using MPRA in five human cell types, the authors assayed 221,412 fine-mapped variants and identified 13,121 trait-associated regulatory variants (TARVs), mapping mechanisms at single-nucleotide resolution. Key terms: massively parallel reporter assay, trait-associated regulatory variants, saturation mutagenesis, transcription factor motifs, regulatory epistasis.

Study Highlights:
The study assayed 221,412 fine-mapped human GWAS and eQTL variants using a massively parallel reporter assay (MPRA) across five cell lines and performed saturation mutagenesis on 136 TARVs. MPRA identified 13,121 trait-associated regulatory variants (TARVs) and showed that emVar status within endogenous CREs improves precision for causal-variant prioritization. Saturation mutagenesis defined activity blocks, assigned transcription factors for 91% of previously non-canonical TARVs, and revealed that only 69% of TARVs disrupt known TF motifs. The authors also detected regulatory epistasis in ~11% of nearby variant pairs, demonstrating non-additive effects between cis variants.

Conclusion:
Large-scale MPRA combined with saturation mutagenesis systematically identifies and mechanistically annotates thousands of human trait-associated regulatory variants at single-nucleotide resolution, revealing motif-disrupting and non-canonical TF mechanisms and local epistasis.

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

Article title:
Functional dissection of complex trait variants at single-nucleotide resolution

First author:
Siraj L

Journal:
Nature, doi:10.1038/s41586-026-10121-6

DOI:
10.1038/s41586-026-10121-6

Reference:
Siraj L., Castro R.I., Dewey H.B., Kales S., Butts J.C., Nguyen T.T.L., Kanai M., et al. Functional dissection of complex trait variants at single-nucleotide resolution. Nature. https://doi.org/10.1038/s41586-026-10121-6

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/mpra-human-regulatory-variants

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-02.

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 MPRA scale and variant coverage, TARV identification and counts, mechanistic categories (motif disruption and non-canonical mechanisms), saturation mutagenesis mapping, regulatory epistasis, recall/precision metrics, cell-type context, and translational HbA1c example.
- transcript topics: MPRA scale and variant coverage; TARV identification and counts; Motif disruption as mechanism; Saturation mutagenesis mapping and activity blocks; Non-canonical TARV mechanisms; Regulatory epistasis in nearby TARV pairs

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:
- MPRA tested 221,412 fine-mapped trait-associated variants
- Identified 13,121 TARVs with high precision
- 69% of TARVs disrupt known transcription factor motifs
- Saturation mutagenesis assigned TFs for 91% of non-canonical TARVs
- Regulatory epistasis detected in ~11% of nearby TARV pairs
- Precision for causal-variant prioritization ~82–83%; recall ~15–20%

QC result: Pass.

Baldwin-Brown JG et al., Annual Review of Ecology and Systematics - Bayesian analysis of 76,445 Utah Population Database pedigrees identifies a patrilineal Y‑chromosome lineage producing a 2:1 male bias, consistent with segregation distortion. Key terms: segregation distortion, Y chromosome, sex ratio, Utah Population Database, Bayesian pedigree analysis.

Episode title:
Patrilineal Y‑chromosome drive in a Utah pedigree (67% male offspring)

Study Highlights:
We analyzed 76,445 anonymized human pedigrees from the Utah Population Database using a Bayesian pedigree-propagation algorithm (Warp), complemented by transmission disequilibrium testing, permutation and Monte Carlo simulations. These methods identified a single patrilineal Y-chromosome lineage with 89 informative transmissions that produced 60 male and 29 female offspring, a 67.4% male proportion. Warp and the TDT independently flagged the same family and permutation/Monte Carlo tests indicated the observed male bias was unlikely to arise by chance (p≈0.001–0.05). The pattern is consistent with a Y-linked segregation distorter and is discussed as a possible contributor to unexplained male infertility and human sex-ratio dynamics.

