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Tibbe D et al., The American Journal of Human Genetics - This study identifies bi-allelic hypomorphic WDHD1 variants in 17 subjects with a clinical spectrum from fetal lethality to microcephalic primordial dwarfism and characterizes cellular defects in patient-derived cells linked to replisome dysfunction. Key terms: WDHD1, microcephalic primordial dwarfism, replication stress, sister chromatid cohesion, splicing variants. Study Highlights:Researchers found bi-allelic WDHD1 variants in 17 subjects presenting with intrauterine growth retardation, microcephaly and a spectrum of organ abnormalities including neonatal acute liver failure. Several intronic variants cause aberrant splicing and markedly reduced WDHD1 protein levels in fibroblasts. Subject-derived cells showed slowed replication fork progression, impaired G1-to-S transition, increased spontaneous DNA damage, abnormal nuclear morphology, and elevated premature sister chromatid separation, supporting a role for WDHD1 in replisome stability and cohesion. Conclusion:Hypomorphic bi-allelic WDHD1 variants cause an autosomal recessive microcephalic primordial dwarfism spectrum by reducing WDHD1 protein and impairing replication fork stability, genome integrity, and sister chromatid cohesion, establishing WDHD1 as essential for normal human growth and development. Music:Enjoy the music based on this article at the end of the episode. Article title:Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism First author:Tibbe D Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.03.010 Reference:Tibbe D., Vogt M.R., Holling T., et al. Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism. The American Journal of Human Genetics. 2026. https://doi.org/10.1016/j.ajhg.2026.03.010 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/wdhd1-microcephalic-primordial-dwarfism QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-10. 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 WDHD1 function as replisome scaffold; intronic WDHD1 variants and splicing; DNA fiber assay and replication fork dynamics; γH2AX signaling; nuclear morphology; PCS; and liver pathology in MPD.- transcript topics: WDHD1 as replisome scaffold; intronic WDHD1 variants and splicing; DNA fiber assay and replication fork speed; γH2AX DNA damage signaling; nuclear morphology and lamin B1; premature sister chromatid separation (PCS) 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:- 17 subjects from 14 families with bi-allelic WDHD1 variants and MPD spectrum- intronic WDHD1 variants cause aberrant splicing and markedly reduced WDHD1 protein levels in patient-derived cells- WDHD1 acts as replisome scaffolding to stabilize replication forks and maintain genome integrity- replication fork progression is slowed and there is increased sp...

Katzourou IK et al., The American Journal of Human Genetics - Population analysis of ~459,000 UK Biobank participants shows that carriers of neurodevelopmental CNVs (ND-CNVs) have higher odds of co-occurring internalizing (depression, anxiety, somatic) and cardiometabolic conditions (hypertension, dyslipidemia, obesity, T2D, CKD). Effects are stronger for deletions than duplications, greater in females, and linked to the number of haploinsufficient genes within deletions. Key terms: copy-number variants, multimorbidity, internalizing disorders, cardiometabolic, UK Biobank. Study Highlights:Using CNV calls and linked EHRs in the UK Biobank, the authors tested associations between 54 ND-CNVs and combinations of internalizing and cardiometabolic conditions (ICM-MM). Aggregated ND-CNV carriers (n≈7,546; ~1.6%) had higher odds of ICM-MM (OR range 1.21–1.57) and a higher ICM-MM frequency (14.2% vs 11.5%). Deletions showed stronger effects than duplications and the number of haploinsufficient genes in deletions was associated with greater ICM-MM risk. No robust interactions were detected between ND-CNV status and polygenic risk scores after multiple testing correction. Conclusion:ND-CNVs increase risk of internalizing–cardiometabolic multimorbidity at the population level, especially for deletions and in females, suggesting the need for heightened clinical monitoring of carriers. Music:Enjoy the music based on this article at the end of the episode. Article title:Neurodevelopmental copy-number variants increase risk of internalizing and cardiometabolic multimorbidity: Findings from the UK Biobank First author:Katzourou IK Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.02.021 Reference:Katzourou IK, LINC consortium, Barroso I, et al. Neurodevelopmental copy-number variants increase risk of internalizing and cardiometabolic multimorbidity: Findings from the UK Biobank. The American Journal of Human Genetics. 2026;113:1–11. https://doi.org/10.1016/j.ajhg.2026.02.021 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/nd-cnv-internalizing-cardiometabolic-multimorbidity QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-08. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections covering ND-CNV–ICM-MM association, UK Biobank design and CNV calling, dosage-sensitivity (haploinsufficient vs triplosensitive), deletion vs duplication effects (notably 16p11.2), sex differences, PRS interaction analyses, and clinical implications including multidisciplinary care and casca- transcript topics: Definition of ND-CNVs and ICM-MM; UK Biobank cohort size, CNV calling methods (PennCNV); Dosage sensitivity: haploinsufficient vs triplosensitive genes; Deletion vs duplication effects on ICM-MM and obesity; 16p11.2 region emphasis; Sex differences in ND-CNV associations 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:<...

Sapp JC et al., The American Journal of Human Genetics - A longitudinal study of recipients of medically actionable secondary genomic findings develops a Bayesian approach that integrates variant, family genotypic, and phenotypic data to estimate the probability that a secondary finding represents a true clinicomolecular diagnosis, with a detailed analysis of BRCA1/BRCA2 families and implications for screening policy and clinical management. Key terms: secondary findings, BRCA1, BRCA2, Bayesian risk assessment, population genomic screening. Study Highlights:The team enrolled 227 secondary findings recipients and completed genotyping and deep phenotyping for 163 probands, using cascade testing and variant reclassification. They piloted a Bayesian method combining prior population prevalence, variant pathogenicity, and family genotype–phenotype data to estimate clinicomolecular diagnosis (CMD) probabilities for BRCA1/2 families. CMD probabilities varied widely (26.2% to >99.9%) and over half of BRCA1/2 families met NCCN diagnostic testing criteria, indicating underuse of diagnostic testing. Conclusion:In opportunistic secondary findings contexts the posterior probability that a patient has the implicated monogenic disease can differ substantially from variant pathogenicity; integrating familial genotypic and phenotypic data via Bayesian methods refines risk estimates and should guide shared decision-making, management strategies, and policy for population genomic screening. Music:Enjoy the music based on this article at the end of the episode. Article title:Measuring disease likelihood in genomic ascertainment First author:Sapp JC Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.03.009 Reference:Sapp JC, Lewis KL, Modlin EW, et al. Measuring disease likelihood in genomic ascertainment. The American Journal of Human Genetics. 2026;113:1–12. doi:10.1016/j.ajhg.2026.03.009 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/measuring-disease-likelihood-genomic-ascertainment QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-07. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections describing the Bayesian CMD approach, the BRCA1/BRCA2 findings, the Family 8334 case, NCCN criteria implications, and study design/limitations.- transcript topics: ACMG secondary findings context and selection bias; Bayesian probability model for CMD; Cascade testing and family data integration; BRCA1 vs BRCA2 variant distribution and penetrance; NCCN criteria and clinical testing underutilization; Study design and recruitment (163 probands from 41 sources) 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:- CMD probability range across BRCA1/BRCA2 families: 26.2% to 100%- Baseline posterior probability for BRCA2-related CMD: 58.2%- Posterior CMD probability for family 8334: 99.2%- Average CMD...

Massilania D et al., PNAS - We summarize a PNAS study reporting a ~37× genome from a ~110,000-year-old male Neandertal (Denisova 17) from Denisova Cave. The genome shows D17 is closely related to an earlier Denisova Neandertal (D5), both carry Denisovan introgressed segments, and Neandertal groups displayed high regional differentiation and small, isolated populations in the Altai. Key terms: Neandertal, Denisova Cave, genome sequencing, population structure, Denisovan admixture. Study Highlights:The authors generated a high-coverage (~37-fold) autosomal genome from a ~110,000-year-old male Neandertal (D17) from Denisova Cave and dated it to ~110 kya. D17 is more closely related to an older Denisova Neandertal (D5) than to European or other Altai Neandertals and both D5 and D17 contain Denisovan-derived genomic segments. Patterns of homozygosity indicate smaller, more isolated groups in Altai Neandertals compared with later European Neandertals. Estimated FST shows Eastern and Western Neandertals were as genetically differentiated as the most divergent present-day human populations, implying rapid drift under small effective sizes. Conclusion:A high-coverage Altai Neandertal genome reveals Denisovan admixture in older eastern Neandertals, small and isolated group sizes in the Altai, and pronounced east–west Neandertal population differentiation exceeding that seen among modern human populations. Music:Enjoy the music based on this article at the end of the episode. Article title:A high-coverage Neandertal genome from the Altai Mountains reveals population structure among Neandertals First author:Massilania D Journal:PNAS DOI:10.1073/pnas.2534576123 Reference:Massilania D, Peyrégne S, Iasi LN M, de Filippo C, Mafessoni F, Mesab AB, Sümer AP, Swiel Y, Popli D, Silverman S, Boylea MJ, Kozlikind MB, Shunkov MV, Derevianko AP, Higham T, Douka K, Meyer M, Zeberg H, Kelso J, Pääbo S. A high-coverage Neandertal genome from the Altai Mountains reveals population structure among Neandertals. PNAS. 2026;123(13):e2534576123. doi:10.1073/pnas.2534576123 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/d17-altai-neandertal-genome-structure QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-05. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive audit focused on the transcript sections describing: specimen, sequencing coverage, population structure, Denisovan admixture, autozygosity and small group sizes, FST differentiation, and dating of D17/D5 lineages, plus migration/replacement dynamics.- transcript topics: Denisova 17 (D17) DNA extraction and high-coverage genome (~37x); Relationship among Neandertals (D17, D5, Chag8, Vi33.19) and Denisovans; Denisovan introgression into D17 and D5; lack of clear Denisovan signal in Chag8; Autozygosity and small population sizes (<50 individuals) in Eastern Neandertals; Genetic differentiation (FST ~0.30) between Eastern and Western Neandertals; Molecular dating and age estimates for D17 (~110 kya) and Y-chromosome lineage QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata c...

Law C-T et al., Cell Genomics - Law and Burns introduce TiMEstamp, a comparative-genomics pipeline that dates LINE-1 insertions from multiple sequence alignments and discovers hundreds of LINE-1 chimeric insertions fused to diverse RNAs across mammalian evolution. Key terms: LINE-1, TiMEstamp, chimeric insertions, retrotransposition, comparative genomics. Study Highlights:The authors developed TiMEstamp to infer TE insertion times from multispecies MSAs and to detect contemporaneous 5′ sequences fused to LINE-1. They compiled a large catalog of LINE-1 chimeras (reported >700 events) including known U6/LINE-1 cases and newly identified partners such as tRNA, 28S rRNA, 7SL, Y RNA, Alu elements, and mRNA 5′ transductions. Alu/LINE-1 chimeras (452 events) and 17 mRNA/lncRNA 5′ transductions were characterized with TSDs, EN motifs, and orientation/length patterns. They also show that promoter co-option (e.g., RAP1GDS1 driving a spliced intronic L1PA2) can restore retrotransposition competence. Conclusion:Comparative MSA-based timing reveals widespread, recurrent recombination between LINE-1 RNA and diverse cellular RNAs, producing chimeric insertions that have contributed to transposon diversification and provide mechanisms (RNA ligation, template switching, twin priming, promoter co-option) that may influence TE evolution and somatic/germline retrotransposition. Music:Enjoy the music based on this article at the end of the episode. Article title:Comparative genomics reveals LINE-1 recombination with diverse RNAs First author:Law C-T Journal:Cell Genomics DOI:10.1016/j.xgen.2026.101165 Reference:Law C-T and Burns K.H., 2026. Comparative genomics reveals LINE-1 recombination with diverse RNAs. Cell Genomics 6, 101165. https://doi.org/10.1016/j.xgen.2026.101165 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/line1-recombination-diverse-rnas QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-05. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections covering the TiMEstamp workflow and data (MSA across mammals), discovery of chimeric LINE-1 insertions (tRNA halves, 28S rRNA, 7SL, Y RNA, 7SK), Alu/LINE-1 chimeras, mRNA/lncRNA 5' transductions (MAP3K13, FHIT), RAP1GDS1 promoter co-option, twin priming and trans-splicing mechanisms, and study limitati- transcript topics: LINE-1 retrotransposition mechanics (TPRT); TiMEstamp methodology and MSA dating; Chimeric LINE-1 insertions with non-LINE-1 RNAs (tRNA halves, 28S rRNA, 7SL, Y RNA, 7SK RNA); Alu/LINE-1 chimeras and temporal activity; 5′ transductions involving mRNAs/lncRNAs (MAP3K13, FHIT, RAP1GDS1); RAP1GDS1 promoter co-option and transcriptional rescue 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:- TiMEstamp uses MSAs across mammals to date LINE-1 insertions and identify contemporaneous adjacencies- Chimeric LINE-1 insertions involve diverse RNAs including tR...

