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Title
Pub. Date
Duration
471: How cancer treatment picks winners among mutant clones in the normal esophagus
30 Oct 2026
00:17:54
Fowler J et al., Nature Genetics - Normal esophageal lining is a patchwork of mutant clones that compete for space as we age. This study asked whether cancer treatment changes which of those clones win. Normal esophagus removed at surgery from 70 patients with esophageal cancer, who had received no treatment, combination chemotherapy (ECX, EOX or FLOT) or chemoradiation (CROSS), was analyzed with duplex (NanoSeq), whole-genome and targeted sequencing, alongside protein structure modeling and a CRISPR experiment in mouse esophageal cultures. Key terms: somatic mutation, clonal selection, esophagus, chemoradiation, TP53.
Study Highlights: Targeted sequencing of 1,995 samples of 2 mm2 across 324 cancer-associated genes found 23,692 independent mutations, and no chemotherapy mutational signature was detected, suggesting most clones existed before treatment. In patients given CROSS, the proportion of epithelium mutant for TP53 and PPM1D was double that of the other groups, their mutational burden and deletion burden were higher, and over 5% of samples carried a copy number event covering the TP53 locus. HLA-B and SPOP mutants were selected only in CROSS patients, with 13 of 22 HLA-B nonsynonymous mutations predicted to abolish the protein. RAC1, NFE2L2 and MTOR mutants were under positive selection only in the FLOT group, the only regimen giving 5-fluorouracil together with leucovorin, and structural modeling suggested the MTOR mutants would likely remain sensitive to rapalogs. In mouse esophageal cultures, guide RNAs targeting exon 6 of Ppm1d were enriched after irradiation but not after 5-fluorouracil.
Conclusion: Weeks of neoadjuvant treatment can reshape a mutational landscape built over decades, selectively expanding preexisting mutant clones in a treatment-specific way, which may point to genes involved in cellular resilience to therapy. The groups were small (FLOT had seven patients), exposure data were limited, the mouse experiment did not test the full CROSS combination, the selection of MTOR, RAC1 and NFE2L2 mutants by 5-fluorouracil is inferred rather than tested, and selection in normal tissue cannot be assumed to match selection in cancer cells.
Article title: Cancer treatment alters mutant selection in normal esophagus
First author: Fowler J
Journal: Nature Genetics
DOI: 10.1038/s41588-026-02738-0
Reference: Fowler J.C., Arbore G., Sood R.K., Abnizova I., Albarello L., Pickering O., et al. Cancer treatment alters mutant selection in normal esophagus. Nature Genetics, 58, 2566-2578. (2026). https://doi.org/10.1038/s41588-026-02738-0
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded.
QC Summary: - sentences checked: 171 - supported by the article: 167 - flagged and reviewed by a human: 4 - metadata checks passed: 4 of 4
QC result: Pass.
Chapters
(00:00:03) - The Forest Fire Analogy: Introduction
(00:00:37) - Introducing Base by Base and the Paper
(00:00:58) - Mutant Clones in the Aging Esophagus
(00:01:29) - The Research Question and Team
(00:02:21) - Treatment Regimens: Chemotherapy and CROSS
(00:03:04) - The Study Opportunity at Surgery
(00:03:44) - Mutational Signatures Explained
(00:04:23) - Patient Cohort and Tissue Sampling
(00:05:07) - Sequencing Methods: Mapping the Clones
(00:06:16) - Measuring Selection in Genes
(00:06:49) - Protein Structure Modeling and Lab Tests
(00:07:23) - No Treatment-Specific Mutational Signature Found
(00:07:50) - CROSS Group Stands Out: Mutation Load
(00:09:01) - PPM1D Mutations and Radiation Resistance
(00:10:07) - Chromosome 17 and TP53 Disruption in CROSS
(00:10:41) - HLA-B and SPOP Selection in CROSS Patients
(00:13:44) - Interpreting the Findings: Speed of Change
(00:14:16) - Why TP53 Results Matter for Cancer Risk
(00:14:57) - The FLOT Question: Resistance Implications
(00:15:34) - Study Limitations
(00:16:12) - Summary: Different Fires, Different Winners
(00:16:50) - Closing Thoughts and Credits
470: The hidden swaps CRISPR leaves between sister chromosomes
29 Oct 2026
00:17:23
Chovanec P et al., eLife - When CRISPR/Cas9 cuts DNA, editing is usually judged by the small insertions and deletions left at the break. But a cut can also be repaired by swapping DNA between the two identical sister chromatids, an exchange that leaves no sequence change and is invisible to standard sequencing. Using sci-L3-Strand-seq, a single-cell method that reads which parental template strand each daughter cell inherited, this study mapped Cas9-induced sister chromatid exchange (SCE) in human cells, after cutting either one unique site or 237 repetitive Alu sites at once. Key terms: CRISPR/Cas9, sister chromatid exchange, Strand-seq, DNA double-strand break repair, structural variants.
Study Highlights: Duplex Cas9 cleavage at a single site or at 237 repetitive targets caused a pronounced G1/S arrest within 24 hr, while the D10A and H840A nickases did not measurably perturb cell-cycle progression after washout. Cutting a unique locus strongly enriched SCE at the break site, reaching 41% in the same cell cycle and 17% in the subsequent division. Across all cells, cutting 237 Alu sites gave only mild on-target enrichment, 1.20-fold in the post-washout condition (n=2547 cells), but a high-SCE subset of 261 cells showed 1.39-fold enrichment with an average of 14.61 on-target SCEs per cell. Reciprocal daughter-cell pair analysis found that 14 of 50 Cas9-induced SCE events were coupled with structural variants, in contrast to 87 of 87 spontaneous SCEs in XRCC1-null cells that were reciprocal and copy-neutral in a companion study. Cutting inside LIG3, LIG4, XRCC1 and XRCC4 did not change genome-wide SCE counts, with a median of three SCEs per cell in all four conditions, consistent with delayed functional loss after editing.
Conclusion: Cas9-induced double-strand breaks are potent local triggers of sister chromatid exchange, and a measurable fraction of these exchanges carries structural alterations that conventional sequencing cannot see, so they do not universally reflect error-free homologous recombination. All experiments were done in wild-type cells, Cas9 can cut the same site several times so individual outcomes cannot be tied to a single cleavage event, and the deletion signature pointing to a TRAIP/under-replicated-region pathway rests on a single daughter-cell pair.
Article title: Genome-wide mapping of Cas9-induced sister chromatid exchange across single and over 200 genomic sites in human cells
First author: Chovanec P
Journal: eLife
DOI: 10.7554/eLife.112073
Reference: Chovanec P., He S., Yin Y. Genome-wide mapping of Cas9-induced sister chromatid exchange across single and over 200 genomic sites in human cells. eLife, 15. (2026). https://doi.org/10.7554/eLife.112073
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-29.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript...
Chapters
(00:00:03) - The Deck of Cards Analogy
(00:00:41) - Intro and Fact-Check Note
(00:01:02) - Sister Chromatids and Silent Swaps
(00:01:33) - Cas9 Scissors and Hidden Repairs
(00:02:08) - Paper Introduction
(00:02:44) - How Cas9 Cuts Are Normally Repaired
(00:03:24) - Bigger Damage Beyond Small Edits
(00:03:57) - Defining Sister Chromatid Exchange
(00:04:17) - Four Broken Ends and Open Questions
(00:05:28) - Strand-Seq: Reading the Backs of the Cards
(00:06:37) - Experimental Design and Guides
(00:07:46) - Cell Cycle Arrest Findings
(00:08:22) - Exchanges Pile Up at the Cut Site
(00:08:53) - Interpreting the 41% Exchange Rate
(00:10:02) - Checking Repair Gene Targets
(00:10:34) - Cutting 237 Sites at Once
(00:11:11) - High-Exchange Cell Subsets
(00:12:22) - Reciprocal Daughter Pairs and Clean Trades
(00:12:53) - When Trades Aren't Clean
(00:13:24) - Rethinking How We Judge Edits
(00:14:00) - Isochromatid Breaks and Mechanism
(00:14:59) - Caveats on Causation and Single Observations
(00:15:55) - Conclusions and Implications
(00:16:51) - Closing and Credits
469: What the shape of a face reveals about cleft risk
27 Oct 2026
00:18:17
Herrick N et al., Human Genetics and Genomics Advances - Orofacial clefts are among the most common birth defects, affecting about 1 in 700 births, yet known genetic signals explain only a fraction of their heritability, and cleft studies cannot reach the huge sample sizes used for traits like height. This study borrowed statistical power from a related trait: the genetics of normal human face shape. Using a pleiotropy-informed method called conditional false discovery rate, the team re-analyzed an existing GWAS of nonsyndromic cleft lip with or without cleft palate and found new candidate risk loci, three of which passed a 5% FDR threshold in an independent replication cohort. Key terms: orofacial cleft, facial shape, GWAS, conditional false discovery rate, pleiotropy.
Study Highlights: The team conditioned summary statistics from a European nsCL/P GWAS of 3,969 individuals on two independent facial shape GWASs, from 4,680 US and 3,566 UK individuals. SNPs associated with nsCL/P were enriched among SNPs associated with facial shape but not among those for unrelated traits such as height, schizophrenia or LDL cholesterol. The cFDR approach identified 21 independent loci at a 5% threshold and 15 more at 10%, and the new loci had effect sizes comparable to known ones, with no significant difference in a Mann-Whitney U test (p = 0.26). Of 13 new lead SNPs tested in The Cleft Collective cohort of 1,084 affected individuals and 7,913 controls, five replicated at p < 0.05, and loci near MSX2, ASPSCR1 and FHOD3 passed a 5% FDR threshold. Spatial transcriptomics of a Carnegie stage 13 human embryo showed expression and gene specificity scores for these genes in the pharyngeal arches, among other regions.
Conclusion: Leveraging the shared genetics of face shape and clefting can recover cleft risk loci that a standard GWAS of the same data misses, and it supports the long-standing idea that embryonic face shape is itself part of cleft risk. The analysis is limited to people of European ancestry, the authors expect about 10% of the 36 loci to be false positives, not every new locus replicated, and the expression data support but do not prove a role for the candidate genes.
Article title: Leveraging the genetics of human face shape boosts the discovery of orofacial cleft risk loci
First author: Herrick N
Journal: Human Genetics and Genomics Advances
DOI: 10.1016/j.xhgg.2026.100655
Reference: Herrick N., Goovaerts S., Manchel A., Lee M.K., Zhang X., Davies A., et al. Leveraging the genetics of human face shape boosts the discovery of orofacial cleft risk loci. Human Genetics and Genomics Advances, 7, 100655. (2026). https://doi.org/10.1016/j.xhgg.2026.100655
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-27.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: All scientific...
Chapters
(00:00:03) - Introduction: Face Shape and Clefts
(00:01:21) - The Study and Researchers
(00:02:18) - Background on Orofacial Clefts
(00:03:28) - The Face-Cleft Genetic Link Hypothesis
(00:04:46) - The CFDR Method Explained
(00:05:21) - Study Data and Controls
(00:07:01) - Analysis Details and Validation Approach
(00:07:41) - Results: Face Shape as a Predictive Map
(00:08:17) - Main Findings: New Cleft Loci Discovered
(00:08:49) - Comparing US and UK Cohorts
(00:09:23) - Are New Loci Real? Effect Size Check
(00:09:56) - Replication in the Cleft Collective Cohort
(00:11:06) - Regional Plots of Three Candidate Genes
(00:11:36) - Gene Expression in the Embryo
(00:12:41) - Spatial Genetic Risk Mapping (GSMap)
(00:13:17) - MSX2: A Known Suspect Confirmed
(00:13:53) - ASPSCR1 and FHOD3: New Biological Clues
468: When a splicing factor breaks in different ways
25 Oct 2026
00:17:30
Lisfeld J et al., The American Journal of Human Genetics - SRSF3 is an essential splicing factor, one of the serine/arginine-rich proteins that help cells cut and paste their RNA messages and send them out of the nucleus. Losing it completely is lethal in mouse embryos. This study describes nine individuals with new, non-inherited SRSF3 variants and variable developmental phenotypes, with developmental delay and/or mild to moderate intellectual disability as the most consistent feature. Functional experiments in patient fibroblasts and human cell lines showed that each variant damaged the protein in a different combination of ways, which may help explain why affected individuals differ so much. Key terms: SRSF3, splicing, de novo variants, neurodevelopmental disorder, spliceosomopathy.
Study Highlights: Through GeneMatcher, the team recruited nine subjects with six heterozygous de novo SRSF3 variants: two missense variants in the RNA recognition motif, three frameshifts and a recurrent nonsense variant, p.Arg149*, found in four unrelated subjects. In fibroblasts from subject 3, transcripts carrying the c.330_331del frameshift were largely degraded by nonsense-mediated decay, with only about 12.5% of SRSF3 reads carrying the deletion, yet overall SRSF3 mRNA and protein levels were normal, suggesting compensation from the other allele. In HEK293T cells, all five variant proteins tested formed less complex with polyadenylated RNA than wild type, while the three C-terminally truncated proteins were poorly phosphorylated, less stable, at about 46% to 59% of wild-type levels, and showed reduced nucleocytoplasmic shuttling in HeLa cells. Complex formation with the export factors YTHDC1 and NXF1 was reduced for p.Arg137Ilefs*16 and p.Arg149* and increased for p.Ser81Trp.