Conclusion:
A multi-method analysis of deep Utah pedigrees identifies a statistically significant male-biased patrilineal lineage consistent with a Y-linked segregation distorter in humans.

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

Article title:
Signatures of sex ratio distortion in humans

First author:
Baldwin-Brown JG

Journal:
Annual Review of Ecology and Systematics

DOI:
10.64898/2026.02.04.702084

Reference:
Baldwin-Brown JG, Wesolowski S, Zimmerman RM, Peterson B, Tristani-Firouzi M, Hernandez EH, Aston KI, Yandell M, Phadnis N. Signatures of sex ratio distortion in humans. Annual Review of Ecology and Systematics. 2026. https://doi.org/10.64898/2026.02.04.702084

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/human-y-chromosome-drive

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-02.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript segments describing segregation distortion concepts, Warp Bayesian algorithm for detecting distorters, the UPDB/focal patrilineal lineage with 67.4% male offspring across 89 transmissions, TDT results, Monte Carlo validation, proposed Y-chromosome mechanisms (PRY cluster), and implications (male infe
- transcript topics: Segregation distortion concepts and Mendelian expectations; Warp Bayesian algorithm for detecting distorters in UPDB pedigrees; UPDB data and identification of a patrilineal Y-chromosome lineage with 60/29 across 89 transmissions; Transmission Disequilibrium Test (TDT) results; Monte Carlo validation of lineage bias (p ≈ 0.00138); Potential molecular mechanisms: PRY ampliconic gene cluster

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:
- Identification of a patrilineal Y-chromosome distorter signal in humans using UPDB data (67.4% male across 89 transmissions in focal lineage)
- Warp Bayesian algorithm applied to UPDB pedigrees identifies putative distorter-carrying lineages (two male-biased families detected; six female-biased families)
- Focal patrilineal lineage across 89 informative transmissions yields 60 male and 29 female offspring (67.4% male)
- Transmission Disequilibrium Test (TDT) identifies the focal patrilineal lineage as significantly male biased (p ≈ 0.0249 after FDR; uncorrected p ≈ 0.00102)
- Monte Carlo simulations yield p ≈ 0.00138 for the focal lineage
- PRY gene cluster on the Y chromosome discussed as a prime mechanistic candidate for distortion

QC result: Pass.

Bleidorn C et al., Trends in Genetics, 42 (2026) 137-149. doi:10.1016/j.tig.2025.09.001 - This review shows how short-read shotgun sequencing and genome skimming recover organellar genomes, estimate genome size and repeat content, and enable scalable biodiversity monitoring. Key terms: short-read sequencing, genome skimming, metagenomics, museum genomics, phylogenomics.

Study Highlights:
The authors review applications across eukaryotic biodiversity, museum specimens, bulk samples and eDNA using short-read shotgun sequencing and genome skimming. They detail assembly-free and mapping-based bioinformatic methods (k-mer analyses, Read2Tree, Kraken2/CONSULT) and target-enrichment approaches for recovering phylogenetic markers. Quantitatively, low-coverage skims (from <1× to ~20×) can reliably recover organellar genomes and estimate genome size and repeat content using tools such as RESPECT and GenomeScope. Functionally, these approaches enable rapid reference database building, biomass estimation, and scalable monitoring that support the Global Biodiversity Framework.

Conclusion:
Short-read sequencing remains a cost-effective, broadly applicable toolkit that complements long-read references by enabling genome skimming, genome-size and repeat estimation, phylogenetics from low-coverage data, and museum-based biodiversity sampling.