Jiang P et al., Cell Genomics - This episode reviews a Cell Genomics study that uses ssDNA '2-end' and novel '4-end' sequencing to profile native 5′ and 3′ termini of plasma cfDNA. The work identifies PREM/POEM markers, links 3′ ends to methylation, and shows improved HCC detection. Key terms: cfDNA fragmentomics, 3' end motifs, 4-end sequencing, hepatocellular carcinoma, DNASE1L3. Study Highlights:The authors adapted single-stranded library preparation (2-end sequencing) to measure native 5′ (EM5) and 3′ (EM3) end motifs and defined flanking PREM and POEM motifs. Combining size‑stratified PREM, EM5, EM3, and POEM features raised hepatocellular carcinoma (HCC) detection to an AUC of 0.95. Fragmentomics-based methylation analysis of 3′ ends (3′ FRAGMA) improved HCC detection further (AUC 0.97). A novel 4-end sequencing approach captured all four termini of double‑stranded cfDNA, yielding 4‑end motif models with AUC up to 0.98 and revealing coordinated nuclease activity, notably DNASE1L3 involvement. Conclusion:Holistic end profiling of cfDNA—integrating native 5′ and 3′ ends, flanking motifs, methylation-informed fragmentomics, and four‑end resolution—enhances cancer detection performance and provides mechanistic insight into coordinated nuclease-mediated fragmentation, warranting larger validation studies. Music:Enjoy the music based on this article at the end of the episode. Article title:Holistic determination of ends of cfDNA molecules First author:Jiang P Journal:Cell Genomics DOI:10.1016/j.xgen.2026.101142 Reference:Jiang P., Ma M.-J. L., Qiao R., et al. Holistic determination of ends of cfDNA molecules. Cell Genomics. 2026;6:101142. doi:10.1016/j.xgen.2026.101142 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/holistic-cfdna-ends-episode-333 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-04. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript’s substantive description of 2-end sequencing (EM5/EM3), PREM/POEM, 3'-FRAGMA, 4-end sequencing, nuclease signatures (DNASE1L3, DNASE1, DFFB), HCC diagnostic performance (AUC values), fragment-size context, and translational limitations as reported in the article.- transcript topics: 2-end sequencing preserving native ends (EM5/EM3); Pre-end (PREM) and post-end motifs (POEM); 4-end sequencing with stem-loop adapters and PacBio SMRT; 3'-FRAGMA methylation analysis; Nuclease-specific end motifs and coordinated fragmentation (DNASE1L3, DNASE1, DFFB); HCC detection performance and AUC values 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:- 2-end sequencing preserves native 5' and 3' ends (EM5/EM3) by omitting end-repair during library prep- PREM and POEM motifs are defined and analyzed as end-motif neighbors around EM5 and EM3- 4-end sequencing enables simultaneous assessment of all four termini using stem-loop adapters and PacBio SMRT sequencing<...

Liao Y et al., PNAS - Human dermal fibroblasts from young and old donors were embedded in 3D collagen and exposed to mechanical tension and TGF-β. Combining bulk RNA‑seq, ATAC‑seq, imaging, and perturbations, the study shows that matrix tension amplifies TGF‑β responses in young but not aged cells and identifies AP‑1 as a central chromatin-associated regulator required for fibroblast activation. Key terms: chromatin accessibility, mechanotransduction, aging, TGF-β signaling, AP-1. Study Highlights:Young fibroblasts under matrix tension mount a strong, synergistic transcriptional response to TGF‑β while aged fibroblasts exhibit blunted or divergent responses. Age-dependent differences in chromatin accessibility, notably at distal regulatory elements, correlate with these transcriptional outcomes. AP‑1 family motifs are highly enriched in TGF‑β- and age-responsive accessible regions and cooperate with age-specific TFs. Inhibiting AP‑1 activity prevents JUNB recruitment to RNA polymerase II and suppresses myofibroblast activation. Conclusion:3D chromatin accessibility acts as a dynamic filter of mechanical and biochemical signals during aging; AP‑1 and its regulatory network drive the age-specific chromatin remodeling that permits synergistic tension + TGF‑β responses in young fibroblasts, and AP‑1 inhibition blocks this activation, suggesting a potential therapeutic axis. Music:Enjoy the music based on this article at the end of the episode. Article title:Chromatin accessibility regulates age- dependent nuclear mechanotransduction First author:Liao Y Journal:PNAS DOI:10.1073/pnas.2522217123 Reference:Liao Y, Land M, Gupta R, Yu L, Sornapudi TR, Shivashankar GV. Chromatin accessibility regulates age-dependent nuclear mechanotransduction. PNAS. 2026;123(13):e2522217123. doi:10.1073/pnas.2522217123. Published March 26, 2026. License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/base-by-base-332-chromatin-age-mechanotransduction QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-02. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive auditing covered the study’s central mechanistic story: aging as a chromatin-filter for mechanochemical signaling; AP-1 as master regulator; age-specific TF partnerships; the 3D collagen tension model; ATAC-seq/RNA-seq integration; and AP-1 perturbation experiments.- transcript topics: Aging as chromatin-based signaling filter; 3D collagen gel tension model with glass ring; TGF-β signaling and mechanical tension synergy; AP-1 as master regulator; age-specific partners (JUNB vs HOXB13); ATAC-seq and RNA-seq integration; Perturbation experiments (siJUNB, T-5224, kinase inhibitors) 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:- Young fibroblasts exhibit synergistic gene expression enhancement to combined mechanical tension and TGF-β; aging cells show a blunted/divergent response- Quantified...

Tan et al et al., The American Journal of Human Genetics - This report identifies bi-allelic NDUFA5 variants in four individuals from three families causing an isolated mitochondrial complex I deficiency with variable multisystem features. The study combines genomic, transcriptomic, proteomic, biochemical, structural modeling, and zebrafish functional data to support pathogenicity. Key terms: NDUFA5, complex I deficiency, mitochondriopathy, proteomics, zebrafish model. Study Highlights:Bi-allelic NDUFA5 variants were found in four individuals from three unrelated families presenting with a variable multisystem phenotype including congenital heart defects, hematological abnormalities, and Leigh-like neurological features. Multi-tissue RNA-seq and RT-PCR revealed aberrant splicing and NMD, while proteomics and BN-PAGE demonstrated reduced NDUFA5 protein, isolated complex I deficiency, and stalled assembly at a Q/P intermediate. CRISPR-Cas9 ndufa5 zebrafish crispants showed developmental delays, locomotor deficits, reduced survival, and epileptiform neural activity, corroborating functional impact. Conclusion:Combined clinical, molecular, and animal-model evidence supports that bi-allelic NDUFA5 variants cause a recessive mitochondriopathy with isolated complex I deficiency and variable multisystem involvement; NDUFA5 should be considered in molecular reanalysis of undiagnosed complex I disorders. Music:Enjoy the music based on this article at the end of the episode. Article title:Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency First author:Tan et al Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.03.003 Reference:Tan et al., 2026, The American Journal of Human Genetics 113, 1–14, May 7, 2026. https://doi.org/10.1016/j.ajhg.2026.03.003 License:CC BY (http://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/ndufa5-complex-i-mitochondriopathy QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-31. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript portions describing NDUFA5 variants, splicing consequences, proteomics/BN-PAGE findings, zebrafish model outcomes, and the diagnostic paradigm shift.- transcript topics: Complex I biology and mitochondrial energy metabolism; Gene discovery via GeneMatcher and patient cohorts; NDUFA5 variant classes and their consequences; RNA sequencing and exon skipping due to synonymous variant; Protein abundance and complex I assembly defects; Blue native PAGE and assembly intermediates 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:- Bi-allelic NDUFA5 variants cause a mitochondrial complex I deficiency with multisystem disease- Two distinct variant classes observed: frameshift + missense in Family 1; start-loss + synonymous splice variant in Family 2; homozygous synonymous splice variant in Family 3- RNA-seq reveals aberrant splicing and nonsense-mediated decay for some alleles; exon 3 skipping yields a 39-amino-acid in-frame deletion- Proteomics shows ma...

Chaldebas M et al., The American Journal of Human Genetics - Chaldebas et al. present 5ULTRA, a computational pipeline that integrates uORF databases, Kozak-motif features, splicing prediction, and a random-forest score to detect and prioritize 5′ UTR variants predicted to alter protein translation. The score correlates with proteomic and MPRA measures and is applied to population, somatic, GWAS, and rare-disease datasets to nominate candidate functional variants. Key terms: 5' UTR, uORF, Kozak motif, translation regulation, machine learning. Study Highlights:The authors developed 5ULTRA to annotate SNVs, indels, and splicing variants that create/disrupt uORFs or alter Kozak strength, integrating comprehensive uORF databases and SpliceAI. A random-forest 5ULTRA score trained on HGMD and gnomAD distinguishes likely translation-impacting variants and achieved strong cross-validation performance and AUC = 0.82 on an independent ClinVar test. The score correlates with cis-pQTL effect sizes (Spearman rho = 0.57) and with MPRA ribosome-load measurements (rho = 0.78). Genome-wide screening found thousands of candidate variants, highlighted rare/conserved signals in disease genes, and nominated examples in cancer, GWAS loci, and rare infections. Conclusion:5ULTRA provides a validated, transcript-aware framework to detect and prioritize 5′ UTR variants that modulate translation, offering mechanistic hypotheses for noncoding variant interpretation in rare disease, cancer, and complex-trait genetics; the tool and data are publicly available under a CC BY license. QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-30. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive auditing focused on the scientific content described in the transcript and its alignment with the AJHG article: 5ULTRA architecture, features, SpliceAI integration, validation metrics, somatic/GWAS/infectious disease applications, limitations, and open-source availability.- transcript topics: 5′ UTR regulatory elements (Kozak motif, uORFs) and translation initiation; 5ULTRA methodology and data integration (MANE transcripts, uORFdb, Ribo-uORF, SpliceAI); Machine-learning scoring (17 features; PhyloP conservation as key predictor; uORF/k Kozak annotations); Model validation (ClinVar, cross-validation AUC, accuracy); Correlation with proteomics and MPRA data (cis-pQTL, ΔMRL); Somatic cancer applications (NRAS and ABI1 examples; splicing effects; N-terminal extensions) 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:- 5ULTRA identifes and prioritizes 5′ UTR variants that affect translation via uORFs and Kozak motifs- 17 features used by the 5ULTRA random forest model; PhyloP conservation of uORF start codon as the strongest predictor- Genome-wide analysis: ~28 million 5′ UTR variants; ~137k predicted to affect translation via URFs or Kozak changes- ClinVar independent test AUC ≈ 0.82 and ClinVar threshold-based accuracy ≈ 80.8%- Cross-validation 5-fold AUC ≈ 0.981; MPRA and pQTL data show concordant translation effects (ΔMRL, Spearman ρ values ~0.78; 5ULTRA vs cis-pQTL ρ ≈ 0.57) QC result: Pass. Chapters (00:00:08) - Genome Wide Detection of Human 5 UTR Variants(00:06:41) - How a Deep Learning Algorithm Can Identify Dangerous Human Variants(00:12:35) - 5 Ultra: The computational genetics of cancer(00:18:46) - How to decode the secrets of the human genome

Mualim KS et al., Proceedings of the National Academy of Sciences - This study develops spatiotemporal population-genetic models calibrated with genomic data to predict how habitat loss and fragmentation drive changes in nucleotide diversity (π). The authors translate IUCN, Living Planet Index, and GBF indicators into estimates of current and future genetic diversity loss across thousands of species. Key terms: genetic diversity, habitat loss, fragmentation, WFmoments, conservation indicators. Study Highlights:The authors built WFmoments and SLiM-based spatiotemporal frameworks and calibrated them with population-scale genomic data from 29 species to model π dynamics after habitat loss. They translated demographic proxies from the IUCN Red List, Living Planet Index, and GBF indicators for 4,611 species to estimate genetic diversity declines. Short-term π loss is often modest, but mid- and long-term losses lag behind habitat declines and can be substantially larger, with average estimates ranging from ~1–13% already lost and mid-term projections much higher under some datasets. Habitat fragmentation can inflate species-wide π while reducing within-population diversity, and recovery of genetic diversity after restoration is slow. Conclusion:Habitat protection alone is insufficient to guarantee long-term genetic health; conservation should incorporate genetic monitoring, connectivity restoration, and policies informed by spatiotemporal genetic forecasts. Music:Enjoy the music based on this article at the end of the episode. Article title:Large future genetic diversity losses are predicted from conservation indicators even with habitat protection First author:Mualim KS Journal:Proceedings of the National Academy of Sciences DOI:10.1073/pnas.2514371123 Reference:Mualim KS, Spence JP, Weiß C, Selmoni O, Lin M, Exposito-Alonso M. Large future genetic diversity losses are predicted from conservation indicators even with habitat protection. Proc. Natl. Acad. Sci. U.S.A. 2026. doi:10.1073/pnas.2514371123 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/predicting-genetic-diversity-losses-329 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-30. 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 the article’s methods (WFmoments, GDAR), habitat-loss scenarios (edge contraction vs fragmentation), key results (short-term vs long-term π losses, wallund/Wahlund effect), real-world examples (Miami Blue Butterfly, Torrey Pine, E. melliodora), and global-scale predictions; excluded- transcript topics: Genetic diversity concept (π) and proxies; WFmoments framework and GDAR; Edge contraction vs fragmentation habitat-loss patterns; Wahlund/Wahlund-like effects and fragmentation inflation; Spatial population structure (FST) and migration; Empirical calibration: 29 species and 4,611 species predictions 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- licen... Chapters (00:00:20) - What's the Hidden Crisis of Genetic Diversity?(00:06:09) - How Human Development Is Wiping Out Genetic Diversity(00:11:02) - The Walland Effect on species(00:13:13) - The ticking time bomb of genetic diversity

Zhou A et al., Human Genetics and Genomics Advances - Comparing LD‑pruning, COJO, SuSiE and PCA in haptoglobin (HP) cis‑region data, the study finds including non‑lead variants substantially increases variance explained (R2) and MR precision. Key terms: haptoglobin, cis-Mendelian randomization, LD-pruning, SuSiE, COJO. Study Highlights:The study analyzed circulating haptoglobin (HP) using Fenland protein GWAS summary statistics with LD from UK Biobank, compared four variant selection methods (modified LD‑pruning, COJO, SuSiE, PCA), and extended results with simulations and 15 additional gene regions. In the HP region, incorporating non‑lead variants produced a median proportional gain in R2 of 145.1% and a median reduction in MR standard error of 36.3% relative to the lead variant alone. In simulations with one or two causal variants the methods recovered the expected genetic variance (≈40%) and, when causal variants were removed, non‑lead‑inclusive methods recovered more variance than lead‑only. The functional implication supported by the data is that including correlated non‑lead variants can materially increase instrument strength and precision in cis‑MR, but may raise risks of pleiotropy and numerical instability. Conclusion:Variant selection methods that incorporate correlated non‑lead variants reliably improve instrument strength (R2) and MR precision in cis‑MR compared with the lead‑variant‑only approach; comparisons with the lead variant are advised to detect instability. Music:Enjoy the music based on this article at the end of the episode. Article title:Variant selection to maximize variance explained in cis-Mendelian randomization First author:Zhou A Journal:Human Genetics and Genomics Advances DOI:10.1016/j.xhgg.2026.100573 Reference:Zhou A, Karhunen V, Tian H, Pott J, Patel A, Slob EAW, Burgess S. Variant selection to maximize variance explained in cis-Mendelian randomization. Human Genetics and Genomics Advances. 2026 Apr 9;7:100573. https://doi.org/10.1016/j.xhgg.2026.100573. 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/hp-variant-selection-cis-mr QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-27. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing: (1) the four variant selection methods and their rationale; (2) HP region results including R2 gains and SE reductions; (3) simulation studies with known causal variance (40%); (4) extension to 15 gene regions; (5) pleiotropy concerns and safeguards; (6) practical recommendat- transcript topics: Four variant selection methods (LD-pruning, COJO, SuSiE, PCA); Modified LD-pruning with adjusted R2 and LD-matrix checks; HP region results: variance explained (R2) gains and MR precision; Simulations with known causal variance (40%); Two-causal-variant scenario and lead variant variance explained; Extension to 15 additional gene regions 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- articl... Chapters (00:00:20) - How a single matrix can cripple genomics(00:01:34) - Deep Dive: The Search for genetic instruments without breaking the math(00:05:59) - The Hidden Problem with Standard LD Pruning(00:11:13) - The Lead Variants vs Non-Lead variants in disease prediction(00:15:27) - Multivariant Analysis: The Right Mix of Variants