Conclusion: De novo SRSF3 variants define a new spliceosomopathy with a broad developmental spectrum, and the variants appear to act through distinct mechanisms rather than simple loss of half the protein. The cohort is small, most functional work used overexpressed proteins in cell lines rather than affected tissues, the evidence against haploinsufficiency comes from one subject and one cell type, and the c.330_331del variant remains of uncertain significance.
Article title: De novo variants in the essential splicing factor gene SRSF3 cause variable developmental phenotypes
First author: Lisfeld J
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.09.018
Reference: Lisfeld J., Chinn I.K., Yuan B., Casar C., Müller C., Elron E., et al. De novo variants in the essential splicing factor gene SRSF3 cause variable developmental phenotypes. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.09.018
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
(00:11:28) - RNA Gripping Deficits Across Variants
(00:11:50) - Nuclear Shuttling Defects
(00:12:36) - Export Partner Binding Differences
(00:13:06) - Each Variant's Unique Defect Combination
(00:13:44) - SRSF3 as a New Spliceosomopathy
(00:14:18) - Comparison to SRSF1 and Clinical Implications
(00:14:52) - Challenging Assumptions About Truncating Variants
(00:15:24) - Study Limitations
(00:16:02) - Summary: One Gene, Many Breaks
(00:16:35) - Closing and Credits
467: Finding mutations carried by fewer than 1 in 100 cells
18 Oct 2026
00:18:37
Jang Y et al., The American Journal of Human Genetics - Every cell in the body picks up its own small set of DNA changes over a lifetime, and many of these somatic mutations are carried by only a tiny fraction of cells. This study, part of the SMaHT Network, asks how reliably standard bulk whole-genome sequencing can find mutations present at a variant allele fraction below 1%. The team built a ground truth from one donor's skin: clonal stem cell lines grown from single fibroblasts defined real mutations, and lines from other skin biopsies of the same donor defined mutations that should be absent. With about 1,360× Illumina coverage confirmed by PacBio and AVITI, point mutations below 1% were detected accurately in the easily mapped parts of the genome. Key terms: somatic mosaicism, whole-genome sequencing, variant allele fraction, benchmarking, SMaHT.
Study Highlights: Primary fibroblasts from a 29-year-old donor contained five subclones, captured as clonal iPSC lines, giving benchmark mutations from 0.1% to 25% variant allele fraction, while iPSC lines from other biopsies of the same donor supplied negative controls; both sets held about 11,000 SNVs and 2,800 indels. Using the negative controls, PacBio and AVITI had the lowest substitution error rates in easy regions, 0.003% and 0.005%, and mismatch rates rose by 1 to 2 orders of magnitude in harder regions. In fibroblasts, more than 99.5% of bulk-only calls above 1% were confirmed by PacBio or AVITI, the estimated false-positive rate was near zero above 0.8% and about 11% below 0.5%, and homopolymer indels could be detected reliably only above 3%. In postmortem lung and colon, combining about 200× from two tissues found 13 additional shared mutations, a 145% gain in sensitivity below 3%, all confirmed by PacBio or single-cell data.
Conclusion: Ultra-deep bulk whole-genome sequencing can detect point mutations below 1% allele fraction with high accuracy, provided calling is restricted to easily mapped regions and sample quality is checked, and pooling coverage across tissues from one donor recovers shared developmental mutations. The benchmark comes from a single donor's fibroblasts, confirmation below 0.5% was limited by long-read and AVITI coverage, most indels sit in homopolymers or hard regions where detection remains unreliable, and postmortem samples needed extra filtering.
Article title: Accurate detection of sub-1% frequency somatic mutations by whole-genome sequencing
First author: Jang Y
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.09.010
Reference: Jang Y., Gardiner S., Wang Y., Natu A., Dehankar M.K., Tomasini L., et al. Accurate detection of sub-1% frequency somatic mutations by whole-genome sequencing. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.09.010
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-18.
QC Scope: - article metadata...
466: A quieter MECP2 switch and the male bias in autism
16 Oct 2026
00:18:45
Meyer-Schuman R et al., The American Journal of Human Genetics - Autism is diagnosed about four times more often in male individuals than in female individuals, and one explanation is mild variants in dosage-sensitive genes on the X chromosome, which a female carrier can buffer with her second copy but a male cannot. This study tests that idea in MECP2, the Rett syndrome gene, by looking at the switches that control how much of it is made rather than the gene itself. Using a massively parallel reporter assay in human stem-cell-derived neurons, the team mapped the active transcription factor binding sites in five MECP2 regulatory elements and tested 22 ultra-rare variants passed from unaffected mothers to autistic sons. Two variants changed regulatory activity, and one in the promoter lowered MECP2 RNA and protein by about 30% when edited into the native gene. Key terms: MECP2, autism, massively parallel reporter assay, noncoding variants, X chromosome.
Study Highlights: Whole-genome data from 30,916 individuals in 8,245 autism families yielded 22 ultra-rare noncoding variants in MECP2 regulatory elements, each private to one family, found only in male probands and inherited from an unaffected mother, tested alongside 19 gnomAD control variants. Shuffling predicted transcription factor motifs mapped activator or repressor hotspots in four of the five elements, and knocking down two predicted activators, TCF3 and ZNF281, lowered MECP2 RNA by about 55% and 47% after three weeks. A variant in the primate-specific repressor element CRE A, carried by two affected brothers, increased activity in both the reporter and luciferase assays. The promoter variant g.154097837A>G, found in a boy with autism and ADHD and a full-scale IQ of 97, weakened NFY-B binding at the MECP2 promoter from the 51st to the 9th percentile of bound promoters and reduced MECP2 RNA and protein by about 30% in edited neurons.
Conclusion: The findings suggest that noncoding MECP2 variants that modestly lower or raise expression can contribute to idiopathic, male-biased autism, and they provide a framework for finding regulatory variants in other X chromosome neurodevelopmental genes. The evidence rests on two families and on reporter assays and edited neurons in a dish, which take short sequences out of their native chromatin context, so the link between these variants and autism still needs additional variant discoveries and molecular validation.
Article title: A massively parallel reporter assay of MECP2 cis-regulatory elements reveals genetic candidates for male-biased autism
First author: Meyer-Schuman R
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.09.011
Reference: Meyer-Schuman R., Cherry F., Sui Y., Papastathopoulos-Katsaros A., Zhong Y., Li Y., et al. A massively parallel reporter assay of MECP2 cis-regulatory elements reveals genetic candidates for male-biased autism. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.09.011
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
(00:10:27) - Switch Teamwork and Context Dependence
(00:10:57) - Element A Variant in Two Brothers
(00:12:14) - Promoter Variants and Luciferase Testing
(00:12:48) - The Boy with the Promoter Variant
(00:13:22) - CRISPR Validation of NFY Binding Loss
(00:14:18) - Measuring the Downstream Effects
(00:14:57) - What the Findings Add Up To
(00:15:32) - Why Mild Cases Survive the Filter
(00:16:03) - Beyond MECP2: Broader Implications
(00:16:33) - Study Limitations
(00:17:15) - Conclusion: Quiet Switches and the Future
(00:18:13) - Closing and Credits
465: When a lysosomal storage gene shows up only in the retina
11 Oct 2026
00:20:03
Lin et al., The American Journal of Human Genetics - Bi-allelic variants in IDUA classically cause mucopolysaccharidosis type I, a lysosomal storage disorder that affects many organs from childhood. This study describes 14 adults and young adults from 12 families who first came to eye clinics with retinitis pigmentosa and were later found to carry bi-allelic IDUA variants. Seven of them showed no systemic features of the disease even after detailed assessment, and enzyme activity in white blood cells was reduced but never absent. Cell-based enzyme assays and long-read RNA sequencing explain how mild, hypomorphic alleles can leave just enough enzyme to spare the body but not the retina. Key terms: IDUA, mucopolysaccharidosis type I, retinitis pigmentosa, hypomorphic variants, splicing.
Study Highlights: Individuals aged 19 to 73 were recruited from inherited retinal disease cohorts in the UK, Ireland, Italy, the Netherlands and the United States, and none carried two null alleles; most had a loss-of-function allele paired with a missense variant. Leukocyte alpha-L-iduronidase activity was reduced but detectable in all nine individuals tested, and urine glycosaminoglycans were above normal in only half of those tested, with modest elevations. In an IDUA-knockout cell line, several missense variants, including p.His91Tyr and p.Arg383His, showed relative specific activity around 0.5% to 1.5% of wild type, with poor processing or stability. The recurrent c.298A>G variant left enzyme activity intact as a protein change, but nanopore long-read sequencing showed that it mostly causes exon 2 skipping, with only about 1.3% of reads from that allele spliced normally.
Conclusion: Hypomorphic IDUA genotypes that leave low residual enzyme activity can cause late-onset retinitis pigmentosa with mild or apparently no systemic disease, extending the known spectrum of MPS I and arguing for including IDUA in inherited retinal disease gene panels. The cohort is small and mostly of European ancestry, systemic assessment varied in depth, and without longitudinal follow-up some individuals classed as having isolated retinal disease may still develop systemic features.
Article title: Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I
First author: Lin
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.09.008
Reference: Lin, S., Yu, S.-H., Browning, A. C., et al., Roosing, S., Steet, R., and Arno, G. (2026). Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I. The American Journal of Human Genetics 113, 1-12. https://doi.org/10.1016/j.ajhg.2026.09.008
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
(00:16:15) - Clinical Implications for Diagnosis and Panels
(00:16:51) - Therapeutic Implications
(00:17:18) - Newborn Screening Dilemma
(00:17:55) - Study Limitations
(00:18:31) - Conclusions and Open Questions
(00:19:31) - Closing and Credits
464: Burning fat while sparing muscle on GLP-1 drugs, in mice
06 Oct 2026
00:18:20
Thorne et al., Proceedings of the National Academy of Sciences - GLP-1 receptor agonists such as semaglutide produce large weight loss, but part of what is lost is lean mass, energy expenditure falls, and weight tends to return when treatment stops. This study tests a complementary idea in mice: switching on heat-producing fat by silencing ZFP423, a repressor of brown and beige fat identity, with an adipose-targeted antisense oligonucleotide. The RNA drug raised energy expenditure and improved metabolism on its own, and combined with semaglutide it produced more weight and fat loss while roughly halving the loss of lean mass. Key terms: GLP-1 receptor agonist, ZFP423, antisense oligonucleotide, adipose thermogenesis, lean mass.
Study Highlights: Antisense oligonucleotides against Zfp423 were linked to palmitic acid to reach fat tissue, and two of twelve candidates, ASO37 and ASO44, were selected for strong knockdown without signs of toxicity. In lean mice on chow, weekly treatment for 10 weeks beiged white fat, raised oxygen consumption and body surface temperature without changing activity, and improved glucose tolerance even though body weight stayed the same, while muscle and heart function were preserved. In obese mice, three doses lowered fasting triglycerides, glucose and body weight, and fat mitochondria from treated mice showed more than threefold higher oxygen consumption than controls, partly through UCP1 and partly through the futile creatine cycle. Combined with semaglutide, ASO37 produced 9.2 g of weight loss against 6.6 g for either drug alone, cut body fat to 4.2 g, and limited lean mass loss to 5.5% compared with about 10% with semaglutide alone.
Conclusion: In mice, silencing ZFP423 in fat with an RNA drug turns on thermogenic beige fat and complements GLP-1 receptor agonist treatment by adding fat loss and sparing lean mass. The work was done only in mice, the antisense drugs target mouse Zfp423 rather than human ZNF423, combination studies lasted three weeks, and several authors are employees of Ionis Pharmaceuticals or inventors on a related patent application.
Article title: An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss
First author: Thorne
Journal: Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2618845123
Reference: Thorne, A. K., Waldeck, N. J., Rose, J. P., Stachowski, M. J., Guak, H., Keeble, A. R., et al., and Bass, J. (2026). An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss. Proceedings of the National Academy of Sciences 123(40), e2618845123. https://doi.org/10.1073/pnas.2618845123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-06.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the ZFP423 rationale...
Chapters
(00:00:20) - Introduction: The Problem with Weight Loss Drugs
(00:01:11) - GLP1 Drugs and Their Limitations
(00:01:41) - A New Hypothesis: Burning Fat as Heat
(00:02:12) - Study Overview and Publication
(00:02:48) - Obesity, Fat Types, and Thermogenesis
(00:04:00) - The Body Clock and ZFP423 Discovery
(00:04:59) - Timing, Metabolism, and the Gene's Role
(00:05:41) - Designing the Antisense Oligonucleotide Drug
(00:06:47) - Single Cell Sequencing Methods
(00:07:22) - Experimental Design Across Mouse Models
(00:07:58) - Results in Lean Mice: Body Composition Shifts
(00:08:29) - Organ and Hormone Effects
(00:09:01) - Extra Eating but No Weight Gain: Energy as Heat
(00:11:02) - Mitochondrial Mechanisms: Two Furnaces
(00:12:08) - Single Cell Reorganization of Fat
(00:12:45) - Combination Therapy: ASO Plus Semaglutide
(00:13:19) - Preserving Muscle Mass and Function
(00:14:21) - Energy Expenditure and Metabolic Outcomes
(00:14:56) - Why This Matters for Obesity Treatment
(00:15:26) - The Muscle Loss Concern Explained
(00:15:56) - Study Limitations
(00:16:31) - Conflicts of Interest Disclosure
(00:16:59) - Conclusions and Future Outlook
(00:17:48) - Closing and Credits
463: Why brain traits leave faint, common genetic signals
04 Oct 2026
00:18:21
Zhu et al., Proceedings of the National Academy of Sciences - Genome-wide studies of schizophrenia and other psychiatric disorders find hundreds of hits, yet those hits barely clear the significance threshold and tend to be common variants, unlike traits such as LDL cholesterol. This study shows that other traits whose heritability is enriched in the central nervous system share the same pattern, that the pattern survives careful matching of statistical power between binary and quantitative traits, and that it is best explained by an evolutionary model in which brain-related traits have very large mutational targets and their variants face stronger selection. Key terms: genetic architecture, natural selection, GWAS, psychiatric genetics, mutational target size.