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

Article title:
The untapped potential of short-read sequencing in biodiversity research

First author:
Bleidorn C

Journal:
Trends in Genetics, 42 (2026) 137-149. doi:10.1016/j.tig.2025.09.001

DOI:
10.1016/j.tig.2025.09.001

Reference:
Bleidorn C, Podsiadlowski L, Sandberg F, Martin S, Vogler AP. The untapped potential of short-read sequencing in biodiversity research. Trends Genet. 2026;42:137-149. https://doi.org/10.1016/j.tig.2025.09.001

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/short-read-genome-skimming

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-28.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s scientific content: GBF motivation, short-read sequencing and genome skimming, museomics (Barcode Blitz), type genomics, assembly-free phylogenomics (USCOs, UCEs, k-mers), environmental DNA/metagenomics and biomass estimation, hologenome/holobiont concept, and sequencing economics.
- transcript topics: GBF motivation and large-scale biodiversity monitoring; Short-read sequencing basics and genome skimming; Museomics and Barcode Blitz (museum collections, degraded DNA); Type genomics and reference database curation; Assembly-free phylogenomics (USCOs, UCEs, k-mers); Environmental DNA/metagenomics and biomass estimation

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:
- Short-read sequencing provides a universal data source across scales from genomes to ecosystems and supports GBF objectives.
- Genome skimming yields high-copy DNA (organellar genomes, ribosomal repeats) from low-coverage data (5×–20×; ultralow <5× sometimes).
- Museum collections enable large-scale genomic data generation (e.g., Barcode Blitz) from degraded DNA.
- Type genomics creates validated reference datasets by sequencing type material.
- USCOs and assembly-free methods (e.g., Skmer, Mash, Read2Tree) enable phylogenomics from unassembled reads.
- PCR/metabarcoding biases are bypassed by genome skimming/metagenomics, improving biomass estimates.

QC result: Pass.

Ein Hommage-Dossier, das die wissenschaftliche Laufbahn von Prof. Brunhilde Wirth würdigt und Arbeiten zum alternativen Spleißen von SMN1/SMN2 hervorhebt. Im Fokus stehen Studien aus der molekularen Genetik und funktionelle Assays, die die Auswirkungen von Varianten bei SMA aufgeklärt haben.

Studien-Highlights:

Dieses Dossier beleuchtet jahrzehntelange Arbeit in der Humangenetik und zur spinalen Muskelatrophie und betont insbesondere Studien zu SMN1 und SMN2. Zu den zentralen Methoden gehörten molekulargenetische Analysen, Spleißanalysen, Messungen der Proteinexpression sowie Stabilitätsassays zur funktionellen Validierung von Varianteneffekten. Ein zentraler mechanistischer Befund ist, dass Störungen sehr spät in der kodierenden Sequenz sich anders verhalten können, als einfache Modelle vorhersagen: Einige Transkripte entgehen dem erwarteten nonsense-mediated decay (NMD) und können die Proteinstabilität verändern. Diese experimentell validierten Erkenntnisse haben direkte Bedeutung für diagnostische Interpretation, Neugeborenen-Screening und Genotyp-Phänotyp-Korrelation bei SMA.

Fazit:

Prof. Wirths Karriere zeigt, dass die experimentelle Validierung von Spleiß- und Proteinstabilitäts-Effekten von SMN1/SMN2-Varianten für eine präzise klinische Interpretation bei SMA essenziell ist.

Musik:

Genieße die Musik, die auf diesem Beitrag basiert, am Ende der Episode.

Support:

Base by Base – Stripe-Spenden: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Offizielle Website: https://basebybase.com

Bei PaperCast Base by Base entdeckst du Aktuelles aus Genomik, funktioneller Genomik, struktureller Genomik und Proteomik.

Episodenlink: basebybase.com/episodes/smn1-smn2-splicing-wirth-2/

The Last Exon Light: A Tribute Dossier Celebrating the Scientific Career of Prof. Dr. Brunhilde Wirth - Special tribute episode honoring Prof. Dr. Brunhilde Wirth and synthesizing recurring themes across her work on SMN1/SMN2 splicing, variant interpretation, and spinal muscular atrophy.

Study Highlights:
This special episode is based on a tribute dossier rather than a single new primary research paper. It highlights recurring scientific themes across Brunhilde Wirth's career: SMN1/SMN2 biology, exon splicing, functional validation of variants, nonsense-mediated decay edge cases, and genotype-phenotype interpretation in SMA.