Lambton J et al., The American Journal of Human Genetics - Bi-allelic ATG12 variants disrupt ATG12‑ATG5 conjugation and LC3 lipidation, impairing autophagy in patient cells and model systems and causing cerebellar vermis hypoplasia. Key terms: ATG12, autophagy, neurodevelopmental disorder, zebrafish, LC3 lipidation. Study Highlights:The study characterized six affected individuals with bi-allelic ATG12 variants using patient fibroblasts, HeLa ATG12 knockout complementation, yeast complementation, and CRISPR zebrafish models. Methods included WES/WGS and Sanger sequencing, immunoblotting, LC3/p62 flux assays, HaloTag-LC3 processing, LDH sequestration, AlphaFold-Multimer structural modeling, yeast GFP-Atg8 assays, and zebrafish behavioral and imaging assays. Structural modeling and biochemical data indicate variants map to ATG12 interfaces with ATG5 and ATG3, destabilize ATG12 or its conjugate with ATG5, reduce LC3/Atg8 lipidation and autophagic flux in a variant-dependent manner. Functionally, ATG12 disruption associates with neurodevelopmental phenotypes including cerebellar vermis hypoplasia, ataxia and seizures in humans, and causes growth, brain-structure and locomotor defects with reduced survival in zebrafish. Conclusion:Bi-allelic ATG12 variants impair ATG12 function and autophagy, producing a recessive neurodevelopmental disorder marked by cerebellar vermis hypoplasia and neurological deficits. Music:Enjoy the music based on this article at the end of the episode. Article title:Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder First author:Lambton J Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.03.002 Reference:Lambton J, Asano S, Huang Y, Suomi F, Eguchi T, Petree C, Huang K, Prigent M, Imam A, McCorvie TJ, Warren D, Hobson E, McCullagh H, Misceo D, Bjerre A, Smeland MF, Klingenberg C, Frengen E, Naik S, Ryan G, Sudarsanam A, Foster K, Vasudevan P, Samanta R, Rahman F, Maqbool S, Udani V, Efthymiou S, Houlden H, McFarland R, Collier JJ, Maroofian R, Yue WW, Varshney GK, Klionsky DJ, Legouis R, McWilliams TG, Mizushima N, Oláhová M, Alston CL, Taylor RW. Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder. The American Journal of Human Genetics. 2026 May 7;113:1–18. https://doi.org/10.1016/j.ajhg.2026.03.002 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/biallelic-atg12-autophagy-disorder QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-27. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited substantive scientific content from the transcript, focusing on the patient cohort, molecular mechanism (ATG12-ATG5 conjugation, LC3 lipidation), structural modeling, model organisms (yeast, zebrafish), and neurological phenotype.- transcript topics: Bi-allelic ATG12 variants and patient cohort; ATG12-ATG5 conjugation and LC3 lipidation; AlphaFold/structural modeling of ATG12 interactions; Yeast and zebrafish functional assays; Cerebellar involvement and mitophagy; Therapeutic implications of autophagy modulation QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- c... Chapters (00:00:20) - Why a single gene is completely lethal in humans(00:05:26) - Flip-flopping mutations in the brain(00:10:47) - Mitophagy 7, The cell survival paradox(00:14:10) - Autophagy Defective in the brain

Strand LG et al., Proc. Natl. Acad. Sci. U.S.A - In C. elegans germline, the deubiquitinase DUO-1 is required for assembly and active maintenance of the synaptonemal complex and REC-8 cohesin, preventing RAD-51 accumulation and ensuring diakinesis compaction. Key terms: DUO-1, Caenorhabditis elegans, synaptonemal complex, REC-8, auxin-inducible degron. Study Highlights:Using C. elegans germline as a developmental timecourse model, the authors combined cytological analyses (immunofluorescence, FISH, RAD-51/MSH-5/COSA-1 staining), temporally controlled auxin-inducible degron (AID) depletion, and TurboID proximity labeling with LC–MS to probe DUO-1 function. Loss or acute depletion of DUO-1 impairs SC assembly, leads to progressive axis/SC instability, depletion of REC-8 cohesin from chromosomes, hyperaccumulation of RAD-51-marked early DSB repair intermediates, and premature sister-chromatid separation. TurboID identifies PARG-1 and cohesin/HORMAD components as proximal partners and DUO-1::GFP localizes to nucleoplasm and a subset of chromosome axes, most prominently in late pachytene/early diplotene. Temporal AID experiments show DUO-1 is required continuously for early SC assembly, late-pachytene SC maintenance, and rapid preservation of diakinesis chromosome compaction, implying an active maintenance role for DUO-1 in preserving chromosome architecture during meiotic prophase. Conclusion:DUO-1 is continuously required throughout meiotic prophase in C. elegans to promote assembly and maintain stability of chromosome axes and synaptonemal complexes, protect REC-8 cohesin distribution, limit accumulation of early DSB repair intermediates, and ensure late-prophase chromosome compaction. Music:Enjoy the music based on this article at the end of the episode. Article title:Active maintenance of meiosis-specific chromosome structures in Caenorhabditis elegans by the deubiquitinase DUO-1 First author:Strand LG Journal:Proc. Natl. Acad. Sci. U.S.A DOI:10.1073/pnas.2532671123 Reference:Strand LG, Choi CP, McCoy S, Nsamba ET, Silva N, Villeneuve AM. Active maintenance of meiosis-specific chromosome structures in Caenorhabditis elegans by the deubiquitinase DUO-1. Proc. Natl. Acad. Sci. U.S.A. 2026;123(12):e2532671123. https://doi.org/10.1073/pnas.2532671123 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/duo-1-c-elegans-meiosis QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-25. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the spoken scientific content reflecting the paper's core findings: DUO-1’s continuous maintenance of meiosis-specific chromosome structures, SC/axis stability, REC-8 cohesin protection, RAD-51 dynamics, AID-time course revealing separable roles, and the DUO-1–PARG-1 interaction revealed by TurboID.- transcript topics: Meiotic prophase architecture (SC/axis) and DUO-1 roles; Duo-1 mutant phenotypes: SC assembly failure and polycomplexes; REC-8 cohesin distribution and sister chromatid cohesion; RAD-51 dynamics and SPO-11 dependency; COSA-1 foci and recombination intermediates; Auxin-inducible degradation (AID) reveals separable roles in assembly, maintenance, and compaction QC Summary: Chapters (00:00:00) - The architectural worksite of life(00:05:24) - The genetic disaster of Meotic mutants(00:10:49) - The Duplicity of Probes(00:16:29) - How does DNA repair become so fragile as we grow?

Lawrence et al., The American Journal of Human Genetics - Using a cis-principal-component (pcQTL) approach in human GTEx tissues, the authors uncover novel multi-gene regulatory variants and 33% more GWAS colocalizations than single-gene eQTLs. Key terms: pcQTL, allelic proxitropy, GTEx, colocalization, HOXB. Study Highlights:The study analyzes 13 human GTEx tissues and identifies clusters of co-expressed neighboring genes, then applies PCA to cluster expression and maps cis-principal-component QTLs (pcQTLs). pcQTL discovery and fine-mapping used SuSiE and TensorQTL permutation-based FDR to identify an average of ~1,396 pcQTLs per tissue, ~27% of which were not found by single-gene eQTL mapping. pcQTLs tend to represent smaller effects distributed across multiple genes in a cluster and often colocalize with GWAS hits missed by single-gene methods. Functionally, pcQTLs increased GWAS colocalizations by 33%, highlighting multi-gene regulatory proxitropy as a source of complex-trait-associated variation. Conclusion:Cis-multi-gene pcQTL mapping uncovers novel regulatory loci and increases GWAS colocalizations compared with single-gene analyses, demonstrating that multi-gene approaches improve detection and interpretation of complex-trait-associated variants. Music:Enjoy the music based on this article at the end of the episode. Article title:Focus on single-gene effects limits discovery and interpretation of complex-trait-associated variants First author:Lawrence Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.02.022 Reference:Lawrence, K.A., Gjorgjieva, T., Nachun, D., and Montgomery, S.B. (2026). Focus on single-gene effects limits discovery and interpretation of complex-trait-associated variants. The American Journal of Human Genetics 113, 1–10. https://doi.org/10.1016/j.ajhg.2026.02.022 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/cis-pcqtl-allelic-proxitropy-gtex QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-24. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections presenting the conceptual shift to neighborhood gene regulation (allelic proxytropy), the cis-pcQTL (pcQTL) methodology, GTEx tissue clustering, key quantitative results (novel pcQTLs, clusters, colocalizations), and concrete examples (HOXB cluster, IL-18 receptor genes), plus discussion- transcript topics: Conceptual shift to gene neighborhoods and allelic proxytropy; cis-pcQTL (pcQTL) methodology and PCA-based signal extraction; GTEx tissue clusters and gene-neighborhood calling; pcQTL discovery statistics (clusters, pcQTLs per tissue, novel signals); pcQTLs and GWAS colocalizations; HOXB cluster example (HOXB3 vs HOXB4) and PC4 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:- pcQTLs reveal novel multi-gene regulatory variants missed by single-gene eQTLs- average pcQTLs per tissue is 1,396-... Chapters (00:00:00) - Deep Dive: The genome's interconnected networks(00:05:27) - The Shared Signal of Genomic Science(00:11:15) - Single gene mapping fails to explain complex traits(00:18:13) - Understanding the genetics of human diseases(00:20:39) - Beyond one gene

Farnung J et al., Nature - Cryo-EM and biochemical reconstitution reveal how the ZSWIM8–CUL3 E3 ligase recognizes human AGO2–miRNA–trigger complexes to polyubiquitylate AGO and drive targeted microRNA degradation. Key terms: ZSWIM8, AGO2, target-directed miRNA degradation, cryo-EM structure, E3 ubiquitin ligase. Study Highlights:Using purified human proteins and cellular assays, the authors combined cryo-EM (3.1 Å), in vitro ubiquitylation, co-immunoprecipitation and sRNA-seq to dissect TDMD. Cryo-EM shows a dimeric ZSWIM8 that forms an asymmetric clamp around AGO2–miR-7–CYRANO, engaging the MID, N and PAZ domains and embracing trigger RNA flanks. Biochemical reconstitution demonstrates that ZSWIM8–CUL3 together with ARIH1 polyubiquitylates surface lysines of AGO only when the miRNA is paired to a trigger that vacates the PAZ pocket and imposes a specific RNA trajectory. Functionally, these multivalent RNA–RNA, RNA–protein and protein–protein interactions establish a two-RNA-factor authentication mechanism that explains TDMD selectivity and indicates ZSWIM8 can destabilize extensively trimmed miRNAs. Conclusion:ZSWIM8–CUL3 recognizes a trigger-induced AGO–miRNA conformation via multivalent interactions—including sensing a vacated PAZ pocket and flanking trigger RNA—to direct ARIH1-dependent polyubiquitylation of AGO and execute TDMD. Music:Enjoy the music based on this article at the end of the episode. Article title:The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation First author:Farnung J Journal:Nature DOI:10.1038/s41586-026-10232-0 Reference:Farnung J., Slobodyanyuk E., Wang P.Y., Blodgett L.W., Lin D.H., von Gronau S., Schulman B.A. & Bartel D.P. The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation. Nature (2026). https://doi.org/10.1038/s41586-026-10232-0 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/zswim8-cul3-tdmd-structure QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-23. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript portions describing TDMD mechanism, ZSWIM8–CUL3 E3 ligase architecture, AGO2–miRNA–trigger complex recognition, CYRANO/HSUR1 triggers, RNA flanking regions and RBEs, PAZ-pocket vacancy, dimeric clamp, and broader biological implications.- transcript topics: TDMD overview and cellular context; ZSWIM8–CUL3 E3 ligase architecture and dimer clamp; AGO2–miRNA–trigger complex recognition by ZSWIM8; Trigger RNAs (CYRANO, HSUR1) and pairing architecture; RNA flanking regions and RBEs in ZSWIM8 binding; PAZ pocket vacancy and RNA trajectory 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:- TDMD is mediated by ZSWIM8–CUL3 E3 ligase polyubiquitylating AGO2–miRNA in the presence of a trigger RNA- ZSWIM8 preferentially binds AGO–miRNA–trigger ternaries over AGO–miRNA–seed-only complexes- ZSWIM8 operates as a dimer that cl... Chapters (00:00:12) - The Papercast(00:00:28) - A single molecular assassin(00:01:34) - The cell's ubiquitin murder(00:06:47) - How the CL3 box manipulates the ZS1 protein(00:11:36) - The ZSMATE hitman