Study Highlights: Using stratified LD score regression across 220 cell types, the authors classified 164 traits and found 50 brain-related quantitative traits and four brain-related disorders, all psychiatric, among 151 UK Biobank traits and 13 diseases. Schizophrenia hits had a narrower spread of z-scores and higher minor allele frequencies than LDL or coronary artery disease hits, and the difference remained after downsampling the other GWAS to the effective sample size of the schizophrenia study. Fitting a pleiotropic stabilizing selection model, they inferred a selection distribution shifted toward stronger selection for brain-related traits and a median mutational target of about 1.32% of the genome, against 0.27% for other traits. Simulations showed that stronger selection, once GWAS ascertainment is applied, enriches hits for common variants, and rare loss-of-function burden tests showed that highly constrained genes have larger effects on brain-related traits than on other traits.
Conclusion: Traits mediated by the central nervous system share a distinct genetic architecture of many small, relatively common effects, which the authors attribute to large mutational target sizes and stronger selection on brain-relevant variants and genes. The brain-related traits studied act as proxies for the processes under selection, so the specific targets of selection cannot be identified, and confounding was not fully excluded because family-based GWAS remain underpowered.
Article title: Genetic architectures of brain-related traits are shaped by strong selective constraints
First author: Zhu
Journal: Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2609814123
Reference: Zhu, H., Simons, Y. B., Spence, J. P., Sella, G., and Pritchard, J. K. (2026). Genetic architectures of brain-related traits are shaped by strong selective constraints. Proceedings of the National Academy of Sciences 123(36), e2609814123. https://doi.org/10.1073/pnas.2609814123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
(00:12:41) - Why Stronger Selection Produces Common Hits
(00:13:19) - Independent Evidence from Gene Constraint
(00:14:22) - Explaining the History of Psychiatric Genetic Discovery
(00:14:58) - Why the Brain May Face Stronger Selection
(00:15:35) - Limitations and Caveats
(00:16:44) - Conclusions and Broader Implications
(00:17:48) - Closing and Credits
462: A vessel gene tied to AMD dims low-light vision in mice
30 Sep 2026
00:20:10
Cheng et al., Proceedings of the National Academy of Sciences - Genome-wide studies have found dozens of risk loci for age-related macular degeneration, but for many of them the gene doing the work is unknown. This study combines AMD genetics with blood and retinal gene-expression data to prioritize nine candidate genes, screens them in zebrafish, and follows the strongest, CNN2, into knockout mice. Mice lacking Cnn2 lose sensitivity in dim light and to fine contrast while acuity stays normal, and their photoreceptor layer thins, even though the gene is expressed mainly in the retina's blood-vessel cells rather than in photoreceptors. Key terms: age-related macular degeneration, CNN2, statistical genetics, photoreceptor degeneration, retinal neurovascular homeostasis.
Study Highlights: Summary-data-based Mendelian randomization combining an AMD genome-wide study of 16,144 cases and 17,832 controls with blood expression data from 2,765 people found 16 genes, and the HEIDI test kept 9 whose signals were not explained by linkage, 4 of which replicated in retinal data from 406 donors. In zebrafish larvae, morpholino knockdown of cnn2 shrank eye area by 48.5% and axial length by 32.5%, cut the light-on visual motor response by 61.9%, and both defects were largely rescued by injecting cnn2 mRNA. Cnn2 knockout mice at 3 months had a 39.2% lower a-wave and a 27.3% lower b-wave in dim-light electroretinograms and needed 15.3% contrast to respond where wild-type mice needed 4.1%, while bright-light responses and visual acuity were unchanged. The photoreceptor layer thinned by 3 and 5 months, cone arrestin and rhodopsin fell, and the 436 genes altered in the retina were enriched 6.02-fold near known AMD risk loci. Cnn2 was expressed mainly in endothelial cells and pericytes, and in human retinas it was lower in AMD but not significantly so.
Conclusion: Human genetic evidence and experiments in two species converge on CNN2, a calponin gene active mainly in retinal blood-vessel cells, as a candidate susceptibility gene for age-related macular degeneration. The authors propose that its loss disturbs neurovascular balance and harms photoreceptors secondarily, but the data do not yet show whether the effect is direct or indirect, and neither model has a macula.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Genetic evidence and cross-species functional characterization implicate CNN2 in age-related macular degeneration susceptibility
First author: Cheng
Journal: Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2533682123
Reference: Cheng, F.-F., Mou, H., Liu, Z., Zhang, C.-J., Zhuang, Y.-Y., Wu, Z., Wen, X.-R., Xue, A., Zhang, X., Yang, J., and Jin, Z.-B. (2026). Genetic evidence and cross-species functional characterization implicate CNN2 in age-related macular degeneration susceptibility. Proceedings of the National Academy of Sciences 123(36), e2533682123. https://doi.org/10.1073/pnas.2533682123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
(00:07:21) - Zebrafish screening of candidate genes
(00:08:30) - Zebrafish results: CNN2 and SARM1 effects
(00:09:38) - Focusing on CNN2 in mice
(00:10:11) - Mouse vision tests: contrast and sensitivity
(00:11:17) - Retinal structure changes in knockout mice
(00:11:44) - Where CNN2 is expressed: vessels not photoreceptors
(00:12:46) - What is CNN2 and proposed mechanism
(00:13:14) - Caveats and limitations of the study
(00:14:27) - Significance and future implications
(00:15:05) - Summary and closing thoughts
(00:16:08) - Credits and outro
(00:16:49) - Original song: The dimming eye ballad
461: Adult Ank3 loss quiets neurons and lowers a myelin protein
24 Sep 2026
00:24:55
Yoon et al., Proceedings of the National Academy of Sciences - ANK3, which encodes the scaffolding protein ankyrin-G, is a major risk gene for bipolar disorder and schizophrenia, yet what it does in adult neurons has been unclear. This study deletes Ank3 from mouse forebrain excitatory neurons either before birth or from adolescence and finds a convergent adult profile: hyperactivity and less anxiety-like and depression-like behavior, with social behavior intact. The neurons become less active, their membrane proteome shifts, and myelin basic protein falls, a protein made by oligodendrocytes rather than by the neurons that lost Ank3. Key terms: ANK3, ankyrin-G, bipolar disorder, myelin basic protein, lithium.
Study Highlights: Deleting Ank3 prenatally with Emx1-Cre or from adolescence with CaMKIIα-Cre produced convergent adult phenotypes, including hyperactivity, reduced anxiety-like behavior and reduced immobility in the forced swim test, while the three-chamber social test was normal in both lines. Calcium imaging showed that ankyrin-G knockdown lowered spontaneous activity in cultured cortical neurons and that knockout slices gave smaller KCl-evoked calcium responses in layer 2/3 of somatosensory cortex. Quantitative TMT proteomics of the cortical membrane fraction quantified 2,357 proteins, of which 75 changed, 59 up and 16 down, and western blots confirmed higher Ryr2 and Taok2 and lower myelin basic protein. Mbp immunostaining was reduced in cortical layers 2/3 and 4 but not in layer 5 or hippocampal CA3, and myelin sheath diameter did not change significantly. A three-week lithium diet restored Mbp in the P3 fraction but not in the P2 membrane fraction, and left Ryr2 and Taok2 unchanged.
Conclusion: Removing ankyrin-G from adult excitatory neurons is enough to produce hyperactive, low-anxiety mice with quieter neurons and less myelin basic protein, which ties a psychiatric risk gene in neurons to a myelin-associated protein made by glia. Lithium's selective restoration of Mbp suggests one possible myelin-related component of its action, although the cellular source of the Mbp change and any structural myelin deficit remain to be shown.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Ank3 loss in adult forebrain excitatory neurons disrupts behavior, neuronal activity, membrane proteome, and myelination
First author: Yoon
Journal: Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2606900123
Reference: Yoon, S., Dos Santos, M., Khalatyan, N., Savas, J.N., and Penzes, P. (2026). Ank3 loss in adult forebrain excitatory neurons disrupts behavior, neuronal activity, membrane proteome, and myelination. Proceedings of the National Academy of Sciences 123(35), e2606900123. https://doi.org/10.1073/pnas.2606900123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
(00:20:06) - Summary and implications for future treatment
(00:20:43) - Closing and credits
(00:21:57) - Original inspired track
460: The lupus variant that also sharpens antiviral defense
21 Sep 2026
00:24:13
Virolainen et al., The American Journal of Human Genetics - A lupus signal on chromosome 11p15 narrows to a coding haplotype in IRF7 that most people in the world carry. This study shows the risk form moves into the nucleus more readily, binds DNA more tightly and shifts its sequence preference, raising interferon-alpha output, and that mice engineered with the equivalent change clear a respiratory virus better while producing more anti-DNA autoantibodies. The same change buys antiviral protection and costs autoreactivity. Key terms: systemic lupus erythematosus, IRF7, type I interferon, evolutionary trade-off, fine mapping.
Study Highlights: Fine mapping across ancestries placed the lupus association at 11p15 on a common coding IRF7 haplotype tagged by rs1131665 (p.Gln412Arg), with odds ratios of 1.20 in European and 1.15 in African ancestry cohorts and 1.18 in the trans-ancestral meta-analysis. The risk allele is carried by most of the world, reaching 98% in East Asian ancestry and 42% in African ancestry datasets, and ancient DNA spanning more than 40,000 years shows it was already common well before the recorded epidemics the authors examined. In cells the risk form increased IRF7 nuclear localization, strengthened DNA binding and altered its sequence specificity, raising interferon-alpha after stimulation of pattern recognition receptors in monocytes and airway epithelial cells. Mice carrying the analogous CRISPR-engineered Arg334Gln change in Irf7 had lower lung viral titers after intranasal vesicular stomatitis virus and produced significantly more anti-dsDNA autoantibodies than mice with the protective form. The authors read this as an evolutionary trade-off, in which the same gain in interferon output buys innate antiviral control at the price of autoreactivity.
Conclusion: A coding haplotype in IRF7 that a majority of people carry tunes interferon-alpha upward, and that single setting produces both better early control of viral infection and a higher tendency to autoantibody production. Reading lupus risk at this locus as the cost of an antiviral advantage helps explain why such a variant stayed common, and it places interferon-directed therapy in a context where the same pathway is doing useful work.
Music: Enjoy the music based on this article at the end of the episode.
Article title: A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-α, enhancing antiviral defense and exacerbating autoimmunity
First author: Virolainen
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.08.016
Reference: Virolainen, S.J., Creighton, K., Dashtiahangar, M., et al., Waggoner, S.N., Weirauch, M.T., and Kottyan, L.C. (2026). A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-α, enhancing antiviral defense and exacerbating autoimmunity. The American Journal of Human Genetics 113, 1-22. https://doi.org/10.1016/j.ajhg.2026.08.016
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
(00:00:14) - Intro: The evolutionary paradox of a 'bad' gene
(00:02:15) - What is lupus? Understanding the disease
(00:03:17) - IRF7: The master regulator of interferon response
(00:04:44) - The globally dominant lupus risk variant
(00:05:59) - Tracing the variant through ancient DNA
(00:07:33) - Engineering cells with CRISPR to test the variant
(00:08:36) - Validating mouse models for human immunity
(00:10:46) - Findings: ancient persistence and cellular mechanics
(00:11:57) - Doubling interferon: the biological amplifier effect
(00:14:19) - Mouse trials: autoimmunity vs viral survival tradeoff
(00:15:31) - The evolutionary bargain: survive now, pay later
(00:16:51) - Treatment implications and the risk of turning off IRF7
(00:18:15) - Future research and remaining mysteries
(00:19:11) - Summary and closing thoughts
(00:20:14) - Closing credits and outro song
(00:20:38) - Original track: 'Same Dial, Both Ways'
459: Cerebral palsy genetics: 515 candidate genes, evidence for 89
13 Sep 2026
00:24:06
Arterbery et al., The American Journal of Human Genetics - Hundreds of genes have been reported as causes of cerebral palsy, yet there is no agreed model of what a pathogenic variant in a child with CP actually means. This study treats CP as a phenotypic feature that some genetic disorders make more likely, tests the reported genes against the population prevalence of CP across tens of thousands of published individuals, and finds statistical evidence of association for only 89 of 515, before applying that stratification to genome sequencing of 460 children with CP. Key terms: cerebral palsy, Mendelian disease, genome sequencing, Human Phenotype Ontology, gene-disease association.