Conclusion:
This release should be read as an editorial tribute and curated scientific overview, not as a summary of one canonical article.

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

Source document:
The Last Exon Light: A Tribute Dossier Celebrating the Scientific Career of Prof. Dr. Brunhilde Wirth

Source type:
Editorial tribute dossier / multi-source compilation

Reference:
The Last Exon Light: A Tribute Dossier Celebrating the Scientific Career of Prof. Dr. Brunhilde Wirth. Editorial tribute dossier and curated retrospective source text.

License:
Not specified in the provided text.

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/smn1-smn2-splicing-wirth

QC:
This episode was reviewed as a special editorial release.

QC Scope:
- source-document framing, descriptive metadata, and publication text
- excludes automated single-article AI QC because this episode is a curated tribute dossier / multi-source compilation rather than one canonical research paper
- title, framing, and source attribution were reviewed manually

QC Summary:
- production mode: editorial tribute / multi-source compilation
- single-article AI QC: not applicable
- listener note: this episode synthesizes a tribute dossier celebrating Brunhilde Wirth's scientific career and related SMA/splicing themes

Metadata Audited:
- episode_title
- source_document_title
- source_type
- reference
- license

Factual Items Audited:
- episode explicitly framed as a tribute dossier / multi-source compilation
- no single canonical research article is represented as the sole source
- publication description was aligned to dossier-style source material
- manual editorial review approved the release

QC result: Editorial exception. This episode was approved after manual review.

Ferolito BR et al., Human Genetics and Genomics Advances, 7 (2026) 100556. doi:10.1016/j.xhgg.2025.100556 - Meta-analysis of MVP, UK Biobank and FinnGen with Mendelian randomization using eQTL/pQTL instruments implicates 6,447 genes and 69,669 causal gene-trait links. Key terms: Mendelian randomization, biobank meta-analysis, pQTL, drug target discovery, machine learning ranking.

Study Highlights:
The authors meta-analyzed GWAS from MVP, UK Biobank, and FinnGen across 2,003 harmonized phenotypes and used cis-eQTLs and cis-pQTLs from GTEx, eQTLGen, ARIC, Fenland, and deCODE to perform two-sample Mendelian randomization. They identified 69,669 significant gene-trait pairs (p ≤ 1.6×10⁻⁹) representing 6,447 genes with strong causal evidence and performed colocalization and sensitivity analyses to assess concordance. An XGBoost classifier trained on ChEMBL-derived approved targets and engineered biological features achieved a precision-recall AUC of 0.79 to rank MR hits by likelihood of clinical success. The resource yields rediscoveries and repurposing leads (e.g., ANXA2 nominated for lipid regulation) and supplies a prioritized list for downstream target evaluation.

Conclusion:
Integrating >1.2 million individuals' GWAS from large biobanks with eQTL/pQTL Mendelian randomization and orthogonal annotations yields 69,669 candidate causal gene-trait links and a machine-learning ranking that prioritizes targets for drug development.

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

Article title:
Leveraging large-scale biobanks for therapeutic target discovery

First author:
Ferolito BR

Journal:
Human Genetics and Genomics Advances, 7 (2026) 100556. doi:10.1016/j.xhgg.2025.100556

DOI:
10.1016/j.xhgg.2025.100556

Reference:
Ferolito BR, Dashti H, Giambartolomei C, Peloso GM, Golden DJ, Gravel-Pucillo K, Rasooly D, Horimoto ARV R, Matty R, Gaziano L, Liu Y, Smit IA, Zdrazil B, Tsepilov Y, Costa L, Kosik N, Huffman JE, Tartaglia GG, Bini G, Proietti G, Ioannidis H, Karim MA, Hunter F, Hemani G, Butterworth AS, Di Angelantonio E, Langenberg C, Ghoussaini M, Leach AR, Liao KP, Damrauer S, Selva LE, Whitbourne S, Tsao PS, Moser J, Gaunt T, Cai T, Whittaker JC, Million Veteran Program, Casas JP, Muralidhar S, Gaziano JM, Cho K, Pereira AC. Leveraging large-scale biobanks for therapeutic target discovery. Human Genetics and Genomics Advances. 7 (2026) 100556. https://doi.org/10.1016/j.xhgg.2025.100556.