Norgren J et al., JAMA Network Open - Population-based SNAC-K study finds higher meat consumption associated with slower cognitive decline and lower dementia risk in APOE ε3/ε4 and ε4/ε4 older adults. Key terms: APOE4, meat consumption, dementia, episodic memory, SNAC-K. Study Highlights:Using the Swedish National Study on Aging and Care–Kungsholmen (SNAC-K) cohort of older adults and repeated validated food-frequency questionnaires, the authors applied panel data analyses with linear regression for cognitive trajectories and Fine and Gray models for dementia incidence. Higher total meat consumption (top vs bottom quintile) in APOE ε3/ε4 and ε4/ε4 participants was associated with better 10-year global cognitive trajectories (β = 0.32) and lower dementia risk (sHR = 0.45). The processed-to-total meat ratio was associated with higher dementia risk (sHR = 1.14) without APOE interaction. Post hoc vitamin B12 analyses suggested APOE-specific differences in nutrient uptake that could help explain the genotype-specific associations. Conclusion:Higher meat consumption was associated with slower cognitive decline and reduced dementia incidence among APOE ε3/ε4 and ε4/ε4 carriers, such that the expected excess risk in these genotypes was not observed at high intake levels. Music:Enjoy the music based on this article at the end of the episode. Article title:Meat Consumption and Cognitive Health by APOE Genotype First author:Norgren J Journal:JAMA Network Open DOI:10.1001/jamanetworkopen.2026.6489 Reference:Norgren J, Carballo-Casla A, Grande G, et al. Meat Consumption and Cognitive Health by APOE Genotype. JAMA Network Open. 2026;9(3):e266489. https://doi.org/10.1001/jamanetworkopen.2026.6489 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/meat-apoe34-44-cognition QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-22. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript’s representation of the paper’s core scientific claims: APOE4 carriers (APOE34/44) show cognitive benefits and reduced dementia risk with higher meat intake; non-APOE34/44 show no such association; processed meat increases dementia risk; unprocessed meat associates with lower mortality in APOE34/- transcript topics: APOE gene and Alzheimer's risk; APOE4 vs APOE3/2 evolution and dietary adaptation; SNAC-K cohort design, dietary assessment, and cognitive outcomes; Total meat intake and cognitive trajectories by APOE genotype; Dementia incidence by APOE genotype and meat quintiles; Processed-to-total meat ratio and dementia risk 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:- APOE34/44 carriers show improved cognitive trajectories and reduced dementia risk with higher meat intake (top quintile) compared with bottom quintile.- Cognition and dementia benefits for APOE34/44 are quantified as β = 0.32 (P = .01) and sHR = 0.45 (P = .04) respectively.... Chapters (00:00:00) - A genetic flag for Alzheimer's disease?(00:05:33) - APOE4 genetic risk of dementia(00:11:30) - APOE4 Genotype and the Food Matrix

Johnson MB et al., The American Journal of Human Genetics - Bi-allelic variants in snRNAs RNU6ATAC and RNU4ATAC cause infancy-onset autoimmune diabetes in humans, with RNA-seq showing U12 intron retention and impaired B cell development. Key terms: RNU6ATAC, RNU4ATAC, minor spliceosome, U12 intron retention, autoimmune diabetes. Study Highlights:In human infants with early-onset diabetes and immune dysregulation, the authors used genome sequencing, RNA-seq, DNA methylation deconvolution, WGCNA, Sanger sequencing, and flow cytometry to define a genetic syndrome. They identified 19 individuals with bi-allelic RNU6ATAC or RNU4ATAC variants and RNA-seq revealed significant U12 intron retention in 274 genes, 94% of which are known U12-intron-containing genes. Multi-omic analyses and targeted immune profiling showed reduced naive B cells and abnormal B cell maturation. Half of tested individuals were GADA-positive, supporting an autoimmune mechanism for the diabetes in these snRNA spliceosome disorders. Conclusion:Bi-allelic pathogenic variants in RNU6ATAC cause early-onset autoimmune diabetes with immune dysregulation and bi-allelic RNU4ATAC variants extend RNU4ATAC-opathy to include infancy-onset autoimmune diabetes. Music:Enjoy the music based on this article at the end of the episode. Article title:Bi-allelic variants in the non-protein-coding minor spliceosome components RNU6ATAC and RNU4ATAC cause syndromic monogenic autoimmune diabetes First author:Johnson MB Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.02.017 Reference:Johnson MB, Russ-Silsby J, Blair PA, Govier M, Bonfield G, Domingo-Vila C, EXE-T1D consortium, ATAC clinical consortium, Wakeling MN, Oram RA, Flanagan SE, Tree TIM, Patel KA, Hattersley AT, De Franco E. Bi-allelic variants in the non-protein-coding minor spliceosome components RNU6ATAC and RNU4ATAC cause syndromic monogenic autoimmune diabetes. The American Journal of Human Genetics. 2026 Apr 2;113:1–11. https://doi.org/10.1016/j.ajhg.2026.02.017 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/rnu6atac-rnu4atac-minor-spliceosome QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-22. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript portions describing (a) minor spliceosome biology and snRNA function, (b) genetic findings in RNU6ATAC and RNU4ATAC, (c) U12 intron retention as a shared mechanism, (d) B cell development impairment and multi-omic immune profiling, (e) autoimmunity evidence (GADA positivity), (f) clinical phenoty- transcript topics: Minor spliceosome biology and U12 introns; RNU6ATAC bi-allelic variants; RNU4ATAC bi-allelic variants and interaction with RNU6ATAC; RNA-seq intron retention in U12 genes; B cell development and maturation defects; Islet autoantibody positivity in early-onset diabetes 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:- 19... Chapters (00:00:11) - The dark matter of human genetics(00:06:06) - Common mutations in the RNU4ATAK gene cause diabetes(00:12:50) - The genetics of autoimmune diabetes

Koga T et al., Nature Astronomy - Ryugu asteroid samples analyzed by HPLC/ESI-HRMS reveal all five canonical nucleobases (adenine, guanine, cytosine, thymine, uracil) and distribution linked to ammonia. Key terms: Ryugu, nucleobases, adenine, HPLC/ESI-HRMS, purine-to-pyrimidine ratio. Study Highlights:The team analysed Ryugu aggregate samples A0480 and C0370 and the Orgueil meteorite using water and HCl extraction followed by HPLC/ESI-HRMS, CE-HRMS and nano-EA/IRMS. They identified all five canonical nucleobases and measured total nucleobase concentrations (C0370 = 1,577 pmol g−1) and purine-to-pyrimidine (Pu/Py) ratios of ~1.1–1.2 in Ryugu contrasted with 0.099 in Orgueil and 3.4 in Murchison. A strong negative correlation (R2=0.89) between Pu/Py ratios and ammonia across Ryugu, Bennu and Orgueil implies ammonia availability influenced nucleobase formation pathways. The results support widespread abiotic nucleobase synthesis in carbonaceous parent bodies and potential delivery of diverse prebiotic molecules to early Earth. Conclusion:All five canonical nucleobases are present in Ryugu samples and their purine-to-pyrimidine distributions, which correlate with ammonia, indicate shared but environment-dependent formation pathways on carbonaceous parent bodies. Music:Enjoy the music based on this article at the end of the episode. Article title:A complete set of canonical nucleobases in the carbonaceous asteroid (162173) Ryugu First author:Koga T Journal:Nature Astronomy DOI:10.1038/s41550-026-02791-z Reference:Koga T., Ogawa N. O., Ohkouchi N., Oba Y., Takano Y., Naraoka H., Sasaki K., Sato H., Yoshimura T. et al. A complete set of canonical nucleobases in the carbonaceous asteroid (162173) Ryugu. Nature Astronomy (2026). https://doi.org/10.1038/s41550-026-02791-z 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/ryugu-nucleobases-ammonia-correlation QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-20. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections presenting nucleobase detection, extraction/analytical workflow, concentration data for Ryugu samples, Pu/Py ratios across samples, ammonia correlation, abiotic/isomer evidence (6-methyluracil, hypoxanthine isomer), Chargaff's rule discussion, isotopic signatures, contamination controls, and- transcript topics: Detection of all five canonical nucleobases in Ryugu; Sequential extraction workflow (water then HCl) and analytical methods (HPLC/ESI-HRMS, CE-HRMS, nano-EA/IRMS); Concentrations of nucleobases in Ryugu samples A0480 and C0370; comparison to Orgueil; Pu/Py (purine/pyrimidine) ratios across Ryugu, Bennu, Orgueil, and Murchison; Correlation between Pu/Py ratios and ammonia concentrations; Evidence for abiotic nucleobase formation: non-biological isomers (6-methyluracil) and hypoxanthine isomer 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:- All... Chapters (00:00:00) - Decoding the cosmic delivery of life(00:03:18) - The Ryugu Meteorite(00:08:52) - The Prebiotic grocery list of Earth(00:14:13) - The structure of DNA in the asteroid(00:15:38) - The Search for Life on Earth(00:21:26) - What Does This All Mean for Life?(00:26:39) - Falling Into You

Amour C et al., Human Genetics and Genomics Advances, Journal Pre-proof - Sex-stratified cQTL mapping in Tanzanian and Dutch adults identifies sex-specific regulators such as TOX-linked IFN-γ in males and EGFR-linked IL-10 in females, revealing multiple genome-wide cQTLs. Key terms: TOX, EGFR, cytokine QTL, sex-stratified GWAS, Tanzania-Netherlands. Study Highlights:The study analyzed cytokine production after ex vivo stimulation in two human cohorts (Tanzania 300TZFG and Dutch 500FG) using sex-stratified cytokine QTL mapping with linear models adjusted for cell counts and covariates. Genotyping, imputation, ELISA cytokine assays, colocalization (coloc) and SNP×sex interaction tests were applied to test sex-specific genetic effects. The authors report twelve genome-wide significant cQTLs in the Tanzanian cohort (seven male-specific, five female-specific) and twelve in the Dutch cohort with multiple sex-specific loci, highlighting TOX-associated IFN-γ regulation in males and EGFR-linked IL-10 regulation in females. These sex-specific autosomal effects altered which associations were detectable in pooled analyses, implying implications for sex-aware precision approaches to immune-related diseases. Conclusion:Sex-stratified autosomal analyses identify distinct genetic regulators of cytokine production, demonstrating that many cQTLs act in a sex-specific manner across Tanzanian and Dutch cohorts and can be missed by pooled analyses. Music:Enjoy the music based on this article at the end of the episode. Article title:Sex-stratified genetic regulators of cytokine production in the Dutch and Tanzanian populations First author:Amour C Journal:Human Genetics and Genomics Advances, Journal Pre-proof DOI:10.1016/j.xhgg.2026.100593 Reference:Amour C, Cetatean R, Ponce IR, Keur N, Temba GS, Kullaya VI, Mmbaga BT, Kavishe R, Joosten LAB, Netea MG, de Mast Q, Boahen CK, Kumar V, Sex-stratified genetic regulators of cytokine production in the Dutch and Tanzanian populations, Human Genetics and Genomics Advances (2026), doi: https://doi.org/10.1016/j.xhgg.2026.100593. 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/sex-stratified-cytokine-qtl QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-19. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing (1) Tanzanian cohort results (12 cQTLs; 7 male-specific, 5 female-specific), (2) Dutch cohort results (12 cQTLs; 6 male-specific, 6 female-specific), (3) exemplar sex-specific loci TOX (male IFN-γ) and EGFR (female IL-10), (4) CNTNAP2 and ANXA8 findings, (5) colocalization ana- transcript topics: Sex differences in immune regulation and cytokine signaling; Cohort design: Tanzanian (TZ) and Dutch (NL) sex-stratified cQTL mapping; TOX locus and IFN-γ response in males (S. pneumoniae); EGFR locus and IL-10 response in females (C. burnetii); CNTNAP2 locus and IFN-γ response in females (M. tuberculosis).; ANXA8 locus and TNF-α response in females (C. albicans) 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:

Fortuno C et al., Human Genetics and Genomics Advances - TP53 germline variant analysis using functional assays finds reduced-penetrance variants have intermediate activity, higher frequency, later onset, and 106 predicted candidates. Key terms: TP53, reduced penetrance, Li-Fraumeni syndrome, functional assays, variant interpretation. Study Highlights:Using ClinVar curation and comparison to benign and pathogenic reference sets, the authors analyzed TP53 germline variants with multiple functional assays, bioinformatic predictors, immune-fitness scores, and gnomAD frequencies. Reduced-penetrance variants tended to show intermediate activity across Kato, Giacomelli, Kotler, and Funk assays and intermediate BayesDel/AlphaMissense/aGVGD scores, with higher allele frequencies than pathogenic variants. A random forest model trained on these features prioritized 106 additional ClinVar missense variants as potential reduced-penetrance candidates. Clinically, carriers of reduced-penetrance variants exhibited later average age at first cancer and weaker enrichment for core Li-Fraumeni phenotypes, supporting consideration of attenuated surveillance criteria. Conclusion:Reported reduced-penetrance TP53 variants display intermediate functional and bioinformatic signatures, higher population frequency, and later cancer onset, and a combined-feature predictive model identifies additional candidate reduced-penetrance variants for follow-up. Music:Enjoy the music based on this article at the end of the episode. Article title:Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53 First author:Fortuno C Journal:Human Genetics and Genomics Advances DOI:10.1016/j.xhgg.2025.100484 Reference:Fortuno C, Richardson ME, Pesaran T, McGoldrick K, James PA, Spurdle AB. Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53. Human Genetics and Genomics Advances. 2025;6:100484. https://doi.org/10.1016/j.xhgg.2025.100484 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/tp53-reduced-penetrance-prediction QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-18. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections describing TP53 reduced-penetrance variants, four functional assays (Kato, Giacomelli, Kotler, Funk), bioinformatic predictors (BayesDel, AlphaMissense, aGVGD), immune fitness, population allele frequency, a random forest model identifying additional candidates, and associated clinical implications.- transcript topics: TP53 and Li-Fraumeni syndrome background; Functional assays (Kato, Giacomelli, Kotler, Funk); Bioinformatic predictors (BayesDel, AlphaMissense, aGVGD); Immune fitness predictions; Population allele frequency (gnomAD); Random forest model and variant prioritization 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:- Reduced penet...