Study Highlights: Across 21 published genomic diagnostic cohorts, variants deemed causal of cerebral palsy had been reported in 515 genes, with no consensus on whether such variants cause CP, mimic it, or coexist with it. The authors modelled CP as a phenotypic feature with a known population prevalence and applied a Bonferroni-corrected binomial test to 280 genes drawn from 5,508 publications describing 43,897 individuals, rejecting the null hypothesis of no association for 86 genes, and for 89 when combined with the genes enriched across the CP sequencing cohorts. Genome sequencing of 460 children with CP from 453 families at Shriners Children's identified pathogenic or likely pathogenic variants in 60 genes in 15.8% of the children. Only 16 of those 60 genes had significant literature evidence for CP association, which still represented a 16.3-fold enrichment over the overlap expected by chance. The results support a stratified approach in which the strength of evidence for each gene shapes how a molecular finding in a child with CP is interpreted.
Conclusion: A pathogenic variant found in a child with cerebral palsy does not carry the same weight for every gene: for most of the 515 genes reported so far, the literature does not yet provide statistical evidence that the associated disorder raises the likelihood of CP. Treating CP as a phenotype with graded genetic evidence offers a framework for attributing causality more carefully in precision genomic diagnosis, while leaving open that more genes may prove to be associated as data accumulate.
Music: Enjoy the music based on this article at the end of the episode.
Article title: A phenotypic paradigm for cerebral palsy genetics
First author: Arterbery
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.08.007
Reference: Arterbery, A.S., Gargano, M.A., et al., and Robinson, P.N. (2026). A phenotypic paradigm for cerebral palsy genetics. The American Journal of Human Genetics 113, 1972-1986. https://doi.org/10.1016/j.ajhg.2026.08.007
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-09-13.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music<...
458: Somatic or inherited? Reading TP53 risk from shared DNA
10 Sep 2026
00:25:09
MacGregor et al., The American Journal of Human Genetics - Pathogenic TP53 variants found in blood have long been read as inherited Li-Fraumeni alleles, but many turn out to be somatic clones that grew with age. Using whole-exome data from 469,391 UK Biobank participants, this study combines variant allele fraction with haplotype sharing to tell the two origins apart, and finds that in cancer-free middle-aged adults the risk is mostly somatic and mostly hematological. Key terms: TP53, clonal hematopoiesis, Li-Fraumeni syndrome, UK Biobank, variant classification.
Study Highlights: Rare coding TP53 variants were called in 469,391 UK Biobank participants aged 40 to 70, and 1,753 nonsynonymous variants were sorted by variant allele fraction combined with haplotype sharing across individuals carrying the same allele. Of 55 unique pathogenic TP53 variants detected, only six were classified as germline, and most of those sit at positions linked to partial rather than complete loss of p53 function. Classic Li-Fraumeni alleles behaved like somatic clonal expansions: their prevalence rose with age at an odds ratio of 2.3 per decade, while likely germline variants showed no age trend. Incident cancer risk separated sharply by origin, with the signal for somatic and inconclusive variants driven almost entirely by blood cancers rather than solid tumors, reaching a hazard ratio of 16.5 for the high-allele-fraction inconclusive class. The prevalence of somatic expansion tracked missense pathogenicity, suggesting that clonal growth in blood is itself an in vivo readout of how much a variant damages p53.
Conclusion: In a population cohort of healthy middle-aged adults, most apparently pathogenic TP53 variants detected in blood reflect somatic clonal expansion rather than inherited predisposition, and the cancer risk they carry is predominantly hematological. Distinguishing the two origins with allele fraction and shared haplotypes gives a scalable way to interpret TP53 variants outside the clinic, where classic Li-Fraumeni assumptions do not hold.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Shared inheritance reveals landscape of somatic and germline cancer risk in TP53
First author: MacGregor
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.07.011
Reference: MacGregor, H.A.J., Blundell, J.R., and Easton, D.F. (2026). Shared inheritance reveals landscape of somatic and germline cancer risk in TP53. The American Journal of Human Genetics 113, 1916-1928. https://doi.org/10.1016/j.ajhg.2026.07.011
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-09-10.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the scientific body from the TP53 and Li-Fraumeni background through clonal hematopoiesis, the allele-f...
457: A deletion that raises Alzheimer risk, a duplication that lowers it
09 Sep 2026
00:24:15
Quenez O et al., The American Journal of Human Genetics - Rare copy-number variants were called from 22,319 exomes covering early-onset Alzheimer disease, late-onset disease and unaffected controls, then tested gene by gene for a dosage effect. One locus came back with the cleanest signal in the field: at the central 22q11.21 region, deletions appeared only in early-onset cases, including one that arose de novo, while duplications piled up in controls, with late-onset cases sitting in between. Replication in nearly 400,000 further individuals confirmed it, and overexpressing SCARF2, one of the genes in the narrowed interval, increased amyloid-beta uptake in cells - the direction the protective duplications would predict. Key terms: copy-number variants, Alzheimer disease, 22q11.21, SCARF2, gene dosage.
Study Highlights: The authors called rare copy-number variants from 22,319 harmonized exomes, comprising 4,150 early-onset Alzheimer cases at 65 years or younger, 8,519 late-onset cases and 9,650 unaffected controls, and found that early-onset cases carried an excess burden of rare CNVs affecting coding genes, driven particularly by deletions in genes already implicated in the disease. Pooling short truncating variants with deletions into a single loss-of-function analysis implicated ABCA1 with an odds ratio of 5.77 and ABCA7 deletions with an odds ratio of 2.29, and raised CTSB as a new candidate at an odds ratio of 5.03. An exome-wide gene-level dosage analysis then flagged 18 genes across five loci below a 10 percent false discovery rate, of which the central 22q11.21 region stood out: deletions were restricted to early-onset cases and absent from all 9,559 controls, duplications were enriched in controls, and late-onset cases fell in between, a gradient the authors narrowed to the SCARF2-KLHL22-MED15 interval. Replication across 33,977 additional cases and 362,322 controls confirmed the association at exome-wide significance, with duplications carrying an odds ratio of 0.34 and a mega-analysis p value of 5.52 times ten to the minus seven. Transfecting SCARF2 into microglial cells significantly increased uptake of fluorescent amyloid-beta with a p value of 2.2 times ten to the minus five, while uptake of inert latex beads did not change, arguing the effect is specific rather than a general boost in cell appetite.
Conclusion: The same stretch of chromosome 22 pushes Alzheimer risk in opposite directions depending on how many copies you carry: losing one raises risk, gaining one lowers it. Duplications of the central 22q11.21 region emerge as one of the strongest risk-decreasing genetic factors described so far in terms of effect size, behind only the ultra-rare Icelandic APP variant, and unlike that variant they are found across multiple ancestries. The authors are careful about what this does not mean: the deletions are extremely rare, protection is relative rather than absolute, and they show it directly by pointing to duplication carriers who developed late-onset disease anyway while carrying other risk factors. Power is the central constraint, because each genome carries hundreds of rare coding point variants but typically only one rare coding CNV, and the analysis was restricted to individuals of European ancestry.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk
First author: Quenez O
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.07.013
Reference: Quenez O, Schramm C, Cassinari K, Nicolas A, Groeneveld J, Huguet G, et al. Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk. The American Journal of Human Genetics. 2026;113(10):1-19. doi:10.1016/j.ajhg.2026.07.013
Li...
456: Beyond exons: where heritability hides as traits get more polygenic
08 Sep 2026
00:45:46
Fuhrer J et al., The American Journal of Human Genetics - Across 34 complex traits and disorders, a MiXeR-based framework partitions SNP heritability over 74 functional annotations and finds that exons carry only a minority of it, and steadily less as a trait becomes more polygenic. Exonic heritability falls from about 22 percent in less-polygenic somatic diseases and biomarkers to about 13 percent in highly polygenic psychiatric and cognitive traits, intergenic heritability rises by the same logic, and intronic heritability stays put. A new annotation contribution score shows the same axis in the annotations themselves: highly polygenic traits load on conservation and variant-effect scores, less-polygenic traits on promoter, transcription and chromatin marks. Key terms: polygenicity, SNP heritability, noncoding variation, functional annotation, complex traits.
Study Highlights: The authors extended the MiXeR framework to model SNP effect-size variance across 74 binary functional annotations, applied it to 34 traits spanning psychiatric, neurological, cardiometabolic, anthropometric, hematological and immune phenotypes, and introduced a likelihood-based annotation contribution score that measures how much a single annotation adds to the full model rather than how enriched it is per SNP. Exons cover 2.55 percent of base pairs and account for a mean of 14.52 percent of heritability, with introns and intergenic regions together explaining the remaining 85.49 percent; introns alone typically carry about half. Regressing regional fractions on log polygenicity, the exonic fraction falls 4.38 percentage points and the intergenic fraction rises 4.87 percentage points per ten-fold increase in polygenicity, while the intronic slope is not significant, and the illustrative spread runs from 8.51 percent exonic in schizophrenia to 29.44 percent in sex-hormone-binding globulin. The contribution score peaks for mid-sized annotations covering roughly 10 to 15 percent of SNPs, so compact conservation tracks such as phastCons, GERP, CADD and Eigen dominate in highly polygenic traits while promoter and chromatin tracks such as H3K4me3 and CpG islands dominate in less-polygenic ones. Sensitivity analyses against sLDSC and sLD4M agreed closely, with heritability fractions correlating at r equals 0.996 and polygenicity estimates at Spearman r equals 0.91.
Conclusion: The functional location of heritability is not a fixed property of the genome but tracks a trait's polygenicity: less-polygenic somatic traits concentrate heritability in coding and gene-proximal regulatory regions, while highly polygenic psychiatric and cognitive traits distribute it across dispersed distal regulatory elements. Because enrichment per SNP and total contribution can point in opposite directions, the authors argue both must be read together, and they note that coding variants explain a minority of heritability throughout, which argues for sequencing designs that maximize noncoding coverage. The analysis relies on European-ancestry reference panels, uses relatively broad annotations with incomplete chromosome X coverage, and depends on polygenicity estimates from two methods that nonetheless agreed closely.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders
First author: Fuhrer J
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.08.012
Reference: Fuhrer J, Shadrin AA, Hughes T, Parker N, Hindley G, Frei E, Nguyen D, Smeland OB, Djurovic S, Andreassen OA, Dale AM, Frei O. Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders. The American Journal of Human Genetics. 2026;113(10):1-13. doi:10.1016/j.ajhg.2026.08.012
License: This episode is based...
455: Agentic genomics: the bottleneck moves from code to judgment
07 Sep 2026
00:13:44
Corpas M et al., Cell Genomics - A Perspective arguing that autonomous AI agents which discover, configure and chain bioinformatics operations from natural-language instructions have shifted the bottleneck in computational biology from building pipelines to validating their output. The authors define four necessary conditions for a system to count as agentic, propose a perturbation test that separates genuine runtime decision-making from pre-specified branching, survey four existing systems, and set out a three-tier validation framework in which none of the surveyed systems yet reaches clinical grade. Key terms: agentic genomics, AI agents, validation, skill libraries, equity in genomics.
Study Highlights: The authors define agentic genomics through four necessary conditions — autonomy, domain constraint via validated skill libraries, iterative refinement, and natural-language mediation — and offer an empirically testable criterion: a system is not agentic if perturbed intermediate outputs fail to change its execution strategy. They distinguish the paradigm from workflow managers like Nextflow and Galaxy, from AutoML, from LLM-assisted scripting, and from general-purpose biomedical copilots. Four systems are surveyed and placed against a proposed three-tier validation framework of research grade, benchmarked and clinical grade; all four currently sit at research grade, and none has published the external multi-site evidence the clinical tier requires. The paper documents a concrete silent failure: in the early weeks of ClawBio, one skill given an empty input file containing no genomic data returned all-normal results including recommended dosages for 51 drugs, a path since closed by community audit. It also reports that a randomized trial of GPT-4-augmented diagnostic reasoning found no significant improvement over conventional resources, 76 percent versus 74 percent with p equal to 0.60, even though the model alone scored well above physicians.
Conclusion: The central claim is that agentic genomics expands the capacity to produce analyses without expanding the capacity to judge them, so validation frameworks must be formalized and tiered, equity-aware defaults must be engineered rather than aspired to, and regulatory frameworks must accommodate non-deterministic software. The authors argue the paradigm is already in use and advancing, and that the open question is not whether it will be adopted but whether the field will build the standards to make it trustworthy first.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Agentic genomics: From pipeline automation to autonomous validation
First author: Corpas M
Journal: Cell Genomics
DOI: 10.1016/j.xgen.2026.101305
Reference: Corpas M, Guio H, Fatumo S. Agentic genomics: From pipeline automation to autonomous validation. Cell Genomics. 2026;6(8):101305. doi:10.1016/j.xgen.2026.101305
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 ▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadat...
454: Efavirenz retarda a doença priônica mexendo no colesterol do cérebro [PT]
02 Sep 2026
00:17:13
Ali T et al., JCI Insight - Um antirretroviral aprovado para HIV, dado por via oral em microdose, prolongou a sobrevida de camundongos que carregam a proteína priônica humana e foram infectados com príons de doença de Creutzfeldt-Jakob esporádica humana. O efavirenz age ativando a CYP46A1, a enzima cerebral que converte colesterol numa forma capaz de sair do cérebro — e não baixando a proteína priônica, como as abordagens dos episódios anteriores desta série. Termos-chave: efavirenz, CYP46A1, doença de Creutzfeldt-Jakob, metabolismo do colesterol cerebral, reposicionamento de medicamento.