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/biobank-mendelian-randomization-targets

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript portions describing Mendelian randomization (MR) as a nature-encoded trial, biobank meta-analysis (MVP/UKBB/FinnGen), molecular instruments (cis-eQTL/pQTL), concordant signal filtering, ML ranking, rediscovery/repurposing highlights, and lipid-target case study with ANXA2.
- transcript topics: Mendelian randomization as a natural clinical trial; Biobank meta-analysis (MVP, UKBB, FinnGen) and phenome-wide scope; cis-eQTL and cis-pQTL instrument sources; Two-sample MR and concordant-instrument filtering; XGBoost classifier for target prioritization; Drug rediscovery and repurposing (ANXA2, PCSK9, HMGCR)

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:
- 69,669 gene-trait pairs with strong causal evidence (p ≤ 1.6×10⁻⁹)
- 6,447 genes with strong causal evidence across 2,003 phenotypes
- rediscovered ~9% of approved drug targets in ChEMBL34
- ML ranking classifier (XGBoost) with precision-recall AUC = 0.79
- ANXA2 nominated as a lipid-regulation target and acts via PCSK9 inhibition
- Trastuzumab-associated cardiotoxicity flagged as a risk

QC result: Pass.

Nyeo SS et al., Nature, doi:10.1038/s41586-025-10020-2 - Population-scale WGS reanalysis quantifies persistent EBV DNA and shows MHC class II–mediated antigen presentation predicts EBV DNAemia and links to autoimmune and respiratory disease. Key terms: Epstein–Barr virus, MHC class II, whole-genome sequencing, HLA, antigen presentation.

Study Highlights:
Using whole-genome sequencing from UK Biobank (n≈490,560) and All of Us (n≈245,394), the authors extracted chrEBV-mapping reads, masked low-mappability regions, and defined EBV DNAemia (>1.2 genomes per 10^4 cells) in 9.7–11.9% of donors. They performed PheWAS, GWAS and ExWAS and identified 22 genome-wide significant loci and 686 missense variants across 148 genes with heritability enrichment in immune regulatory regions and B cells/antigen-presenting cells. Single-cell module scoring, pathway analyses and NetMHCpan/NetMHCIIpan peptide-presentation modeling implicated variable antigen processing and MHC class II presentation as primary determinants of EBV persistence, with stronger predicted presentation linked to lower EBV DNAemia. EBV DNAemia was reproducibly associated with autoimmune, respiratory, neurological and cardiovascular phenotypes across cohorts.

Conclusion:
Reanalysis of population-scale WGS demonstrates that host genetic variation—predominantly in antigen processing and MHC class II peptide presentation—modulates persistent EBV DNA in blood and associates with multiple complex diseases.

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

Article title:
Population-scale sequencing resolves determinants of persistent EBV DNA

First author:
Nyeo SS

Journal:
Nature, doi:10.1038/s41586-025-10020-2

DOI:
10.1038/s41586-025-10020-2

Reference:
Nyeo SS, Cumming EM, Burren OS, Pagadala MS, Gutierrez JC, Ali TA, Kida LC, Chen Y, Chu H, Hu F, Zou XZ, Hollis B, Fabre MA, MacArthur S, Wang Q, Ludwig LS, Dey KK, Petrovski S, Dhindsa RS & Lareau CA. Population-scale sequencing resolves determinants of persistent EBV DNA. Nature. 2026 Feb 19;650:664–672. https://doi.org/10.1038/s41586-025-10020-2