Mendez R et al., Human Genetics and Genomics Advances, Journal Pre-proof - Biallelic RNU6ATAC variants disrupt the U6atac minor spliceosomal snRNA, causing transcriptome-wide minor intron retention and short stature with variable multisystem manifestations. Key terms: RNU6ATAC, U6atac, minor spliceosome, minor intron retention, whole-genome sequencing. Study Highlights:This study analyzed three unrelated human individuals using RNA-seq on whole-blood and fibroblasts and applied a FRASER-based minor intron retention (MIR) outlier pipeline alongside whole-genome sequencing. The integrated approach identified biallelic RNU6ATAC variants that map to U4atac–U6atac Stem I/II and the central stem-loop of U6atac. Affected individuals show transcriptome-wide excess MIR (for example A1 exhibited 254 MIR outliers in whole blood and B1 exhibited 16 MIR outliers in fibroblasts), indicating impaired minor spliceosome function. The molecular defect correlates with impaired growth and variable multisystem phenotypes including immunodeficiency and neurodevelopmental involvement. Conclusion:Biallelic RNU6ATAC variants cause a multisystem minor spliceopathy defined by transcriptome-wide minor intron retention and variable short stature, immunologic, and neurodevelopmental manifestations. Music:Enjoy the music based on this article at the end of the episode. Article title:Biallelic Variants in RNU6ATAC Result in a Minor Spliceopathy Characterized by Transcriptome-Wide Minor Intron Retention Events and Short Stature with Variable Multisystem Manifestations First author:Mendez R Journal:Human Genetics and Genomics Advances, Journal Pre-proof DOI:10.1016/j.xhgg.2026.100588 Reference:Mendez R, Arriaga TM, Ma J, Bonner DE, Emami S, Levy RJ, Alsagheir A, Alhaddad B, Bakur K, Ungar RA, Matalon DR, Miller AM, Nguyen J, Smith KS, Scott SA, Liao L, Ng Z, Marwaha S, Ward A, Undiagnosed Diseases Network, Genomics Research to Elucidate the Genetics of Rare Diseases Consortium, Novacic D, Alkuraya FS, Bernstein JA, Ganesh VS, O’Donnell-Luria A, Montgomery SB, Wheeler MT, Biallelic Variants in RNU6ATAC Result in a Minor Spliceopathy Characterized by Transcriptome-Wide Minor Intron Retention Events and Short Stature with Variable Multisystem Manifestations, Human Genetics and Genomics Advances (2026), doi: https://doi.org/10.1016/j.xhgg.2026.100588 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/rnu6atac-minor-spliceopathy QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-18. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections describing MIR as a transcriptome-wide effect, structural disruption of U4atac–U6atac, FRASER MIR filtering, need for WGS over WES, CADD/conservation evidence, tissue-specific effects, and the bridging C1 phenotype.- transcript topics: Minor intron retention (MIR) and transcriptome-wide MIR pattern; RNU6ATAC structural disruption (Stem I/II and central stem-loop); FRASER MIR outlier analysis and tissue specificity; Whole-genome sequencing vs whole-exome sequencing; CADD scores and evolutionary conservation; Clinical bridging phenotype (A1, B1, C1) and spectrum of RNU6ATAC-opathy QC Summary:-...

Saferali A et al., Human Genetics and Genomics Advances - Overlap between COPD genetic association results and transcriptional quantitative trait loci. RNA-seq in human lung (LTRC) and blood (COPDGene) reveals COPD-associated variants colocalize with splicing QTLs, implicating FBXO38 cryptic exon NMD and BTC exon4 isoform shifts. Key terms: COPD, sQTL, FBXO38, Betacellulin (BTC), long-read RNA-seq. Study Highlights:The study analyzed RNA-seq from COPDGene whole blood (n≈3,743) and LTRC lung tissue (n=1,241) using LeafCutter for splicing and tensorQTL for cis associations, followed by Moloc colocalization and targeted Oxford Nanopore long-read sequencing. Authors identified 58,258 lung splice sites and widespread eQTLs/sQTLs, and found 38 genomic windows (corresponding to 33 GWAS loci) with strong colocalization between QTLs and COPD GWAS signals. Top colocalizations in lung sQTLs included NPNT, FBXO38, HHIP, NTN4, and BTC, and long-read data resolved isoform changes for FBXO38 and BTC. Functionally, FBXO38 cryptic exon inclusion is associated with predicted nonsense-mediated decay and decreased expression, and BTC exon 4 inclusion alters isoform ratios that affect the EGF-like domain. Conclusion:Multiple COPD GWAS associations colocalize with sQTLs and eQTLs in lung and blood, identifying candidate genes such as FBXO38 and BTC and implicating splicing-mediated mechanisms in COPD risk. Music:Enjoy the music based on this article at the end of the episode. Article title:Overlap between COPD genetic association results and transcriptional quantitative trait loci First author:Saferali A Journal:Human Genetics and Genomics Advances DOI:10.1016/j.xhgg.2025.100493 Reference:Saferali A., Kim W., Chase R.P., NHLBI TransOmics in Precision Medicine (TOPMed), Vollmers C., Silverman E.K., Cho M.H., Castaldi P.J., Hersh C.P. Overlap between COPD genetic association results and transcriptional quantitative trait loci. Human Genetics and Genomics Advances. 2026 Jan 15;7:100493. https://doi.org/10.1016/j.xhgg.2025.100493. 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/copd-sqtl-fbxo38-btc QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-16. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited substantive transcript content describing COPD genetic architecture, sQTL/eQTL mapping in lung tissue (LTRC) and whole blood (COPDGene), the LeafCutter/TensorQTL/Moloc pipeline, FBXO38 cryptic exon and NMD, BTC exon 4 splicing, long-read validation, and translational implications.- transcript topics: COPD genetic architecture and regulatory mechanisms; sQTL/eQTL mapping in lung tissue (LTRC) and whole blood (COPDGene); LeafCutter splicing analysis; TensorQTL cis associations; Moloc colocalization; FBXO38 cryptic exon and nonsense-mediated decay 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:- 38 colocalization windows across 33 COPD GWAS loci w...

Pimplaskar A et al., The American Journal of Human Genetics - In UCLA ATLAS EHR-linked biobank analyses, random forest-derived enrollment probabilities and inverse-probability weighting increased replication of known GWAS variants and altered PGS associations. Key terms: inclusion bias, UCLA ATLAS, inverse-probability weighting, random forest, polygenic scores. Study Highlights:Using the UCLA ATLAS EHR-linked biobank, the authors trained random forest classifiers on demographics, healthcare utilization, and ICD-10 features to distinguish enrolled from background patients. They converted predicted enrollment probabilities into inverse-probability weights and applied these to GWAS replication tests and PGS-PheWAS scans. The classifier achieved AUROC≈0.85 and weighting increased replication of known GWAS variants by 54% while changing phenome-wide PGS association patterns. These results indicate that enrollment-driven inclusion bias can materially affect variant discovery and downstream PGS-based phenotypic associations in health-system biobanks. Conclusion:Inclusion bias in EHR-linked biobanks like UCLA ATLAS measurably affects common-variant discovery and PGS associations, and enrollment-aware inverse-probability weighting can improve replication while reducing effective sample size. Music:Enjoy the music based on this article at the end of the episode. Article title:Inclusion bias affects common variant discovery and replication in a health-system linked biobank First author:Pimplaskar A Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.02.011 Reference:Pimplaskar A, Qiu J, Lapinska S, Tozzo V, Chiang JN, Pasaniuc B, Olde Loohuis LM. Inclusion bias affects common variant discovery and replication in a health-system linked biobank. The American Journal of Human Genetics. 2026;113:1–13. https://doi.org/10.1016/j.ajhg.2026.02.011 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/inclusion-bias-ucla-atlas QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-14. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing enrollment-bias methodology (random forest classifier, inverse-probability weighting), key numeric results (AUROC/AUPRC, enrollment counts, ORs), GWAS replication improvements, and PGS-PheWAS outcomes, plus implications and limitations.- transcript topics: Enrollment bias in UCLA ATLAS biobank; Random forest classifier for enrollment prediction; Inverse-probability weighting and normalization; Effective sample size and trade-offs; GWAS variant replication under weighting; Variant-level associations and ancestry effects 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:- Enrollment in ATLAS: background population ~1.57–1.57 million; enrolled ~104,516- Primary care at UCLA strongly predicts enrollment: ~70.2% enrolled vs ~21.8% unenrolled; OR ≈ 8.44- Enrol...

Mathur Y et al., Nature - Clinical surveillance in Bangladesh shows Vibrio cholerae acquired PLE11 encoding Rta that restricts ICP1 tail assembly, driving a selective sweep of phage-resistant strains. Key terms: Vibrio cholerae, ICP1, PLE11, Rta, phage coevolution. Study Highlights:This study analysed clinical Vibrio cholerae and ICP1 isolates from stool in Bangladesh using genomic surveillance, plaque assays, qPCR, experimental phage evolution, TEM and mass spectrometry. The authors identify a newly acquired mobile element, PLE11, whose small protein Rta disrupts ICP1 tail assembly by targeting the phage tape measure protein (TMP), producing genome-filled tailless capsids. PLE11 also encodes a TMP and other tail factors enabling assembly of chimeric virions that incorporate PLE-encoded TMP and BhuB, preserving satellite transmission. Continued surveillance documented natural ICP1 counteradaptation via CRISPR–Cas acquisition and convergent TMP substitutions that restore infectivity. Conclusion:Acquisition of PLE11 encoding the tail-targeting protein Rta drove selection of phage-resistant Vibrio cholerae in Bangladesh and prompted convergent ICP1 counteradaptations that restore phage propagation. Music:Enjoy the music based on this article at the end of the episode. Article title:Capturing dynamic phage–pathogen coevolution by clinical surveillance First author:Mathur Y Journal:Nature DOI:10.1038/s41586-026-10136-z Reference:Mathur Y., Boyd C. M., Farnham J. E., Monir M. M., Islam M. T., Sultana M., Ahmed T., Alam M. & Seed K. D. Capturing dynamic phage–pathogen coevolution by clinical surveillance. Nature (2026). https://doi.org/10.1038/s41586-026-10136-z 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/ple11-rta-icp1-tail-assembly QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-12. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections that discuss the phage–bacteria arms race, PLE11 and Rta, TMP/TAC/BhuB, chimeric tail assembly, phage counterdefenses (CRISPR–Cas, Odn, Adi), and clinical surveillance data from Bangladesh, including outbreak dynamics and convergent evolution.- transcript topics: Phage–bacteria arms race overview; Phage satellites (PLEs) and anti-PLE strategies; Rta-mediated tail assembly restriction via TMP targeting; Chimeric tail assembly with PLE11-encoded components; ICP1 counterdefenses (CRISPR–Cas, Odn, Adi) and phage evolution; Clinical surveillance in Bangladesh (BD-1.2 sweep, 2022 outbreak) 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:- Rta (PLE11-encoded) restricts ICP1 tail assembly by targeting TMP- PLE11 encodes its own TMP and tail assembly factors (TAC) and BhuB to form chimeric tails enabling PLE transmission- BD-1.2 Vibrio cholerae populations acquired PLE11 and reached ~91% prevalence within 9 months- ICP1 populations shifted from Odn-me...

Rockowitz S et al., Human Genetics and Genomics Advances - Boston Children's Hospital used VS-NN, HPO NLP, and DRAGEN reprocessing in a proactive genomic reanalysis to identify candidate diagnoses in 2% of pediatric ES/GS cases. Key terms: genomic reanalysis, proactive reanalysis, VS-NN, HPO NLP, rare disease diagnostics. Study Highlights:The study deployed a centralized Proactive Genomic Reanalysis (PGR) workflow on a Boston Children’s Hospital pediatric ES/GS cohort integrated into the CRDC infrastructure. Key methods combined DRAGEN reprocessing, automated HPO extraction from EHR notes, CFA filtering on the GeneDx research platform and a VS-NN variant-scoring neural network followed by two-pass manual review. Applied to 2,144 previously unsolved cases, the pipeline flagged 310 variants, manual review prioritized 45 variants in 42 patients, and clinicians judged 33 variants to have high suspicion of disease causality, yielding ~2% candidate diagnostic rate. The work shows that institution-led, semi-automated reanalysis can produce clinically actionable findings while reducing reliance on clinician-initiated lab reanalysis, though it requires infrastructure for data transfer, confirmation and patient recontact. Conclusion:A centralized, semi-automated, clinically integrated Proactive Genomic Reanalysis workflow at Boston Children’s Hospital is feasible and identified candidate diagnostic variants in 2% of reviewed pediatric ES/GS cases, demonstrating a scalable model that can increase diagnoses while requiring institutional resources for confirmation and recontact. Music:Enjoy the music based on this article at the end of the episode. Article title:Scaling genomic reanalysis to unlock diagnoses and transform rare disease care First author:Rockowitz S Journal:Human Genetics and Genomics Advances DOI:10.1016/j.xhgg.2026.100582 Reference:Rockowitz S, Shao W, French C, Truong TK, Hagen J, McGonigle R, et al.; and Wendy K. Chung. Scaling genomic reanalysis to unlock diagnoses and transform rare disease care. Human Genetics and Genomics Advances. 2026;7:100582. https://doi.org/10.1016/j.xhgg.2026.100582. 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/proactive-genomic-reanalysis-bch QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-11. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the portion of the transcript describing the centralized Proactive Genomic Reanalysis (PGR) workflow, VS-NN AI scoring, NLP-based HPO extraction, CFA/DRAGEN pipelines, pilot results, and implementation challenges including data access and recontact.- transcript topics: Centralized Proactive Genomic Reanalysis (PGR) workflow; VS-NN variant scoring neural network; HPO NLP and phenotype matching; DRAGEN read mapping and CFA filtering; Two-pass manual review process; Pilot results: dataset size, variant counts, and diagnostic yield 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- licens...