⚠️ Importante: nada neste episódio é motivo para tomar efavirenz. O efavirenz é um antirretroviral de prescrição com efeitos colaterais reais, incluindo distúrbio do sono, sonhos vívidos, tontura e efeitos psiquiátricos. A dose usada neste estudo — cerca de 0,09 mg/kg por dia — é algo entre 300 e 400 vezes menor que a dose prescrita para HIV, e não é algo que alguém consiga aproximar por conta própria. Nenhum ser humano teve benefício demonstrado com efavirenz para doença priônica. Existe um ensaio de Fase 3 registrado como NCT07482085 no ClinicalTrials.gov, que ainda não reportou resultados. Se a doença priônica afeta você ou sua família, converse com um neurologista e pergunte sobre ensaios registrados — não sobre a farmácia. Este é o quarto episódio da nossa série sobre a doença de Creutzfeldt-Jakob, que começou como homenagem ao Lito Sousa. Todos os ensaios citados na série estão registrados publicamente no ClinicalTrials.gov.
Destaques do estudo: Os autores inocularam camundongos tg650, que superexpressam a PrP humana, com príons MM1 de CJD esporádica humana e começaram o efavirenz oral em dose baixa aos 30 ou aos 130 dias após a infecção, prolongando a sobrevida em 17 e 23 dias respectivamente. Na fase clínica inicial, os animais tratados apresentaram menos PrPSc, menor teor de colesterol e de gotículas lipídicas no cérebro, e níveis mais altos de CYP46A1 e de 24S-hidroxicolesterol no cérebro e no soro. Superexpressar a CYP46A1 sozinha em células neuronais infectadas já reduziu a PrPSc e elevou o 24S-hidroxicolesterol, ligando o efeito antipriônico à enzima e não a outra propriedade do remédio. A dose usada foi de cerca de 0,09 mg/kg por dia, algo entre 300 e 400 vezes menor que a dose padrão prescrita para HIV. A eficácia no início tardio importa clinicamente, porque o paciente chega depois que os sintomas começaram.
Conclusão: O efavirenz oral em dose baixa ativa a CYP46A1, restaura a renovação de colesterol no cérebro, reduz o acúmulo de PrPSc e prolonga a sobrevida num modelo humanizado de CJD esporádica, o que sustenta avaliar melhor esse medicamento reposicionado em doença priônica humana.
Música: Ouça a música criada a partir deste artigo no final do episódio.
Título do artigo: Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism
Primeiro autor: Ali T
Revista: JCI Insight
DOI: 10.1172/jci.insight.190296
Referência: Ali T, Cashion J, Hannaoui S, Ahmed-Hassan H, Schatzl H, Gilch S. Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism. JCI Insight. 2025;10(14):e190296. doi:10.1172/jci.insight.190296
Licença: Este episódio é baseado em um artigo de acesso aberto publicado sob a Licença Creative Commons Atribuição 4.0 Internacional (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
Apoie: O Base by Base é independente e sem anúncios — sem patrocinadores, sem paywall. Se o episódio valeu o seu tempo, contribua e ajude a manter os artigos auditados e as músicas originais: ❤️ Apoio mensal: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ Doação única: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Mais em basebybase.com
453: Efavirenz slows sCJD progression by reshaping brain cholesterol
31 Aug 2026
00:20:56
Ali T et al., JCI Insight - Repurposed low-dose efavirenz slowed disease progression and extended survival in tg650 mice inoculated with MM1 sCJD prions by activating CYP46A1, raising 24S‑hydroxycholesterol and reducing PrPSc, brain cholesterol and lipid droplets at the early clinical stage. Key terms: efavirenz, CYP46A1, Creutzfeldt-Jakob disease, cholesterol metabolism, prion disease.
⚠️ Important: nothing in this episode is a reason to take efavirenz. Efavirenz is a prescription antiretroviral with real side effects, including sleep disturbance, vivid dreams, dizziness and psychiatric effects. The dose used in this study — about 0.09 mg/kg per day — is roughly 300 to 400 times lower than the dose prescribed for HIV, and is not something anyone can approximate on their own. No human being has yet been shown to benefit from efavirenz for prion disease. A Phase 3 trial is registered as NCT07482085 on ClinicalTrials.gov and has not reported results. If prion disease affects you or your family, talk to a neurologist and ask about registered trials — not about a pharmacy. This episode is the fourth in our series on Creutzfeldt-Jakob disease, which began as a dedication to Lito Sousa. Every trial named in the series is registered publicly on ClinicalTrials.gov.
Study Highlights: Oral low-dose efavirenz given to human-PrP–overexpressing tg650 mice starting at 30 or 130 days postinoculation significantly slowed clinical progression and extended survival by 17 and 23 days, respectively. At the early clinical stage EFV-treated mice showed reduced PK-resistant PrPSc, decreased brain cholesterol and lipid droplets, and increased CYP46A1 expression with higher 24S‑hydroxycholesterol in brain and serum. Overexpression of CYP46A1 in prion-infected neuronal cells likewise reduced PrPSc, supporting a causal link between CYP46A1 activation and antiprion effects.
Conclusion: Low-dose oral efavirenz activates CYP46A1, restores cholesterol turnover, reduces early PrPSc accumulation and lipid pathology, and extends survival in a humanized sCJD mouse model, supporting EFV as a candidate for further evaluation in human prion disease.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism
First author: Ali T
Journal: JCI Insight
DOI: 10.1172/jci.insight.190296
Reference: Ali T, Cashion J, Hannaoui S, Ahmed-Hassan H, Schatzl H, Gilch S. Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism. JCI Insight. 2025;10(14):e190296. https://doi.org/10.1172/jci.insight.190296.
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-31.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript's core biomedical claims about EFV's e...
452: Reduzir a PrP funciona em todas as linhagens [PT]
28 Aug 2026
00:28:42
Minikel EV et al., Nucleic Acids Research - Este estudo testa a redução da proteína priônica (PrP) por oligonucleotídeos antisense (ASOs) em camundongos, variando doses, esquemas de aplicação, linhagens de príon e estágios da doença. O tratamento reduziu o RNA do Prnp, prolongou a sobrevida, atrasou os sintomas e reverteu biomarcadores de lesão neuronal e de gliose em vários cenários. O benefício apareceu mesmo com redução parcial, nas cinco linhagens testadas, e em alguns casos até depois do início dos sintomas. Termos-chave: proteína priônica, oligonucleotídeo antisense, neurodegeneração, biomarcadores, terapias.
Destaques do estudo: A redução da PrP mediada por ASO prolongou a sobrevida e atrasou o início da doença tanto no esquema profilático quanto no tardio, em diferentes químicas de ASO. O benefício foi dose-dependente — uma redução de apenas cerca de 21 por cento do RNA já produziu ganho mensurável de sobrevida — e apareceu contra cinco linhagens distintas de príon adaptadas a camundongo, sem sinal de linhagens resistentes ao tratamento. Uma dose única aplicada depois da detecção da patologia reverteu a alta do neurofilamento leve no plasma e reduziu a bioluminescência de GFAP; a supressão crônica iniciada até o começo da neuropatologia alcançou benefício comparável ao de camundongos com apenas uma cópia funcional do gene da PrP. Alguns animais tratados já com sintomas francos tiveram sobrevida prolongada, embora a tolerabilidade de certas químicas de ASO em fase tardia tenha sido limitada.
Conclusão: Reduzir a PrP por ASO, via mecanismo dependente de RNase H, é uma estratégia modificadora de doença amplamente eficaz nos modelos de príon em camundongo — atravessando linhagens e estágios — e justifica o desenvolvimento de terapias que baixem a PrP, com esquemas de dose apropriados.
Música: Ouça a música criada a partir deste artigo no final do episódio.
Título do artigo: Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints
Primeiro autor: Minikel EV
Revista: Nucleic Acids Research
DOI: 10.1093/nar/gkaa616
Referência: Minikel EV, Zhao HT, Le J, O’Moore J, Pitstick R, Graffam S, Carlson GA, Kavanaugh MP, Kriz J, Kim JB, Ma J, Wille H, Aiken J, McKenzie D, Doh-ura K, Beck M, O’Keefe R, Stathopoulos J, Caron T, Schreiber SL, Carroll JB, Kordasiewicz HB, Cabin DE, Vallabh SM. Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Research. 2020;48(19):10615–10631. doi:10.1093/nar/gkaa616
Licença: Este episódio é baseado em um artigo de acesso aberto publicado sob a Licença Creative Commons Atribuição 4.0 Internacional (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
Apoie: O Base by Base é independente e sem anúncios — sem patrocinadores, sem paywall. Se o episódio valeu o seu tempo, contribua e ajude a manter os artigos auditados e as músicas originais: ❤️ Apoio mensal: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ Doação única: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Mais em basebybase.com
No PaperCast Base by Base você acompanha o que há de mais recente em genômica, genômica funcional, genômica estrutural e proteômica.
Link do episódio: https://basebybase.com/episodes/prion-protein-lowering-across-strains-pt
QC: Este episódio foi conferido contra o PDF original do artigo e os metadados da publicação, para a edição publicada em 2026-08-28.
Escopo do QC: - metadados do artigo e as afirmações científicas centrais da narração - exclui analogias, abertura/encerramento e música - cobertura da transcrição: Audited the transcript sections describing mechanism of action (RNase H–mediated PrP reduction), dose-response and minimal knockdown, cross-strain efficacy across five prion strains, treatmen...
451: Prion protein lowering is disease-modifying across stages and strains
25 Aug 2026
00:24:36
Minikel EV et al., Nucleic Acids Research - This study uses antisense oligonucleotides (ASOs) to lower prion protein (PrP) RNA in mice and shows dose-dependent extension of survival, efficacy across multiple prion strains, reversal of molecular biomarkers, and benefit even when treatment is delayed into symptomatic stages. Key terms: prion protein, antisense oligonucleotide, neurodegeneration, biomarkers, survival.
Study Highlights: Using ASOs to reduce PrP RNA in intracerebrally inoculated mice produced dose-dependent extension of survival in both prophylactic and delayed dosing paradigms. Less than 25% PrP suppression was sufficient to delay symptoms and extend survival. Treatment was effective across five distinct prion strains without evidence of drug-resistant prions. Biomarkers of neuronal injury (plasma NfL) and astrocytosis (GFAP bioluminescence) were reversed after ASO treatment, and chronic early dosing matched benefits seen in heterozygous PrP knockout animals.
Conclusion: ASO-mediated PrP lowering is a robust, disease-modifying approach in mouse models of prion disease across strains and disease stages, supporting advancement of PrP-lowering therapeutics and use of CSF PrP and blood NfL as pharmacodynamic biomarkers.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints
First author: Minikel EV
Journal: Nucleic Acids Research
DOI: 10.1093/nar/gkaa616
Reference: Minikel EV, Zhao HT, Le J, O’Moore J, Pitstick R, Graffam S, Carlson GA, Kavanaugh MP, Kriz J, Kim JB, Ma J, Wille H, Aiken J, McKenzie D, Doh-ura K, Beck M, O’Keefe R, Stathopoulos J, Caron T, Schreiber SL, Carroll JB, Kordasiewicz HB, Cabin DE, Vallabh SM. Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Research. 2020;48(19):10615–10631. doi:10.1093/nar/gkaa616
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-25.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections include PrP biology and PrP function; ASO mechanism and RNase H action; dose-response and minimal PrP knockdown; cross-strain efficacy across five mouse prion strains; biomarkers (plasma NfL and GFAP bioluminescence); therapeutic timing (prophylactic, early/delayed, late/symptomatic); resistance and tr - transcript topics: Prion protein biology and PrP function; ASO mechanism and RNase H action; Dose-response and minimal PrP knockdown; Cross-strain efficacy across five mouse prion strains; Biomarkers: plasma neurofilament light (NfL) and GFAP bioluminescence; Behavioral readouts: rotarod and nest-building
450: ASOs que reduzem PrP prolongam a sobrevida [PT]
24 Aug 2026
00:24:57
Raymond GJ et al., JCI Insight - This episode covers a 2019 study showing that sequence-specific antisense oligonucleotides (ASOs) targeting the prion protein (PrP) mRNA, delivered by bolus intracerebroventricular injection, lower PrP levels in the CNS, slow neuropathology, and markedly extend survival in prion-infected wild-type mice when given prophylactically or even near symptom onset. Key terms: antisense oligonucleotide, prion disease, prion protein, intracerebroventricular, mouse model.
Study Highlights: Two PrP-targeting ASOs (active ASO 1 and 2) reduced Prnp mRNA and PrP protein across brain regions and produced robust survival benefits in RML prion–infected wild-type mice, with prophylactic extension of lifespan by 61%–98%. A single bolus dose given at 120 days post-infection (near clinical onset) extended survival by 55% and slowed symptomatic progression. A non‑targeting control ASO showed no efficacy, indicating a sequence-specific, on‑target mechanism mediated by RNase H–dependent RNA lowering. Some tolerability issues were observed with particular ASO candidates at late-stage treatment, but at least one active ASO was both tolerated and effective.