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/ebv-mhc-class-ii

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken content for core EBV DNAemia measurement, population-scale findings, genetic architecture (GWAS/ExWAS), MHC class II/HLA roles, peptide presentation modeling, cell-type enrichment, phenotype associations, viral genome considerations, and replication across UKB and AoU.
- transcript topics: Definition and measurement of EBV DNAemia from population-scale WGS; Population-scale prevalence in UKB and AoU, threshold and binarization; Genome-wide and exome-wide association results (22 loci; 686 missense variants in 148 genes); Role of MHC class II and HLA variation in EBV DNAemia; Specific HLA alleles: HLA-A*03:01 risk; HLA-DRB1*12:01 protection; NetMHC/NetMHCIIpan predictions and HBR-based antigen presentation

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:
- EBV DNAemia is quantified from chrEBV reads in population-scale WGS; threshold set at 1.2 EBV genomes per 10^4 human cells
- UKB prevalence of EBV DNAemia: 9.7% (47,452 individuals); AoU replication prevalence: 11.9%
- Genome-wide analysis identified 22 independent loci associated with EBV DNAemia; 686 missense variants across 148 genes
- Heritability enriched in immune regulatory regions; pronounced enrichment in B cells and antigen-presenting cells
- HLA region drives strongest genetic associations; HLA-A*03:01 increases risk; HLA-DRB1*12:01 is protective
- Predicted EBV epitope presentation strength by MHC class II alleles correlates with lower EBV DNAemia; class II alleles show strongest associations

QC result: Pass.

Perdigão C et al., EMBO Molecular Medicine, doi:10.1038/s44321-026-00389-6 - In mouse neurons, UFM1 loss or UFM1-R81C expression reduces protein translation, triggers ER stress and PERK activation, impairing dendrite and synapse development. Key terms: UFM1, UFMylation, ER stress, protein translation, Trazodone.

Study Highlights:
Using murine UFM1-deficient neurons generated by conditional knockout and CRISPR/Cas9 in vivo manipulations and lentiviral rescue, the study combined FUNCAT, puromycin labeling, patch-clamp electrophysiology, RNA-seq, mass spectrometry, TEM tomography, and in vitro UFMylation assays. UFM1 loss caused reduced dendrite complexity, a ~70% drop in colocalized synaptic puncta, decreased EPSC amplitudes and RRP size, induction of ER stress and PERK-UPR activation, and a substantial reduction in global protein translation. The UFM1-R81C variant was hypomorphic: it partially rescued morphology and function but showed drastically impaired activation by the E1 enzyme UBA5 and an aggravated ER-stress response to thapsigargin. Pharmacologically, Trazodone normalized translation in UFM1-R81C neurons and increased synapse numbers in both UFM1-KO and UFM1-R81C conditions, linking UPR/translation modulation to phenotypic rescue.

Conclusion:
UFMylation is required for neuronal development and function: UFM1 loss and the UFM1-R81C variant impair protein translation and ER homeostasis, and Trazodone restores translation in UFM1-R81C neurons while increasing synapse numbers.

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

Article title:
Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function

First author:
Perdigão C

Journal:
EMBO Molecular Medicine, doi:10.1038/s44321-026-00389-6

DOI:
10.1038/s44321-026-00389-6

Reference:
Perdigão C, Torres J, Magnussen HM, Koch J, Rudashevskaya E, Moschref F, Fiosins M, Benseler F, Wenger S, Nilsson T, Beuermann S, Bonn S, Rizzoli SO, Kulathu Y, Jahn O, Cooper BH, Ambrozkiewicz MC, Rhee JS, Brose N & Tirard M (2026) Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function. EMBO Molecular Medicine. https://doi.org/10.1038/s44321-026-00389-6

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/ufm1-r81c-neuronal-translation