Cromer SJ et al., The American Journal of Human Genetics - This paper reviews polygenic risk scores (PRS) and social determinants of health (SDoH) and outlines best practices for integrating PRS and SDoH across diverse populations to improve prediction and equity. Key terms: polygenic risk scores, social determinants of health, PRS transferability, data harmonization, type 2 diabetes. Study Highlights:This review focuses on human populations and uses conceptual frameworks, hypothetical population examples, and synthesis of methodological studies to evaluate PRS and SDoH integration. It summarizes methods for PRS construction and transferability, SDoH measurement at individual and area levels, and analytic approaches including interaction, mediation, and calibration. Quantitatively, the authors note substantial declines in PRS predictive accuracy when applied to genetically distinct populations (for example, African-ancestry performance often ~20–40% of European-derived PRS). The review highlights harmonization, population-specific calibration, and interdisciplinary teams as functional steps to improve predictive validity and reduce inequitable impacts. Conclusion:Integrating PRSs with carefully measured and harmonized SDoH across diverse populations requires population-aware conceptual frameworks, calibrated analytic methods, diverse datasets, and ethical safeguards to improve predictive validity and equity. Music:Enjoy the music based on this article at the end of the episode. Article title:Incorporating polygenic risk scores and social determinants of health across populations: Considerations and best practices in research First author:Cromer SJ Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.02.007 Reference:Cromer SJ, Cobran EK, Iyer HS, Hysong MR, Vargas LB, Smith JL, Konigsberg IR, Bogumil D, Glover L, King G, PRIMED Consortium SDoH Working Group, Lange LA, Patel A, Wojcik G, Raffield L, Conti DV, et al. Incorporating polygenic risk scores and social determinants of health across populations: Considerations and best practices in research. The American Journal of Human Genetics. 2026;113:1–25. https://doi.org/10.1016/j.ajhg.2026.02.007 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-risk-sdoh-harmonization QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-10. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited substantive sections of the transcript covering PRS basics, PRS transferability across populations, SDoH domains and measurement, harmonization challenges, analytical frameworks (main effects, interactions, mediation), T2D as an illustrative case, and ethical considerations.- transcript topics: PRS basics and transferability; SDoH four-domain framework (socioeconomic, sociocultural, physical environment, healthcare access); Individual vs area-level SDoH measures; SDoH harmonization across datasets; Analytical frameworks (main effects, interaction/effect modification, mediation); T2D as illustrative example QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 8- claims flagged for review: 0- metadata chec...

Wong BHH et al., Proc. Natl. Acad. Sci. U.S.A - Mouse and human studies show the LPC transporter Mfsd2a enables plasma-derived LPC uptake into keratinocytes, preserving linoleate-rich phosphatidylcholine pools and promoting epidermal differentiation. Key terms: Mfsd2a, lysophosphatidylcholine, keratinocyte differentiation, linoleic acid, lipidomics. Study Highlights:Using epidermis-specific (2aEpKO) and conventional (2aKO) Mfsd2a-deficient mice, lineage tracing, untargeted shotgun lipidomics, LightOx-LPC uptake assays, and primary human keratinocyte cultures, the authors mapped Mfsd2a expression to suprabasal/granular keratinocytes and demonstrated Mfsd2a-dependent uptake of plasma-derived LPC in vivo. Lipidomic quantification showed reductions in linoleate-containing phospholipids (PL-18:2 decreased ~15% in 2aEpKO and ~13% in 2aKO) and a marked loss of TAG-18:2 (−79% in 2aEpKO). Inducible epidermal Mfsd2a loss produced transient dermatitis, defective desquamation, retained lamellar bodies, and keratinocyte activation, while MFSD2A knockdown in human keratinocytes reduced LPC-driven differentiation. Functional rescue experiments in vitro revealed that LPC-18:1 and LPC-18:2 promote keratinocyte differentiation in an MFSD2A-dependent manner, linking plasma LPC uptake to epidermal lipid homeostasis and differentiation. Conclusion:Mfsd2a mediates uptake of plasma-derived LPC (notably LPC-18:2) into suprabasal keratinocytes to maintain linoleate-containing phospholipid pools and support keratinocyte differentiation and normal desquamation. Music:Enjoy the music based on this article at the end of the episode. Article title:Mfsd2a is important for maintaining epidermal homeostasis First author:Wong BHH Journal:Proc. Natl. Acad. Sci. U.S.A DOI:10.1073/pnas.2531159123 Reference:Wong BHH, Behmoaras J, Chua AWC, Galam DLA, Tan BC, Torta F, Chin CF, Mishra K, Ding M, Silver DL. Mfsd2a is important for maintaining epidermal homeostasis. Proc. Natl. Acad. Sci. U.S.A. 2026 Feb 19;123(8):e2531159123. https://doi.org/10.1073/pnas.2531159123 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/mfsd2a-lpc-epidermal-homeostasis QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-09. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing MFSD2A expression in epidermal keratinocytes, inducible epidermis-specific and conventional Mfsd2a knockout phenotypes, epidermal lipidomics (18:2 species and DAG shifts), LightOx-LPC uptake demonstrating MFSD2A dependence, and MFSD2A-dependent differentiation of human keratin- transcript topics: MFSD2A expression in differentiated epidermal keratinocytes; Inducible postnatal Mfsd2a deficiency and dermatitis; Conventional Mfsd2a knockout and desquamation defects; Epidermal lipidomics: PL-18:2 and TAG-18:2 reductions; DAG shifts; LPC uptake into epidermis using LightOx-LPC and MFSD2A dependence; MFSD2A-dependent differentiation of human keratinocytes with LPCs 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 M...

Herpe L et al., Proc. Natl. Acad. Sci. U.S.A - CRISPR knockout of Drosophila mtG3PDH (GPO1) reduces ATP production by ~60% and O2 consumption by ~33%, lowering mitochondrial efficiency and ROS emission. Key terms: mtG3PDH, GPO1, Drosophila melanogaster, mitochondrial efficiency, reactive oxygen species. Study Highlights:Using CRISPR/Cas9-generated GPO1 mutant Drosophila and isolated thoracic mitochondria, the authors combined enzymatic assays, ATP production and oxygen consumption measurements, and H2O2 emission assays to probe mtG3PDH function. Loss of mtG3PDH markedly reduced mtG3PDH enzymatic activity and drove a ~60% decrease in ATP production and ~33% decrease in O2 consumption, producing a pronounced drop in mitochondrial efficiency (ATP/O). mtG3PDH-linked ROS emission was also strongly reduced (~70%), reflecting diminished direct and reverse electron-transfer ROS generation. Functionally, GPO1 flies showed sharply reduced survival and severe climbing impairment, linking the bioenergetic defects to organismal outcomes. Conclusion:mtG3PDH is essential for mitochondrial bioenergetics and redox homeostasis in Drosophila, with GPO1 loss causing major decreases in ATP production, O2 consumption, mitochondrial efficiency, and mtG3PDH-linked ROS that correlate with reduced survival and locomotion. Music:Enjoy the music based on this article at the end of the episode. Article title:When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase First author:Herpe L Journal:Proc. Natl. Acad. Sci. U.S.A DOI:10.1073/pnas.2535701123 Reference:Herpe L, Aminot M, Pichaud N. When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 2026;123(9):e2535701123. https://doi.org/10.1073/pnas.2535701123 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/drosophila-mtg3pdh-gpo1 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-08. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections cover mtG3PDH function, CRISPR/Cas9 GPO1 knockout in Drosophila, thoracic mitochondria bioenergetics (ATP production, oxygen consumption, ATP/O), ROS production and RET, organismal outcomes (lifespan, climbing), and translational implications.- transcript topics: mtG3PDH shuttle function and GPO1; CRISPR/Cas9 GPO1 knockout in Drosophila; thoracic mitochondria bioenergetics: ATP production; oxygen consumption and coupling efficiency (ATP/O); ROS production and reverse electron transfer; complex I independence and grid collapse 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:- mtG3PDH knockout reduces ATP production by ~60%- O2 consumption decreases by ~33%- mitochondrial efficiency (ATP/O) is markedly reduced (uncoupling observed)- mtG3PDH-linked ROS emission decreases by ~70%- survival (median lifespan) drops from ~33 days to ~...

Korpela K et al., Gut Microbes - Review finds maternal fecal microbiota transplantation and targeted probiotics can restore Bifidobacterium and Bacteroides after C‑section or intrapartum antibiotics, with breastfeeding aiding recovery. Key terms: maternal fecal microbiota transplantation, C-section, Bifidobacterium, vaginal seeding, probiotics. Study Highlights:This review focuses on term infants, particularly C‑section and intrapartum antibiotic–exposed neonates, synthesizing cohort and intervention data using 16S rRNA gene amplicon sequencing and metagenomic approaches. Maternal fecal microbiota transplantation (maternal FMT) shifted C‑section infants’ gut communities to resemble vaginally born infants and uniquely restored Bacteroidaceae, while a Bifidobacterium–Lactobacillus–FOS supplement increased bifidobacteria; vaginal seeding did not normalize overall gut composition. The authors link restoration of key taxa to potential reductions in risks such as allergy and overweight and emphasize breastfeeding as an essential adjunct to restoration strategies. Conclusion:Evidence supports action to address early-life gut microbiota disruption: probiotics and maternal FMT show promising restorative effects, but optimal, scalable solutions and long-term immune outcomes remain to be established. Music:Enjoy the music based on this article at the end of the episode. Article title:Infant gut microbiota restoration: state of the art First author:Korpela K Journal:Gut Microbes DOI:10.1080/19490976.2022.2118811 Reference:Korpela K, de Vos WM. Infant gut microbiota restoration: state of the art. Gut Microbes. 2022;14(1):e2118811. https://doi.org/10.1080/19490976.2022.2118811 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/maternal-fmt-bifidobacterium-restoration QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-07. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing vertical transmission, HMOs and breast milk, birth-mode and antibiotic effects, restoration interventions (vaginal seeding, Lactobacillus probiotics, Bifidobacterium-Lactobacillus-FOS multispecies, maternal FMT), PCA-based analysis, preterm considerations, and long-term health- transcript topics: Vertical transmission and HMOs feeding infant gut microbes; Birth mode and intrapartum antibiotic effects on microbiota; Microbiota restoration interventions: vaginal seeding, probiotics, multispecies probiotics, maternal FMT; PCA analysis as a measure of restoration efficacy; Bifidobacteriaceae and Bacteroidaceae dynamics across interventions; Preterm infant microbiota and NICU interventions 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:- Maternal FMT can restore CS-born infant gut microbiota toward vaginal births, with persistence at 1 and 3 months- Bacteroidaceae restoration is achieved by maternal FMT; other interventions fail to...

Li Z et al., Human Genetics and Genomics Advances - LASI-DAD 30× whole-genome sequencing of 2,680 Indian participants produced a 69.5M-variant LD panel that improves genotype imputation accuracy and PRS performance for Indian populations. Key terms: LASI-DAD, linkage disequilibrium, genotype imputation, whole-genome sequencing, polygenic risk scores. Study Highlights:Using 30× WGS of 2,680 LASI-DAD participants, the authors constructed an LD lookup panel (69.5 million variants), phased with Eagle2.4, and identified LD structure with LDetect and Big-LD. They compared regional varLD to 1000G super-populations and evaluated imputation with Minimac4 and meta-imputation against TOPMed and GAsP. LASI-DAD increased imputation accuracy (aggregated r2) by a mean 38% versus TOPMed and 27% versus GAsP across allele frequencies and improved PRS predictive performance by 2.1%–35.1% across traits and studies. Finer-scale stronger LD and regional LD differences in LASI-DAD translate into more accurate LD estimates and better imputation and PRS transferability for Indian sub-populations. Conclusion:LASI-DAD is the largest nationally representative Indian WGS reference panel to date and it improves LD estimation, genotype imputation accuracy, and PRS construction for Indian and South Asian populations. Music:Enjoy the music based on this article at the end of the episode. Article title:A reference panel for linkage disequilibrium and genotype imputation using whole-genome sequencing data from 2,680 participants across India First author:Li Z Journal:Human Genetics and Genomics Advances DOI:10.1016/j.xhgg.2026.100579 Reference:Li Z, Zhao W, Zhou X, Leung YY, Schellenberg GD, Wang L-S, Schönherr S, Forer L, Fuchsberger C, Dey S, Lee J, Smith JA, Dey AB, Kardia SLR. A reference panel for linkage disequilibrium and genotype imputation using whole-genome sequencing data from 2,680 participants across India. Human Genetics and Genomics Advances. 7 (2026) 100579. https://doi.org/10.1016/j.xhgg.2026.100579. 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/lasi-dad-india-reference-panel QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-06. 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 scientific content covered the LASI-DAD cohort design and sequencing depth; LD/imputation methodology (LD blocks, LDetect/Big-LD, varLD); LD panel variant counts; subpopulation structure (ANI/ASI) and PRS transferability; imputation performance and meta-imputation; and data avai- transcript topics: LASI-DAD cohort design and 30× whole-genome sequencing; LD reference panel construction and variant counts (69.5 million) and comparisons; LD blocks and varLD analyses across populations; LASI-DAD sub-populations by ANI percentage and geographic cline; PRS transferability and cross-population performance; Imputation performance and meta-imputation across reference panels 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...