Conclusion: Bolus CNS delivery of sequence-specific PrP‑lowering ASOs lowers PrP, delays prion neuropathology, and substantially extends survival in infected mice, supporting further development of PrP‑lowering therapy and use of CSF PrP as a pharmacodynamic biomarker.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Antisense oligonucleotides extend survival of prion-infected mice
First author: Raymond GJ
Journal: JCI Insight
DOI: 10.1172/jci.insight.131175
Reference: Raymond GJ, Zhao HT, Race B, et al. Antisense oligonucleotides extend survival of prion-infected mice. JCI Insight. 2019;4(16):e131175. doi:10.1172/jci.insight.131175.
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-24.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections describing ASOs targeting Prnp, PrP reduction, i.c.v. bolus delivery, prophylactic vs late-stage treatment in prion-infected mice, and the role of control ASOs and sequence specificity. - transcript topics: Antisense oligonucleotides targeting Prnp mRNA; PrP reduction and PrP biology; Intracerebroventricular bolus delivery vs continuous infusion; Prophylactic vs late-stage treatment in prion-infected mice; Sequence specificity and non-targeting control ASO; Pharmacodynamic biomarker: CSF PrP measurement
Factual Items Audited: - ASOs targeting Prnp mRNA discussed as a therap...
449: siRNA divalente para doença priônica [PT]
24 Aug 2026
00:28:46
Gentile JE et al., Nucleic Acids Research - Discovery and preclinical development of divalent siRNA candidates targeting PRNP, identifying 2439-s4 as a potent, durable human PRNP-lowering drug candidate with IND clearance. Key terms: prion disease, PrP lowering, divalent siRNA, 2439-s4, RNAi therapeutics.
Study Highlights: Authors screened divalent siRNA libraries and identified mouse-targeting 1682-s4 that lowered brain PrP to ~49% and extended survival in prion-infected mice when dosed pre- or post-symptomatically. They generated human PRNP transgenic mouse lines (Tg25109, Tg26372) and nominated 2439-s4, which reduced whole-hemisphere human PrP to as low as 17% after a single dose. Mechanistic analysis showed that the s4 scaffold’s fixed 3' UU tail and exNA terminal linkages each contributed to superior potency and durability versus other scaffolds. GLP toxicology in rats and dogs found no significant adverse findings and the US FDA cleared an IND to advance 2439-s4 to clinical trials.
Conclusion: Divalent siRNA 2439-s4 is a potent, durable PRNP-lowering candidate with favorable preclinical safety and regulatory clearance to proceed to clinical testing.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Divalent siRNA for prion disease
First author: Gentile JE
Journal: Nucleic Acids Research
DOI: 10.1093/nar/gkag287
Reference: Gentile JE, Corridon TL, Serack FE, et al. Divalent siRNA for prion disease. Nucleic Acids Research. 2026;54:gkag287. doi:10.1093/nar/gkag287
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-24.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript sections covering PRNP biology, divalent siRNA mechanism (s4 scaffold with UU tail and exNA), lead sequences (1682-s4 and 2439-s4), human PRNP transgenic mice models, intrathecal delivery, RT-qPCR and ELISA readouts, PK/PD durability, prion-infected survival data, and IND status. - transcript topics: Prion biology and PRNP as therapeutic target; Divalent siRNA mechanism and s4 scaffold features (UU tail, exNA); Lead sequences 1682-s4 and 2439-s4 and in vivo screening; Transgenic human PRNP mice Tg25109 and Tg26372; Intrathecal delivery and brain distribution; Analytical readouts: RT-qPCR and PrP ELISA
Factual Items Audited: - DOI canonical form 10.1093/nar/gkag287 - Article title: Divalent siRNA for prion disease - Journal: Nucleic Acids Research - License: Creative Commons Attribution 4.0 International License (CC BY 4.0) - Lead sequences identified: 1682-s4 (mouse Prnp) and 2439-...
448: PrP‑lowering ASOs prolong survival in prion‑infected mice
23 Aug 2026
00:25:16
Raymond GJ et al., JCI Insight - This study tests antisense oligonucleotides (ASOs) targeting Prnp in wild‑type mice infected with RML prions and shows that sequence‑specific PrP lowering by bolus i.c.v. ASO dosing delays disease and extends survival, even when given near clinical onset. Key terms: prion disease, antisense oligonucleotide, PrP lowering, mouse model, intracerebroventricular delivery.
Study Highlights: Two sequence‑specific ASOs targeting mouse Prnp lowered Prnp mRNA and PrP protein in brain and delayed neuropathology compared with a non‑targeting control. Prophylactic bolus i.c.v. dosing given every 2–3 months extended survival by 61%–98%. A single ASO dose at 120 days post‑infection, near expected symptom onset, extended survival by 55% and slowed symptomatic progression. Control ASO showed no benefit, supporting RNA‑lowering as the mechanism of action.
Conclusion: Bolus intracerebroventricular delivery of PrP‑targeting ASOs lowers PrP via RNase H–mediated mRNA degradation, slows accumulation of misfolded PrP, and substantially extends survival in prion‑infected mice, including when treatment is initiated near clinical onset.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Antisense oligonucleotides extend survival of prion‑infected mice
First author: Raymond GJ
Journal: JCI Insight
DOI: 10.1172/jci.insight.131175
Reference: Raymond GJ, Tran Zhao H, Race B, Raymond LD, Williams K, Swayze EE, Graffam S, Le J, Caron T, Stathopoulos J, O’Keefe R, Lubke LDL, Reidenbach AG, Kraus A, Schreiber SL, Mazur C, Cabin DE, Carroll JB, Minikel EV, Kordasiewicz H, Caughey B, Vallabh SM. Antisense oligonucleotides extend survival of prion‑infected mice. JCI Insight. 2019;4(16):e131175. https://doi.org/10.1172/jci.insight.131175.
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
Factual Items Audited: - ASOs lowered Prnp mRNA and reduced PrP protein in brain regions - Prophylactic ASO...
Chapters
(00:00:00) - The genetic silencing approach to Creutzfeldt-Jak
(00:02:27) - What is Prion Disease?
(00:06:16) - How to Turn off prion disease's spread
(00:11:54) - AsO 1, the scrambled ASO
(00:12:47) - ASO2 delays the RML prion progression by nearly three
(00:17:14) - The neuroscience of prion disease
(00:21:11) - Thanks for listening to Prion Disease Podcasts
(00:22:35) - Silence the Spark
447: Divalent siRNA for prion disease
23 Aug 2026
00:23:33
Gentile JE et al., Nucleic Acids Research - This study develops and tests divalent siRNA molecules that lower prion protein (PrP) in the brain, identifies a potent human-targeting candidate (2439-s4), demonstrates survival benefit in prion-infected mice with a mouse-targeting tool compound, and reports IND-enabling toxicology supporting clinical testing. Key terms: prion disease, PrP lowering, divalent siRNA, 2439-s4, transgenic mouse.
Study Highlights: The authors identify a mouse Prnp-targeting divalent siRNA (1682-s4) that lowers brain PrP to ~49% residual and extends survival in RML prion–infected mice (2.7-fold when dosed presymptomatically, 64% increase after a single symptomatic dose). They generate two transgenic mouse lines expressing full human PRNP (Tg25109, Tg26372) and use them to discover human-targeting siRNA 2439, optimized as 2439-s4, which lowers whole-hemisphere human PrP to 17% residual at 348 μg and to 49% at 52 μg. Chemical features—an exNA terminal linkage and a fixed 3' UU tail—each contribute substantially to potency, and a single dose shows durability out to months while 1–2% of CSF dose is retained in brain. GLP toxicology in rats and dogs identified no major liabilities and the FDA cleared an IND to advance 2439-s4 to human trials.
Conclusion: Divalent siRNA can achieve deep, durable PrP lowering in the CNS, confer disease-modifying benefit in a mouse prion model, and yield a clinical candidate (2439-s4) with supportive nonclinical toxicology and regulatory clearance for a first-in-human study.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Divalent siRNA for prion disease
First author: Gentile JE
Journal: Nucleic Acids Research
DOI: 10.1093/nar/gkag287
Reference: Gentile JE, Corridon TL, Serack FE, Echeverria D, Kennedy ZC, et al. Divalent siRNA for prion disease. Nucleic Acids Research. 2026;54:gkag287. doi:10.1093/nar/gkag287
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections covering: divalent siRNA mechanism and CNS delivery; mouse Prnp knockdown and survival data for 1682-s4; human PRNP targeting with 2439-s4 in transgenic mice; scaffold optimization (exNA, fixed tail, PS); PK/PD and IND-enabling GLP tox; and FDA IND clearance. - transcript topics: Divalent siRNA mechanism and CNS delivery; Mouse Prnp knockdown and survival in prion model with 1682-s4; Human PRNP transgenic mouse models Tg25109/Tg26372 and lead candidate 2439-s4; Chemical scaffold optimization (PS reductions, exNA, fixed UU tail); IND-enabling GLP toxicology and FDA IND clearance; PK/PD metrics (IC50 ~1.2 μg/g; tissue retention 1–2% dose)
(00:00:28) - The science of Creutzfeldt Jakob Disease
(00:05:56) - Turning off the prion protein
(00:13:13) - Quantum therapy for prion disease
(00:20:18) - CJD Foundation on Lito Sousa
(00:21:32) - Cut the Thread
446: Cilia, Synuclein, and Survival: G51D Mice Reveal a Shared Parkinson’s Pathway
23 Aug 2026
00:28:38
Lin Y‑E et al., PNAS - Knock‑in SncaG51D/G51D mice show selective loss of primary cilia in specific striatal interneurons, astrocytes, piriform cortex PV cells and olfactory basal stem cells, with concomitant reduction in Hedgehog‑dependent neurotrophic signaling linked to Parkinson’s disease vulnerabilities. Key terms: alpha-synuclein, primary cilia, neurotrophic signaling, Parkinson’s disease, G51D mouse.
Study Highlights: Using SncaG51D/G51D knock‑in mice, the authors document selective loss of primary cilia in striatal cholinergic and parvalbumin interneurons and in ALDH1L1+ astrocytes while medium spiny neuron ciliation is preserved. Cilia loss associates with reduced Ptch1 expression and decreased production of neurotrophic factors (GDNF, NRTN, BDNF), indicating impaired Hedgehog signaling. PV neurons in the piriform cortex and horizontal basal cells in the olfactory epithelium also lose cilia and show reduced NRTN, whereas multiciliated olfactory sensory neurons remain intact. Higher phospho-Ser129 α‑synuclein correlates with reduced ciliation within ChAT neurons but does not predict vulnerability across all cell types.
Conclusion: G51D α‑synuclein drives cell type–selective loss of primary cilia and impaired cilia‑dependent neurotrophic signaling, highlighting disrupted ciliary signaling as a convergent pathogenic pathway in Parkinson’s disease.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Selective loss of primary cilia and neurotrophic signaling in G51D α- synuclein mice highlights a common pathway to Parkinson’s disease
First author: Lin Y‑E
Journal: PNAS
DOI: 10.1073/pnas.2619797123
Reference: Lin Y‑E, Chiang C‑Y, et al., Selective loss of primary cilia and neurotrophic signaling in G51D α‑synuclein mice highlights a common pathway to Parkinson’s disease. Proc Natl Acad Sci U S A. 2026;123:e2619797123. doi:10.1073/pnas.2619797123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-23.
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 reporting of the G51D α-synuclein mouse model findings, including: cell-type–specific cilia loss, Hedgehog signaling impairment, neurotrophic factor downregulation, olfactory system involvement (piriform cortex and olfactory epithelium), pS129-α-synuclein correlations, and thera - transcript topics: G51D α-synuclein knock-in mouse model; Cell-type specific loss of primary cilia in striatum (ChAT and PV interneurons) and astrocytes; Hedgehog signaling impairment and Ptch1 transcription; Downregulation of neurotrophic factors: GDNF, NRTN, BDNF; Olfactory system involvement: piriform cortex PV neurons and Neurturin downregulation; Olfactory epithelium ciliopathy: horizontal basal cells vs olfactory sensory neurons
(00:24:03) - Parkinson's disease: The cellular blackout
(00:25:47) - Bring Back the Signal, Let it Come Alive
445: Why Thymine Survived the UV: Photodamage Pathways Explained
22 Aug 2026
00:26:55
Khosh Abady K et al., PNAS - Spectroscopic comparison of thymine and uracil under 265 nm UVC shows thymine is more photoreactive and absorbs more primordial UVC, yet channels damage into reversible CPDs rather than irreversible (6-4) lesions, supporting an evolutionary 'molecular sunscreen' role. Key terms: UV photodamage, thymine, uracil, cyclobutane pyrimidine dimer, origin of life.
Study Highlights: The authors used absorption, fluorescence, and Raman spectroscopy with 265 nm UVC irradiation to compare thymine and uracil photochemistry under controlled conditions. Thymine shows a faster overall absorbance decay (k = 0.174 min−1) than uracil (k = 0.064 min−1) and ~9% broader, redshifted absorption that increases overlap with primordial UVC. Thymine exhibits ~4.5× stronger intrinsic fluorescence and produces higher-amplitude photoproduct fluorescence while accumulating irreversible (6-4) photoproducts more slowly (k = 1.56 min−1) than uracil (k = 2.04 min−1). Raman markers distinguish CPD and (6-4) pathways and indicate thymine preferentially funnels damage into reversible CPD formation amenable to nonenzymatic self-repair.