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core scientific claims and experimental findings presented in the episode and mapped them to the paper's results: UFM1 loss causes reduced dendritic complexity and synapses, reduced translation; UFM1-R81C is hypomorphic with reduced UBA5 activation; PERK-UPR activation; Trazodone rescues translation and increas
- transcript topics: UFMylation pathway and enzymes (UFM1, UBA5, UFC1, UFL1); UFM1 loss: neuronal development and synapse reduction; UFM1-R81C variant mechanism; ER stress and PERK-UPR activation; Protein translation assessment (FUNCAT, puromycin); Trazodone rescue effects on translation and synapses

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:
- UFM1 loss reduces dendritic complexity and synapse numbers and lowers EPSC amplitudes and RRP size
- Global protein translation is reduced in UFM1-KO neurons
- UFM1 loss induces ER stress and activates the PERK-UPR pathway
- UFM1-R81C is hypomorphic with reduced activation by UBA5 and only partial rescue, with aggravated ER stress under challenge
- Trazodone restores translation in UFM1-R81C neurons and increases synapse numbers in both UFM1-KO and UFM1-R81C neurons

QC result: Pass.

Lin S et al., The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.015 - Bi-allelic FSD1L variants cause retinitis pigmentosa; FSD1L localizes to the photoreceptor axoneme and a deep intronic deletion abolishes retina-enriched exon 10b inclusion. Key terms: FSD1L, retinitis pigmentosa, photoreceptor axoneme, exon 10b, minigene assay.

Study Highlights:
In human and mouse retinal tissues and six affected individuals from four families, exome/genome sequencing identified bi-allelic ultra-rare FSD1L variants associated with retinitis pigmentosa. Single-cell RNA-seq, immunofluorescence, and ultrastructure expansion microscopy show FSD1L is enriched in cones and rods and localizes along the photoreceptor microtubule axoneme including the connecting cilium and outer segment. Functional assays including ARPE-19 minigene splicing and long-read nanopore sequencing of patient lymphocytes demonstrate that a deep intronic 26-nt deletion abolishes inclusion of a retina-enriched exon (exon 10b). Together these data link isoform-specific mis-splicing and axonemal localization to a plausible disruption of intracellular trafficking leading to photoreceptor degeneration.

Conclusion:
Bi-allelic disruption of FSD1L is associated with retinitis pigmentosa, and retina-enriched exon 10b mis-splicing provides a plausible mechanism for isolated retinal disease.

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

Article title:
Bi-allelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement

First author:
Lin S

Journal:
The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.015

DOI:
10.1016/j.ajhg.2026.01.015

Reference:
Lin S., Cancellieri F., Cao Y., et al. Bi-allelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement. The American Journal of Human Genetics 113, 1–11 (2026). https://doi.org/10.1016/j.ajhg.2026.01.015

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/fsd1l-retinitis-pigmentosa-axoneme

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive scientific content in the transcript: discovery of bi-allelic FSD1L variants in RP families; retina-enriched isoform with exon 10b; deep intronic deletion disrupting exon 10b; minigene splicing assays; FSD1L localization to photoreceptor axoneme/connecting cilium/outer segment; expression pattern in
- transcript topics: RP and inherited retinal disease overview; FSD1L as RP gene candidate; Retina-enriched isoform and exon 10b; Deep intronic deletion c.1025+624_1025+649del and exon 10b skipping; Minigene splicing assays in ARPE-19 cells; FSD1L localization to photoreceptor axoneme via U-ExM

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:
- Bi-allelic ultra-rare FSD1L variants identified in six individuals from four families
- FSD1L expression enriched in cone photoreceptors (and present in rods) in human retina
- FSD1L localizes along the photoreceptor microtubule axoneme, including the connecting cilium and outer segment
- Retina-enriched isoform includes exon 10b; deep intronic deletion disrupts exon 10b inclusion
- Minigene splicing assays show exon 10b skipping with the intronic deletion
- Clinical spectrum includes RP with variable neurological involvement; isoform- and allele-specific effects explain phenotypic variability

QC result: Pass.