Shi J et al., The EMBO Journal, doi:10.1038/s44318-025-00687-8 - PANDORA-seq profiling of mouse and human sperm heads identifies a conserved rsRNA length shift with age and a tsRNA/rsRNA 'aging cliff' that reprograms embryonic transcripts. Key terms: sperm sncRNA, rsRNA length shift, PANDORA-seq, aging cliff, tRNA-derived small RNA. Study Highlights:Using PANDORA-seq on C57BL/6J mouse sperm (intact and de-membranated heads) across five age groups and two independent human sperm cohorts, the authors identify a sharp tsRNA/rsRNA "aging cliff" in mice between 50–70 weeks and a head-specific rsRNA length shift. PANDORA-seq overcomes modification-induced detection bias to reveal increases in longer rsRNAs and decreases in shorter rsRNAs, particularly from 28S- and 18S-rRNAs, with parallel trends in human cohorts. Mitochondrial tsRNAs/rsRNAs in sperm heads, although low abundance, covary with genomic sncRNAs and help distinguish age groups. Transfection of age-mimicking tsRNA/rsRNA cocktails into mouse embryonic stem cells reprograms gene expression, upregulating metabolic and neurodegeneration-related pathways, providing a functional link to offspring phenotypes. Conclusion:PANDORA-seq uncovers a conserved, sperm head–specific rsRNA length shift and a tsRNA/rsRNA aging cliff in mice and humans, and age-mimicking sncRNA combinations can alter embryonic transcriptomes linked to metabolic and neurodegenerative pathways. Music:Enjoy the music based on this article at the end of the episode. Article title:Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging First author:Shi J Journal:The EMBO Journal, doi:10.1038/s44318-025-00687-8 DOI:10.1038/s44318-025-00687-8 Reference:Shi J, Zhang X, Cai C, Liu S, Yu J, James ER, et al. Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging. The EMBO Journal. 2026;45(4):1362–1380. https://doi.org/10.1038/s44318-025-00687-8 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/sperm-rsrna-length-shift QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-05. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited the transcript segments describing (1) the aging cliff in mouse sperm tsRNA/rsRNA profiles, (2) rsRNA length shifts in sperm heads, (3) cross-species conservation in humans, (4) mitochondrial sncRNA patterns, (5) functional RNA transfection experiments in mouse embryonic stem cells, (6) the PANDOR- transcript topics: PANDORA-seq methodology; mouse sperm aging cliff at 50-70 weeks; rsRNA length shift in mouse sperm heads (28S/18S origin); mitochondrial tsRNA/rsRNA patterns in sperm heads; conservation of rsRNA length shift in human sperm cohorts; functional reprogramming of mESC transcriptomes by age-mimicking sncRNA cocktails 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:- Aging cliff between 50 and 70 weeks in mouse sp...

Saxton DS et al., Nature, doi:10.1038/s41586-026-10207-1 - In E. coli, the membrane-bound nuclease SNIPE directly cleaves incoming phage λ DNA during genome injection, blocking infection via ManYZ and tape-measure protein interactions. Key terms: SNIPE, GIY-YIG nuclease, lambda phage, ManYZ, tape measure protein. Study Highlights:In Escherichia coli, the membrane-anchored protein SNIPE was shown to block phage λ by directly cleaving DNA during genome injection. The authors combined radiolabelled 32P phage DNA assays, time-lapse CFP-ParB/ParS microscopy, TurboID proximity labelling and pBPA crosslinking to map SNIPE localization and interactions. They report that membrane-localized SNIPE requires a DUF4041 domain and a GIY-YIG nuclease domain to generate DNA fragments during injection, reducing CFP-ParB puncta ~30-fold and producing a smear of 32P-labelled fragments; an E414A nuclease mutant abolished activity. Functionally, SNIPE prevents λ replication and cell lysis and provides broad defence against many siphoviruses via interactions with ManYZ and phage tape-measure proteins. Conclusion:SNIPE is a membrane-localized bacterial defence protein that associates with ManYZ and phage tape-measure proteins to directly cleave incoming phage DNA during genome injection, thereby blocking infection. Music:Enjoy the music based on this article at the end of the episode. Article title:A membrane-bound nuclease directly cleaves phage DNA during genome injection First author:Saxton DS Journal:Nature, doi:10.1038/s41586-026-10207-1 DOI:10.1038/s41586-026-10207-1 Reference:Saxton DS, DeWeirdt PC, Doering CR, Roney IJ & Laub MT. A membrane-bound nuclease directly cleaves phage DNA during genome injection. Nature. 2026. https://doi.org/10.1038/s41586-026-10207-1 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/snipe-membrane-nuclease-phage-injection QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-04. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections covering SNIPE architecture and membrane localization, autoinhibition, phage DNA cleavage during genome injection (Hershey–Chase style), interactions with ManYZ andTape-measure proteins (TMP), proximity labelling, Bas14 mutation experiments, and SNIPE homologues/evolution.- transcript topics: SNIPE membrane localization and domain architecture; Autoinhibition and self-DNA protection at the membrane; Cleavage of phage DNA during genome injection and Hershey–Chase-like evidence; Interaction with ManYZ and phage tape-measure protein during infection; TurboID proximity labelling findings for ManYZ and TMP interactions; Broad siphovirus defense and Bas14 mutation findings 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:- SNIPE is a membrane-anchored protein with an N-terminal transmembrane domain, a DUF4041 domain in the middle, and a GIY-YIG nuclease domain at the C...

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 fou...

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- Saturatio...

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:...

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... Chapters (00:00:20) - Base by Bass(00:02:08) - The untapped potential of short-read sequencing in biodiversity science(00:09:38) - Genome Skimming to accurately estimate the biomass of marine organisms(00:16:23) - The race for low-cost sequencing(00:24:16) - Short-read sequencing: The secrets of the last ice age

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. Chapters (00:00:10) - The End of an Era in Genetic Science(00:01:57) - The discovery of SMN2 in spinal cord disease(00:06:13) - The journey from bench to bed(00:08:00) - The mystery of SMA(00:12:18) - A Legacy of SMA: Katherine Worth's work(00:15:31) - Stitch the Science Into Life

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... Chapters (00:00:00) - Base by Bass(00:00:31) - Seeking the cause of disease with a single trial(00:03:01) - The Mendelian randomization study(00:07:51) - The Machine-Learning Drug Hunter(00:10:49) - Treasure Hunt for old drugs(00:12:07) - The New Way to Lower Cholesterol(00:16:19) - Finding the cures to diseases by sequencing their genomes

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:... Chapters (00:00:00) - Base by Base(00:00:28) - A viral ghost in my body(00:03:32) - Herpes virus: When it's active, how to spot it(00:05:42) - The Hidden EBVD Genome(00:08:45) - The smoking gun in chronic fatigue(00:14:01) - Does Your Genetic Lock Fit With EBV?(00:19:01) - Finding the Secret of the Immune Program

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 Chapters (00:00:20) - Genetics of encephalopathy: the mystery behind the disease(00:03:40) - UFM1 defects in the brain(00:08:08) - What Happened to Myelation in Tertiary neurons?(00:10:49) - Fixing the RA1C mutation in the brain(00:15:42) - UFM1 regulates synaptic firing in the brain(00:16:41) - A Small Voice for the Cell

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 indiv... Chapters (00:00:11) - The missing heritability of inherited retinal diseases(00:03:00) - Globally, retinal disease 1, Introduction(00:04:14) - The genetic cause of blindness(00:08:28) - The secret to retinitis pigmentosa(00:13:54) - Deep Dive into the dark corners of the genome(00:17:21) - Follow the Light Along the Axle

Serpieri V et al., The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.014 - Bi-allelic FSD1L variants disrupt a microtubule-associated protein, causing hydrocephalus, corpus callosum defects and an L1 syndrome-like neurodevelopmental disorder in humans and models. Key terms: FSD1L, microtubules, ciliogenesis, hydrocephalus, iPSC neuronal differentiation. Study Highlights:Exome sequencing in eleven affected individuals (including five fetuses) identified bi-allelic FSD1L variants associated with hydrocephalus and corpus callosum defects. Using iPSC-derived neural progenitor differentiation, neurosphere assays, patient fibroblasts, immunohistochemistry, and in utero CRISPR-Cas9 mouse knockdown, the authors show that FSD1L localizes to mitotic spindle microtubules and to the transition zone/axoneme of the primary cilium. Patient NPCs fail to differentiate into premature neurons, undergo increased cell death, and form smaller disorganized neurospheres, while patient fibroblasts show abnormal spindles, reduced ciliogenesis and shorter cilia. Fsd1l repression in mouse embryos produced lateral ventricular dilation, functionally linking FSD1L to mitotic spindle assembly, ciliogenesis, neuronal differentiation and axon guidance. Conclusion:Bi-allelic pathogenic variants in FSD1L cause a neurodevelopmental syndrome overlapping L1 syndrome by disrupting a microtubule-associated protein required for mitotic spindle assembly, ciliogenesis, and neuronal differentiation. Music:Enjoy the music based on this article at the end of the episode. Article title:Bi-allelic variants in FSD1L cause a neurodevelopmental disorder overlapping with L1 syndrome First author:Serpieri V Journal:The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.014 DOI:10.1016/j.ajhg.2026.01.014 Reference:Serpieri V., Vezain-Mouchard M., Orsi A., et al. Bi-allelic variants in FSD1L cause a neurodevelopmental disorder overlapping with L1 syndrome. The American Journal of Human Genetics. 113, 1–16 (March 5, 2026). https://doi.org/10.1016/j.ajhg.2026.01.014 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-microtubule-ciliogenesis 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 transcript’s presentation of the AJHG 2026 FSD1L study’s main claims, cellular mechanisms, experimental models, and clinical implications as described in the article.- transcript topics: Clinical features resembling L1 syndrome; Gene discovery via exome sequencing and GeneMatcher; Autosomal recessive inheritance; FSD1L as a microtubule-associated protein localizing to mitotic spindle and primary cilium; iPSC-derived neural progenitor differentiation defects; Fibroblast spindle abnormalities and ciliogenesis defects 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:- B... Chapters (00:00:20) - The genetic sleuths who solved a brain disease(00:03:50) - GeneMatch: The L1 Syndrome match(00:08:57) - FSD1L protein deficiency in the brain(00:11:26) - Why does L1 syndrome look so much like FSD1L(00:16:41) - Many single diseases are actually clusters of lookalikes, according to Bass(00:18:25) - A Story of Connections

Zhou S et al., Nature Communications, doi:10.1038/s41467-025-65448-x - snaR-A noncoding RNA interacts with U2 snRNP subunit SF3B2 and nuclear speckles, increasing intron retention and promoting proliferation in human cancer-relevant cells. Key terms: snaR-A, SF3B2, intron retention, nuclear speckles, RNA polymerase III. Study Highlights:Using human cell lines (HEK293T, A549, THP-1) and tumor chromatin data, the authors combined biotinylated RNA pulldown mass spectrometry, PAR-CLIP/CLIP-qPCR, HCR-RNA-FISH, TSA-seq, and ultra-deep RNA-seq (IRFinder, rMATS) to map snaR-A interactions and splicing outcomes. snaR-A directly binds splicing factors and shows nucleotide-level crosslinking to the U2 snRNP protein SF3B2, and localizes to subnuclear foci adjacent to nuclear speckles and U6-containing sites. Functionally, snaR-A overexpression increases intron retention and selectively depletes SF3B2 protein, whereas snaR-A depletion reduces intron retention for transcripts with high U2 occupancy and speckle proximity. These splicing changes alter protein abundance for multiple targets and coincide with reduced proliferation after snaR-A depletion, consistent with tumor-level associations to growth. Conclusion:snaR-A acts as a molecular antagonist of U2-dependent splicing by interacting with SF3B2 and perturbing processing of specific mRNA subpopulations, promoting intron retention and proliferation in cancer-relevant contexts. Music:Enjoy the music based on this article at the end of the episode. Article title:Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations First author:Zhou S Journal:Nature Communications, doi:10.1038/s41467-025-65448-x DOI:10.1038/s41467-025-65448-x Reference:Zhou S., Lizarazo S., Chorghade S., Mouli L., Cheng R., Rajendra K. C., Kalsotra A., Van Bortle K. Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations. Nature Communications. 2025;16:10460. https://doi.org/10.1038/s41467-025-65448-x 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/snar-a-sf3b2-splicing QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-21. 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 snaR-A study: interaction with SF3B2 and U2 snRNP, localization to nuclear speckles, intron retention effects, SF3B2 protein depletion, depletion effects on splicing and protein abundance, proliferation/migration phenotypes, TCGA prognosis, and limitations.- transcript topics: snaR-A interaction with SF3B2 and U2 snRNP; localization of snaR-A to nuclear speckles and proximity to U6; snaR-A-induced intron retention and splicing disruption; SF3B2 protein depletion upon snaR-A overexpression; snaR-A depletion reduces IR in U2-residency, speckle-proximal transcripts; OGFR and other targets affected by splicing changes 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 Chapters (00:00:20) - Cancer's editing room: The heist(00:03:27) - The SNAR A saboteur(00:07:14) - Snarra disrupts the splicing machinery(00:11:53) - Snare A in lung cancer(00:16:50) - A whisper in the dark

Yu M et al., Cell Genomics, 6 (2026) 101071. doi:10.1016/j.xgen.2025.101071 - Large-scale exome sequencing shows CFTR risk variants, including deltaF508, reduce susceptibility to inflammatory bowel disease, suggesting targeted CFTR modulation as a potential IBD therapy. Key terms: CFTR, deltaF508, inflammatory bowel disease, exome sequencing, rare-variant burden test. Study Highlights:The authors analyzed large-scale human exome and genome sequencing data (38,558 cases and 66,945 controls in European discovery; 42,475 cases and 192,050 controls in replication across ancestries) using single-variant tests and gene-based rare-variant burden tests. They report a protective single-variant association for CFTR deltaF508 with IBD (meta-analysis p = 8.96E-11, OR = 0.82) and a significant protective gene-level burden of clinically annotated CF-risk variants (meta-analysis p = 3.9E-7, OR = 0.85). The study also compared variant prioritization methods and found clinically curated CFTR2 annotations outperform in silico predictors such as AlphaMissense for powering burden tests. Replication signals were observed in non-European groups at nominal significance and the results support exploration of selective, tissue-targeted CFTR modulators as a potential therapeutic implication. Conclusion:Clinically annotated CFTR risk variants, including deltaF508, confer a reproducible protective effect against IBD in large sequencing cohorts, supporting investigation of selective tissue-targeted CFTR modulation while balancing cystic fibrosis risks. Music:Enjoy the music based on this article at the end of the episode. Article title:Cystic fibrosis risk variants confer protection against inflammatory bowel disease First author:Yu M Journal:Cell Genomics, 6 (2026) 101071. doi:10.1016/j.xgen.2025.101071 DOI:10.1016/j.xgen.2025.101071 Reference:Yu M., Zhang Q., Yuan K., Sazonovs A., Stevens C.R., Fachal L., et al. Cystic fibrosis risk variants confer protection against inflammatory bowel disease. Cell Genomics. 6 (2026) 101071. https://doi.org/10.1016/j.xgen.2025.101071 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/cftr-deltaf508-ibd-protection QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-19. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the Results and Discussion segments of the transcript, including the DeltaF508 association with IBD, CFTR2-based burden tests, replication across ancestries, AlphaMissense evaluation and mechanistic discussion about mucus and BEST4+ enterocytes, and therapeutic implications.- transcript topics: CFTR deltaF508 single-variant association with IBD; CFTR2-based rare-variant burden test; negative control with non-CF-risk variants; ancestry-adjusted analysis and replication (EUR, AFR.AMR, EAS); CFTR variant prioritization: AlphaMissense vs CFTR2; mechanistic discussion: mucus hydration and BEST4+ enterocytes 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...