Conclusion: Thymine, though more photoreactive and exposed to higher primordial UVC flux, appears evolutionarily selected to localize UV damage into reversible lesions (CPDs) and provide molecular 'sunscreen' protection while enabling nonenzymatic self-repair, complementing later biochemical fidelity mechanisms.
Music: Enjoy the music based on this article at the end of the episode.
Article title: UV photodamage pathways and the evolutionary selection of thymine over uracil in early genetic systems
First author: Khosh Abady K
Journal: PNAS
DOI: 10.1073/pnas.2615278123
Reference: Khosh Abady K, Karpourazar N, Rentzepis PM. UV photodamage pathways and the evolutionary selection of thymine over uracil in early genetic systems. PNAS. 2026. doi:10.1073/pnas.2615278123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-22.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript sections: background on RNA world and thymine vs uracil, experimental design with frozen-state bases, absorption/fluorescence/Raman results, and interpretation including CPD vs (6-4) pathways, molecular sunscreen hypothesis, evolutionary implications, and applications to pathogen detection/UV disinfe - transcript topics: RNA world background and thymine vs uracil photochemistry; Experimental design: frozen-ice state, 130 µM concentration, 265.3 nm narrowband UVC LED, -15 °C; Absorption spectra and photodegradation kinetics (k values for thymine and uracil); Fluorescence kinetics and photoproduct formation; Raman signatures for CPD and (6-4) photoproducts; Methyl group effects on base stacking and CPD bias
(00:00:29) - Why DNA vs RNA was the ultimate solar hard drive
(00:06:02) - The UV glow of early life
(00:10:51) - Thiine protects the DNA from UV damage
(00:16:00) - Molecular sunscreen: The UV protection
(00:21:19) - How DNA protected its ancestors from the sun
(00:24:26) - Make It Bend, Don't Let It Break
444: Many-eyes or Sentinels? How Cost Curvature Shapes Collective Vigilance
19 Aug 2026
00:24:40
Pilgrim C et al., PNAS - A minimal analytical model shows that whether animal groups adopt distributed low-level vigilance (many-eyes) or concentrated high-vigilance roles (sentinels) depends on how individual vigilance costs scale with effort. The same dichotomy appears in selfish and cooperative groups and explains switching, edge effects, and turn-taking. Key terms: collective vigilance, many-eyes, sentinel behavior, vigilance costs, behavioral ecology.
Study Highlights: The authors derive a minimal model where collective vigilance benefit is a function of summed individual vigilance and costs depend on individual effort. When vigilance costs are convex (steepening) many-eyes strategies with equal low vigilance across individuals are optimal; when costs are concave (flattening) sentinel strategies with vigilance concentrated in one or a few individuals are optimal. This outcome holds in both selfish (game-dynamic) and cooperative (group-optimal) contexts and is supported by simulations. Extensions reproduce behavioral switching with S-shaped costs, edge effects from heterogeneous costs, and turn-taking when energy state dynamics are included.
Conclusion: The curvature of individual vigilance costs determines whether groups distribute vigilance across many members or concentrate it in sentinels; habitat structure that creates flattening costs (vantage points) favors sentinels, while uniform habitats with steepening costs favor many-eyes.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Many-eyes and sentinels in selfish and cooperative groups
First author: Pilgrim C
Journal: PNAS
DOI: 10.1073/pnas.2536017123
Reference: Pilgrim C, Bate AM, Sigalou A, Aellen M, Morford J, Warren E, Krupenye C, Biro D, Mann RP. Many-eyes and sentinels in selfish and cooperative groups. PNAS. 2026;123(33):e2536017123. doi:10.1073/pnas.2536017123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-19.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript sections describing the minimal model fi = b(S) − c(vi); S = ∑vi; cost-curvature (convex vs concave); environmental structure; selfish vs cooperative results; behavioral switching (sigmoidal costs); edge effects; turn-taking; energy-state dynamics; and discussed limitations. - transcript topics: Model of collective vigilance (fi = b(S) − c(vi)); Cost curvature and environmental structure (convex vs concave); Selfish vs cooperative group outcomes; Behavioral switching with sigmoidal costs; Edge effects and spatial positioning; Energy-state dynamics and turn-taking
443: 5D‑ASO boosts exon 51 skipping and restores dystrophin in DMD models
18 Aug 2026
00:19:35
Feng P et al., PNAS - This paper describes a bipartite antisense oligonucleotide (5D‑ASO) design that appends a short 5′ splice site decoy tail to improve exon skipping, demonstrating robust efficacy for DMD exon 51 in cells, mice, and cynomolgus monkeys with a favorable safety profile. Key terms: antisense oligonucleotide, exon skipping, Duchenne muscular dystrophy, U1 snRNA decoy, dystrophin restoration.
Study Highlights: The authors developed a bipartite ASO approach (5D‑ASO) that appends a short 5′ splice site–complementary tail to enhance exon skipping. An optimal 7–8 nt decoy appended to exon 51 ASOs markedly increased exon skipping in human cells and in multiple genetically modified mouse models, restoring dystrophin and improving muscle function. The lead MOE/PS 5D‑ASO showed durable tissue retention, dose‑dependent efficacy, and an overall favorable safety profile in mice and cynomolgus monkeys. The method was operative across multiple genes and exon targets, indicating broad applicability.
Conclusion: Appending a short 5′ splice site decoy to exon‑targeting ASOs substantially increases exon‑skipping potency and therapeutic benefit in preclinical DMD models, supporting further clinical development of 5D‑ASO designs.
Music: Enjoy the music based on this article at the end of the episode.
Article title: An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy
First author: Feng P
Journal: PNAS
DOI: 10.1073/pnas.2606494123
Reference: Feng P., Gao P., Meng S., Yuan Y., Krainer A.R., Hua Y. An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy. PNAS. 2026;123(33):e2606494123. doi:10.1073/pnas.2606494123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-18.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the core narrative: Duchenne muscular dystrophy background; 5D-ASO design and 5′ splice site decoy tail mechanism; U1 snRNP decoy action; in vitro exon 51 skipping in RD cells; in vivo huEx51/huΔ52 mice data including dystrophin restoration; cynomolgus monkey efficacy/safety; off-target considerations; delivery - transcript topics: DMD background and dystrophin function; 5D-ASO design and 5′ splice site decoy tail mechanism; U1 snRNP decoy mechanism and splicing repression; In vitro exon skipping in RD cells (Etep-L8c and MOE-Etep); In vivo exon 51 skipping in huEx51/huΔ52 mice and dystrophin restoration; Cynomolgus monkey exon 51 skipping and safety
Factual Items Audited: - 5D-ASO tail acts as a decoy to misdirect U1 snRNP...
442: When pumps go missing: Ca2+ control of PMCA2 in Tmc1 deafness mutants
17 Aug 2026
00:22:57
Rolseth AB et al., Proceedings of the National Academy of Sciences (PNAS) - This study links reduced Ca2+ entry through mutant TMC1 mechanotransducer channels to decreased PMCA2 pump density in outer hair cell stereocilia. PMCA2 turnover is rapid in the early postnatal period and is regulated by stereociliary Ca2+ via insertion from an apical vesicular pool; Neuroplastin (NPTN) later stabilizes the pump complex. Persistent pump reduction at hearing onset may contribute to hair cell mitochondrial dysfunction and death in Tmc1 mutants. Key terms: TMC1, PMCA2, hair cells, Ca2+ regulation, neuroplastin.
Study Highlights: Tmc1 point mutations that reduce MET channel Ca2+ permeability show markedly decreased PMCA2 immunolabeling in outer hair cell bundles. PMCA2 density scaled with calculated Ca2+ entry, and experimental lowering of extracellular Ca2+ or pharmacological block of endocytosis or PtdIns(4,5)P2 synthesis reduced PMCA2 during the first postnatal week. PMCA2 is supplied from an apical vesicular pool, turns over rapidly before P11, and NPTN expression lags PMCA2 by ~2 days and less Ca2+ sensitivity, consistent with a stabilizing accessory role. The lower PMCA2 density persists at hearing onset and may contribute to mitochondrial dysfunction and subsequent hair cell death.
Conclusion: Reduced stereociliary Ca2+ influx through mutant TMC1 channels decreases Ca2+-regulated insertion and rapid turnover of PMCA2 from an apical vesicular pool during early postnatal development. Because PMCA2 becomes less plastic after ~P11 and NPTN-mediated stabilization follows PMCA2 expression, early pump loss is maintained into hearing onset and may exacerbate intracellular Ca2+ dysregulation, mitochondrial impairment, and hair cell apoptosis in Tmc1 mutants.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Ca2+ regulation of PMCA2 calcium pump expression in hair cells of Tmc1 deafness mutants
First author: Rolseth AB
Journal: Proceedings of the National Academy of Sciences (PNAS)
DOI: 10.1073/pnas.2607733123
Reference: Rolseth AB, Beurg M, Konrad DE, Augusta BK, Fettiplace R. Ca2+ regulation of PMCA2 calcium pump expression in hair cells of Tmc1 deafness mutants. Proc Natl Acad Sci U.S.A. 2026;123:e2607733123. doi:10.1073/pnas.2607733123.
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-17.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the core scientific narrative in the transcript: MET Ca2+ permeability reductions in Tmc1 mutants, Ca2+-dependent PMCA2 regulation and vesicle trafficking, dynamic turnover and endocytosis, NPTN's stabilizing role, pharmacological perturbations (Pitstop2, PAO, GSK-1), endolymphatic potential effects at hearing - transcript topics: MET channel Ca2+ permeability in Tmc1 mutants; PMCA2 density regulation and Ca2+ entry relationship; Ca2+-dependent PMCA2 turnover and vesicle tra...
441: Evolutionary mapping of Cav1.3 functional sites
14 Aug 2026
00:24:01
Tang X et al., PNAS - The authors apply an evolutionary sequence-covariation model to the Cav1.3 (CACNA1D) α1-subunit, map predicted pathogenicity onto structural models, and validate five predicted sites by patch-clamp electrophysiology and structural analysis. Predictions recapitulate known functional regions, reveal previously unrecognized clusters, and the tested variants produce diverse functional outcomes from nonconducting channels to gain- and loss-of-function gating changes. Key terms: Cav1.3, evolutionary modeling, CACNA1D, voltage-gated calcium channel, variant pathogenicity.
Study Highlights: An evolutionary epistasis model predicted context-dependent conserved residues across Cav1.3 and recapitulated known functional sites. Mapping scores onto structural models highlighted novel clusters outside classical pore and voltage-sensor regions. Electrophysiological testing of five predicted variants confirmed diverse functional effects, including nonconducting (N745A), left-shifted activation (S635I, A376V, R1401A), and right-shifted or slowed gating (F1362A; Q1156E increased inactivation). The combined evolutionary, structural, and biophysical approach provides a scalable framework to prioritize and interpret CACNA1D variants.
Conclusion: Evolutionary sequence-covariation combined with structural modeling and electrophysiology identifies novel functionally critical residues across Cav1.3 and enables rapid prioritization of pathogenic CACNA1D variants; the approach is generalizable to other ion channels but requires experimental follow-up to define gain- versus loss-of-function.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Identification of novel functional sites in the Cav1.3 calcium channel α1-subunit using evolutionary modeling
First author: Tang X
Journal: PNAS
DOI: 10.1073/pnas.2602636123
Reference: Tang X, Hermenean HC, Yakimchyka A, Tuluc P, Ortner NJ, Liedl KR. Identification of novel functional sites in the Cav1.3 calcium channel α1-subunit using evolutionary modeling. PNAS. 2026;123(32):e2602636123. doi:10.1073/pnas.2602636123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-14.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the core scientific sections: evolutionary modeling predictions, structure mapping onto Cav1.3 models, electrophysiology validation in tsA-201 cells, and the functional effects of Cav1.3 variants (N745A, S635I, A376V, F1362A, R1401A, Q1156E); also reviewed limitations and clinical interpretation. - transcript topics: Evolutionary sequence covariation and context-dependent conservation in Cav1.3; Mapping pathogenicity scores onto Cav1.3 cryo-EM structures; Electrophysiological validation of Cav1.3 variants in tsA-201 cells; Functional consequences of specific Cav1.3 variants (N745A, S635I, A376V, F1362A, R1401A, Q1156E); Limitations...
440: DENV-4: Suppressing DNA Repair and Causing Genome Damage
12 Aug 2026
00:23:41
Lamkina EN et al., PNAS - This episode reviews a PNAS brief report showing that DENV-4 infection induces marked DNA damage in infected cells while broadly suppressing transcription of DNA repair pathways, with selective upregulation of a mutagenic translesion polymerase and suppressed ATR expression. The findings raise concerns about long-term molecular "scars" after dengue infection that could influence cancer and postdengue syndromes. Key terms: Dengue, DENV-4, DNA damage, DNA repair, Genome instability.
Study Highlights: Using Vero E6 and HUH-7 cells infected at MOI 0.1 and followed up to 5 days, the authors detected a large increase in γH2AX signaling indicating DNA damage. A 96-gene qPCR panel showed widespread suppression of DNA repair and DDR transcripts across multiple pathways while mismatch repair proteins remained stable. ATR protein expression was reduced and the mutagenic polymerase POLι was upregulated, telomere length and TRF2 were unchanged, and LC3 I/II levels decreased. The authors propose these changes create durable molecular vulnerabilities that warrant patient-based validation.