Hunter CE et al., The EMBO Journal, doi:10.1038/s44318-025-00666-z - Review shows how alternative splicing, via TE exonization and cis-regulatory changes and revealed by long-read RNA-seq, reshapes gene regulation and drives phenotypic evolution in mammals. Key terms: alternative splicing, exonization, long-read RNA-seq, microexons, comparative transcriptomics. Study Highlights:This review synthesizes comparative transcriptomic studies across multicellular eukaryotes with emphasis on vertebrates and mammals. It highlights methods including short- and long-read RNA-seq, single-cell transcriptomics, and MS proteomics to map isoform diversity. The authors emphasize that lineage-specific AS is often driven by cis-regulatory changes and exonization of transposable elements, with trans-factor innovations (e.g., SRRM3/4, PTBP1 isoforms) modulating microexons and isoform ratios. Functional examples linking AS to phenotypes include an Alu-derived IFNAR2 decoy receptor reducing JAK/STAT signaling, TNNI3 exon3 loss or skipping associated with extreme heart rates, and hominoid shifts in MAPT exon10 splicing altering tau isoform proportion. Conclusion:Alternative splicing, shaped largely by cis-sequence changes and TE exonization and illuminated by long-read and single-cell transcriptomics, is a flexible evolutionary mechanism that can produce lineage-specific regulatory and phenotypic innovations. Music:Enjoy the music based on this article at the end of the episode. Article title:The splice of life: how alternative splicing shapes regulatory and phenotypic evolution First author:Hunter CE Journal:The EMBO Journal, doi:10.1038/s44318-025-00666-z DOI:10.1038/s44318-025-00666-z Reference:Hunter CE, Xing Y. The splice of life: how alternative splicing shapes regulatory and phenotypic evolution. The EMBO Journal. 2026. https://doi.org/10.1038/s44318-025-00666-z 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/alternative-splicing-exonization-evolution QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-18. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited sections covering splicing mechanisms, exonization and TE-derived exons, three main evolutionary modes of AS, cis vs trans regulation, sequencing technologies (long-read, single-cell, proteomics), and case studies (TBXT tail loss, TNNI3, MAPT). Also reviewed Tc1 humanized mouse results and immune/- transcript topics: Basics of alternative splicing and spliceosome regulation; Exon creation via TE exonization (Alu elements) and exonization examples (IFNAR2); Exon loss and splicing level changes as evolutionary modes; Three case studies: TBXT tail loss via exon skipping; TNNI3 exon 3 loss/skip for high heart rate; MAPT exon 10 splicing and tau isoforms; Cis-regulatory vs trans-acting factors in splicing evolution (Tc1 human chromosome 21 study); Splicing regulators and microexons (SRRM3/4, PTBP1) and their evolutionary implications 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:

Gracia Carmona O et al., Patterns, 7 (2026) 101425. doi:10.1016/j.patter.2025.101425 - IndeLLM uses protein language models (ESM2) to score in-frame indels and a compact Siamese transfer-learning model that achieves state-of-the-art pathogenicity prediction with MCC = 0.77. Key terms: IndeLLM, protein language models, in-frame indels, Siamese network, ESM2. Study Highlights:Using human protein sequences and ESM2 embeddings, the authors develop IndeLLM, a zero-shot scoring function that sums overlapping-region probabilities to correct length bias in in-frame indels. They train a compact Siamese one-hidden-layer network on PLM embeddings with biologically guided embedding splitting and achieve MCC = 0.77 on the test set. Per-residue probability differences mapped onto structures (FGFR1, GLMN) identify local regions affected by indels and improve interpretability. The framework reduces insertion false negatives and is released with Colab and GitHub tools for indel annotation and disease-variant analysis. Conclusion:IndeLLM zero-shot scoring and a small Siamese transfer-learning model provide improved, interpretable indel pathogenicity prediction, with the Siamese model achieving MCC = 0.77. Music:Enjoy the music based on this article at the end of the episode. Article title:Leveraging protein language models and a scoring function for indel characterization and transfer learning First author:Gracia Carmona O Journal:Patterns, 7 (2026) 101425. doi:10.1016/j.patter.2025.101425 DOI:10.1016/j.patter.2025.101425 Reference:Gracia Carmona O, Leipart V, Amdam GV, Orengo C, Fraternali F. Leveraging protein language models and a scoring function for indel characterization and transfer learning. Patterns. 7 (2026) 101425. https://doi.org/10.1016/j.patter.2025.101425 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/indellm-indel-siamese-model QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-17. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the scientific content conveyed in the transcript: indel biology, IndeLLM zero-shot scoring, Siamese Model 4, performance metrics, interpretability via structure-mapped probability changes, structural validation with AlphaFold, and broad applicability including non-human systems and accessible tooling.- transcript topics: Indel biology: in-frame indels vs frameshift indels; Protein language models and length bias; Indel scoring: IndeLLM zero-shot (overlapping regions); Probability scoring math: sum vs log-sum; Siamese network (Model 4) and transfer learning; Performance metrics: MCC 0.65 (zero-shot) and 0.77 (Siamese); comparison to Provean 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:- IndeLLM zero-shot scoring uses overlapping regions to correct length bias- Switch from log probability sums to sum of probabilities to reduce noise- Model 4 Siamese network with embedding split...

Tong Y et al., EMBO Molecular Medicine, doi:10.1038/s44321-025-00362-9 - Patient data, population genetics and iPSC-derived βcell models show INS R6C impairs preproinsulin ER translocation and causes recessive insulin-deficient diabetes in homozygotes. Key terms: INS R6C, preproinsulin translocation, iPSC-derived beta cells, monogenic diabetes, population genetics. Study Highlights:The study integrates clinical pedigrees, large-scale population screens and patient-derived iPSC βcell models, plus in vivo transplantation and transcriptomics. AlphaFold 3 structural modeling suggested weakened SRP54 interaction and altered SEC61 orientation for the R6C signal peptide, and population data showed no enrichment of diabetes among heterozygotes. In homozygous R6C iPSC-βcells up to two-thirds of nascent preproinsulin failed to translocate, preproinsulin accumulated, and insulin content and secretion were reduced by roughly 50% with altered proinsulin processing. Functionally, homozygous R6C grafts produced minimal human C-peptide in mice and responded poorly to GLP-1 receptor agonists, while heterozygotes were largely compensated by a single wild-type allele. Conclusion:INS R6C is a recessive loss-of-function mutation that causes early-onset, insulin-deficient diabetes in homozygotes while heterozygous carriers show variable or absent glycemic phenotypes. Music:Enjoy the music based on this article at the end of the episode. Article title:A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data First author:Tong Y Journal:EMBO Molecular Medicine, doi:10.1038/s44321-025-00362-9 DOI:10.1038/s44321-025-00362-9 Reference:Tong Y, Becker M, Schierloh U, Natividade da Silva F, Haataja L, Cai Y, Patel KA, Kobaisi F, Mirshahi UL, Colclough K, Javed MS, Wakeling MN, Fantuzzi F, Lytrivi M, Sawatani T, Arroyo MN, Yi X, Vinci C, Montaser H, Pachera N, Otonkoski T, Igoillo-Esteve M, Scharfmann R, Hattersley AT, Arvan P, De Beaufort C, Cnop M. A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data. EMBO Molecular Medicine. 2026;18:620–645. https://doi.org/10.1038/s44321-025-00362-9 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/ins-r6c-recessive-diabetes QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-17. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the core scientific narrative conveyed in the transcript, focusing on: INS R6C zygosity-dependent diabetes; ER translocation defect caused by the signal peptide; SRP54 and SEC61 translocon involvement; heterozygous vs homozygous iPSC-derived β-cell phenotypes; population-genetic evidence; in vivo transplantatio- transcript topics: INS R6C mutation and zygosity; ER translocation defect and signal peptide mechanism; SRP54 and SEC61 translocon interactions; iPSC-derived β-cell modeling (heterozygous and homozygous); In vivo transplantation and C-peptide outcomes; Population genetics data (UK Biobank, Geisinger) and penetrance QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4

Wirth B et al., The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.012 - Two SMN1 exon 7 4-bp deletions (p.Arg288AlafsTer5) evade standard PCR newborn screening but produce a low-abundance, thermostable SMN protein that functionally rescues smn1-deficient zebrafish and averted therapy. Key terms: SMN1, spinal muscular atrophy, newborn screening, p.Arg288AlafsTer5, zebrafish rescue. Study Highlights:In two clinically healthy newborns flagged as lacking SMN1 by PCR-based NBS, long-range SMN1-specific PCR, Sanger sequencing, MLPA and ddPCR identified distinct 4-bp exon 7 deletions producing the same frameshift p.Arg288AlafsTer5. Cellular assays showed preserved exon 7 splicing, markedly reduced SMN protein abundance, and unchanged protein thermostability, while AlphaFold3 predicted only mild C-terminal structural alteration. Functional complementation in smn1-deficient zebrafish—using both mRNA injection and a stable Tg(UBI-mKate_SMN1-861VUS) transgene—fully rescued morphology, motor behavior, and survival. Population gnomAD analysis indicates these variants are rare but present in Europeans at a carrier frequency that predicts hundreds of compound heterozygotes without reported SMA, informing diagnostic sequencing and avoidance of unnecessary therapy. Conclusion:Integrated genetic, functional, structural, and population-level evidence supports likely non-pathogenic reclassification of the SMN1 c.855_858delAGAA and c.861_864delAAGG alleles and shows that very low levels of the altered SMN protein can preserve normal motor development. Music:Enjoy the music based on this article at the end of the episode. Article title:SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions First author:Wirth B Journal:The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.012 DOI:10.1016/j.ajhg.2026.01.012 Reference:Wirth B., Das J., Kölbel H., Goh S., Farrar M.A., Piano V., Zetzsche S., Fuhrmann N., Becker J., Karakaya M., Zhang Y., Cao Y., Taghipour-Sheshdeh A., Stringer B.W., Giacomotto J., et al. SMN1 variants identified by false-positive SMA newborn screening tests: Therapeutic hurdles and functional and epidemiological solutions. The American Journal of Human Genetics. 2026 Mar 5;113:1–9. https://doi.org/10.1016/j.ajhg.2026.01.012 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/smn1-exon7-frameshift-variants QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-15. 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 two SMN1 exon 7 4-bp deletions, their molecular consequences, splicing, protein abundance and thermostability, in vivo zebrafish rescue, and population-genetics data with implications for clinical practice.- transcript topics: Identification of two SMN1 exon 7 4-bp deletions; Molecular confirmation and variant characterization; SMN1 exon 7 splicing preservation; SMN protein abundance and thermostability assessments; Zebrafish functional rescue experiments; Population genetics (gnomAD) data and carrier frequencies QC Summary:-...

Kay CJ et al., Nature, doi:10.1038/s41586-025-09808-z - Relaxed-clock dating of pre-LECA gene duplications in Asgard archaeal and alphaproteobacterial lineages shows a complex archaeal host with cytoskeleton, endomembrane system and nucleus before mitochondrial acquisition around 2.2 Ga. Key terms: eukaryogenesis, Asgard archaea, mitochondrial endosymbiosis, gene duplication, molecular clock. Study Highlights:The study interrogates eukaryogenesis using a time-resolved species tree and a sequential Bayesian relaxed molecular clock applied to 135 gene family trees. Analyses with MCMCTree dated divergence nodes (nFECA 3.05–2.79 Ga, mFECA 2.37–2.13 Ga, LECA 1.80–1.67 Ga) and pre-LECA duplication events of archaeal and bacterial origin. Most archaeal-derived duplications (about 85% of those sampled) were fixed prior to inferred mitochondrial endosymbiosis, with archaeal duplications for actin, tubulin, vesicle trafficking and spliceosomal components dated between ~3.0 and ~2.25 Ga. Functionally, these timings indicate the host lineage had an elaborated cytoskeleton, endomembrane trafficking and nuclear compartmentalization before mitochondrial integration, while alphaproteobacterial duplications cluster near ~2.2 Ga consistent with mitochondrial establishment. Conclusion:Gene-duplication dating supports a complexified archaeal host with cytoskeleton, endomembrane system and nucleus preceding mitochondrial endosymbiosis, favoring a late-mitochondrion model of eukaryogenesis. Music:Enjoy the music based on this article at the end of the episode. Article title:Dated gene duplications elucidate the evolutionary assembly of eukaryotes First author:Kay CJ Journal:Nature, doi:10.1038/s41586-025-09808-z DOI:10.1038/s41586-025-09808-z Reference:Kay CJ, Spang A, Szöllősi GJ, Pisani D, Williams TA & Donoghue PCJ. Dated gene duplications elucidate the evolutionary assembly of eukaryotes. Nature 650, 129–140 (2026). https://doi.org/10.1038/s41586-025-09808-z 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/asgard-archaea-duplication-timeline QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-15. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections that describe the eukaryogenesis timeline, gene duplication events, and the CALM model, including specific date ranges and functional system developments (cytoskeleton, endomembrane system, nucleus, mitochondrion).- transcript topics: Eukaryogenesis timeline and debate (mitochondria early vs late); Relaxed molecular clock and cross-bracing dating approach; Pre-LECA duplications in archaeal origin (cytoskeleton, nucleus, trafficking); Endomembrane system and vesicle trafficking gene duplications; Nuclear components and RNA polymerase duplications; Mitochondrial endosymbiosis timing and alphaproteobacterial duplications 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:-...