Conclusion: DENV-4 causes significant host DNA damage while repressing many DNA repair transcripts, a combination that may leave lasting molecular scars and elevate long-term disease risk, but confirmation in patient samples is needed.
Music: Enjoy the music based on this article at the end of the episode.
Article title: DENV-4 infection suppresses transcription of DNA repair genes
First author: Lamkina EN
Journal: PNAS
DOI: 10.1073/pnas.2536909123
Reference: Lamkina EN, Reich J, Victora JA, et al. DENV-4 infection suppresses transcription of DNA repair genes. PNAS. 2026;123(32):e2536909123. doi:10.1073/pnas.2536909123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-12.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the main scientific narrative: DENV-4 infection at MOI 0.1 in Vero E6 and HUH-7 cells; γH2AX DNA damage; broad suppression of DDR/DNA repair transcription with selective maintenance of MMR; ATR suppression; telomere length/TRF2 status; autophagy marker LC3 I/II; POLι upregulation; serotype-specific contrasts; a - transcript topics: DENV-4 infection setup in vitro (MOI 0.1, 5 days, Vero E6 and HUH-7); γH2AX DNA damage signaling in infected cells; Broad suppression of DDR/DNA repair transcripts (BER, HR, NHEJ, NER) with MMR largely unchanged; ATR suppression and its consequence for DNA repair coordination; Telomere length and TRF2 status in infected cells; Maintenance of MMR proteins (MLH1, MSH2, MSH6) despite widespread suppression
439: Coembedding Sequence and Structure: CLSS Maps the Protein Universe
11 Aug 2026
00:23:08
Longo LM et al., PNAS - This episode summarizes a PNAS study introducing CLSS, a contrastive two-tower protein language model that coembeds domain sequences, structures, and subsequences into a shared 32-dimensional latent space. Trained self-supervised on one million ECOD domains, CLSS aligns sequence and structure modalities, yields compact embeddings that recapitulate ECOD and CATH hierarchies, outperforms several state-of-the-art PLMs on ProteinShake classification tasks, and powers an interactive viewer for exploring protein space. Key terms: contrastive learning, protein sequence, protein structure, protein domains, protein embeddings.
Study Highlights: The authors developed CLSS, a contrastive two-tower model that coembeds full domain sequences, structures, and sampled subsequences into a single latent space. CLSS embeddings recapitulate expert ECOD and CATH hierarchical labels despite never using those labels during training. A subsequence-trained variant (CLSS-sub) meaningfully embeds fragments, and CLSS outperforms comparison PLMs on downstream ProteinShake classification benchmarks. Visualizations of CLSS maps reveal a strong partitioning of domains by cofactor binding and other functional annotations.
Conclusion: CLSS demonstrates that sequence and structure can be jointly organized into a compact, informative embedding space that captures domain hierarchy, subsequence reuse, and functional preferences; these embeddings enable efficient downstream classification, visualization, and potential applications in database search, alignment, protein design, and evolutionary analysis.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Contrastive learning unites sequence and structure in a global representation of protein space
First author: Longo LM
Journal: PNAS
DOI: 10.1073/pnas.2532702123
Reference: Longo LM, Yanai G, Axel G, Kolodny R, Ben-Tal N. Contrastive learning unites sequence and structure in a global representation of protein space. PNAS. 2026;123(32):e2532702123. doi:10.1073/pnas.2532702123.
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-11.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript portions describing CLSS concept and motivation, two-tower architecture, CLSS-sub subsequences, training on ECOD domains, evaluation on ProteinShake, TSNE visualizations, cofactor and zinc-binding patterns, and limitations. - transcript topics: CLSS concept and motivation; Two-tower architecture: sequence tower (ESM2) and frozen structure encoder (ESM3); CLSS-sub subsequences (20-60 residues); Self-supervised training on ~1 million ECOD domains; Evaluation on ProteinShake and ECOD/CATH hierarchies; t-SNE visualizations showing coembedding of sequence and structure
438: Mapping AIRE: a proactive atlas of 9,790 missense variants
10 Aug 2026
00:24:02
Axakova A et al., The American Journal of Human Genetics - Axakova et al. generated a variant effect map for AIRE using an insulin‑promoter GFP reporter in HEK293 cells to measure the functional impact of 9,790 missense substitutions and provide calibrated evidence for clinical variant interpretation. Key terms: AIRE, missense variants, variant effect map, APS-1, functional assay.
Study Highlights: The authors used an insulin‑promoter‑driven GFP reporter in HEK293 cells and a DT‑POPCode mutagenesis library to assay 9,790 AIRE missense variants. The resulting map recapitulated known functional regions (CARD, SAND, PHD2, C‑terminal), revealed both loss‑ and gain‑of‑function changes, and exposed a blind spot for PHD1 in this assay. Benchmarking against ClinVar and computational predictors enabled calibrated evidence for 70% of ClinVar VUSs and supported reclassification of 32% (109/345) of VUSs. The map also correlated quantitatively with APS‑1 severity in an international cohort and associated damaging variants with hypoparathyroidism and vitamin B12 deficiency anemia in UK Biobank.
Conclusion: This proactive, calibrated AIRE variant effect map provides immediate functional evidence to improve missense variant classification and expedite APS‑1 diagnosis, while highlighting assay limitations (PHD1 blind spot, cDNA-based design) that warrant follow-up studies.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Systematic and proactive evaluation of AIRE missense variant effects
First author: Axakova A
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.07.008
Reference: Axakova A., Berger A.H., van Loggerenberg W., et al. Systematic and proactive evaluation of AIRE missense variant effects. The American Journal of Human Genetics 113, 1–21 (2026). https://doi.org/10.1016/j.ajhg.2026.07.008
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
437: Cell villages and Dirichlet modeling map human cell fitness genetics
09 Aug 2026
00:28:03
Hanson C et al., The American Journal of Human Genetics - Hanson et al. combine pooled multi-donor human neural progenitor cell "villages" with Townlet, a hierarchical Dirichlet regression model, to estimate donor-specific proliferation and treatment responses from Census-seq. They identify 16p11.2 deletion–associated NPC hyperproliferation and nominate common variants near ZFHX3 for proliferation and an ARNT2-linked locus for lead (Pb) sensitivity. Key terms: cell villages, Dirichlet regression, neural progenitor cells, 16p11.2 deletion, lead (Pb) sensitivity.
Study Highlights: The authors developed and validated cell villages of 12–39 donor-derived NPC lines and Townlet, a Dirichlet regression framework, to analyze compositional time-series Census-seq data and estimate donor proliferation and treatment effects. Using this system they detected hyperproliferation of NPCs carrying the 16p11.2 deletion, mapped a common variant near ZFHX3 associated with proliferation, and identified ARNT2-linked variants associated with differential sensitivity to lead. Villages preserved donor-intrinsic growth rates while reducing technical variation, and Townlet outperformed standard models in simulations and empirical benchmarks.
Conclusion: Pooled multi-donor NPC villages combined with the Townlet Dirichlet model provide a scalable, reproducible platform to map genetic and gene–environment effects on human cell fitness, nominating 16p11.2, ZFHX3, and ARNT2 as contributors to NPC proliferation and Pb sensitivity.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Cell villages and Dirichlet modeling map human cell fitness genetics
First author: Hanson C
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2026.07.005
Reference: Hanson C., Derebenskiy T., Rodriguez Vega A., et al. Cell villages and Dirichlet modeling map human cell fitness genetics. The American Journal of Human Genetics. 2026;113:1–21. doi:10.1016/j.ajhg.2026.07.005
License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
Support: Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-09.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript sections describing Townlet and cell villages, validation against array cultures, 16p11.2 deletion hyperproliferation, GWAS identifying ZFHX3-associated proliferation variants, and lead (Pb) resistance modifiers linked to ARNT2; also reviewed environmental exposome implications and limitations di - transcript topics: Cell villages concept and Townlet model; Census-seq and compositional data challenges; Village vs array validation and donor-intrinsic proliferation; 16p11.2 deletion NPC hyperproliferation in villages; GWAS in villages identifying ZFHX3 locus and rs34470044; Lead (Pb) exposure and ARNT2-associated Pb resistance
436: KIAP4 and the ARND family: building the Leishmania adhesion plaque
08 Aug 2026
00:24:51
Owino BO et al., PNAS - Using TurboID proximity proteomics and microscopy, researchers identify KIAP4 as the canonical member of a conserved Adhesion Related NTPase-like Domain (ARND) family that localizes to the Leishmania adhesion plaque. Deleting KIAP4 disrupts haptomonad adhesion in vitro and prevents colonization of the sand fly stomodeal valve without blocking metacyclogenesis. Key terms: Leishmania, adhesion, KIAP4, ARND family, sand fly.
Study Highlights: TurboID::KIAP3 proximity labeling and mass spectrometry identified KIAP4 and multiple ARND family paralogs enriched at the adhered flagellum. KIAP4 colocalizes with KIAP3 at the adhesion plaque and accumulates during haptomonad differentiation. KIAP4 deletion severely reduces in vitro adhesion and abolishes stomodeal valve colonization in Lutzomyia longipalpis, while ARND paralogs are conserved across kinetoplastids and localize to adhered flagella in Trypanosoma congolense.
Conclusion: KIAP4 is a foundational adhesion-plaque protein of a conserved ARND family required for Leishmania haptomonad adhesion and stomodeal valve colonization, making the family a potential target for transmission-blocking strategies.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Identifcation of a conserved gene family with an essential role in Leishmania parasite–insect vector adhesion
First author: Owino BO
Journal: PNAS
DOI: 10.1073/pnas.2603653123
Reference: Owino BO, Sunter JD, et al. Identifcation of a conserved gene family with an essential role in Leishmania parasite–insect vector adhesion. Proc Natl Acad Sci U S A (PNAS). 2026;123(30):e2603653123. doi:10.1073/pnas.2603653123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-08.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections cover: identification of KIAP4 as canonical ARND member; TurboID proximity-labeling workflow and enrichment results; KIAP4 localization to the adhesion plaque; KIAP4 deletion effects on in vitro adhesion and sand fly stomodeal valve colonization; ARND conservation across kinetoplastids; ARND domain arc - transcript topics: KIAP4 as canonical ARND member localizes to adhesion plaque; TurboID proximity labeling workflow and enriched protein cohort; Localization of ARND paralogs in Leishmania and Trypanosoma congolense; KIAP4 deletion phenotype: impaired adhesion and valve colonization; KIAP4 add-back rescues adhesion defects; ARND domain architecture and Walker A motif absence (inactive NTPase-like domains)
435: E. coli TGT binds two tRNAs — cryo-EM reveals dual engagement
07 Aug 2026
00:19:03
Ember M et al., PNAS - This episode examines a cryo-EM study of Escherichia coli tRNA-guanine transglycosylase (TGT) that solves the enzyme structure and its covalent intermediate with tRNATyr. Unexpectedly, the TGT homodimer can form covalent intermediates with two tRNAs simultaneously. The work maps peripheral RNA-binding residues required for activity and uses those insights to design higher-affinity dual-TAG RNA substrates for improved RNA-TAG labeling. Key terms: tRNA-guanine transglycosylase, cryo-EM, tRNA modification, RNA-TAG, Escherichia coli.
Study Highlights: Using cryo-EM, the authors solved E. coli TGT and its covalent intermediate with tRNATyr and observed that the functional homodimer can form covalent intermediates with two tRNAs, displaying C2 symmetry. They identify peripheral residues (K285, K292, R320, Y35) and a dynamic loop (L98–I104) that stabilize the flipped anticodon loop and are required for covalent intermediate formation. Mutational analysis shows loss of activity for key substitutions, and structure-guided design of dual TAG32 hairpins yields markedly higher-affinity RNA substrates for RNA-TAG labeling. Biophysical assays estimate TAG3 KD ~3–5 µM versus dual TAG32 KD ~0.7–1 µM.
Conclusion: The cryo-EM structures revise the canonical model of TGT function by demonstrating dual-substrate engagement and revealing peripheral binding determinants that enable both antibiotic-targeting strategies and improved, high-affinity RNA-labeling reagents.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Cryo-EM reveals that Escherichia coli tRNA-transglycosylase can bind and act upon two tRNAs
First author: Ember M
Journal: PNAS
DOI: 10.1073/pnas.2601895123
Reference: Ember M. Rutha, Mariusz Matyszewski, Alexander Harjung, Jaehee Park, Caroline Knittel, Evan McCormack, and Neal K. Devaraja. Cryo-EM reveals that Escherichia coli tRNA-transglycosylase can bind and act upon two tRNAs. PNAS. 2026;123:e2601895123. doi:10.1073/pnas.2601895123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-07.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections describing (i) the cryo-EM structure of E. coli TGT and its covalent intermediates with tRNA, (ii) binding of two tRNAs and C2 symmetry, (iii) peripheral RNA-binding residues and their mutational analyses, (iv) the L98–I104 dynamic loop and A37 flipping, (v) Y35 involvement, (vi) R112 cross-monomer int - transcript topics: Cryo-EM structure of E. coli TGT and covalent intermediate; Dual tRNA binding and C2 symmetry; Peripheral RNA-binding residues outside active site (K285, K292, R320, Y35, R112); Dynamic loop L98–I104 and anticodon loop A37 flipping; Mutational analyses and effects on covalent intermediate formation; Structure-based design of dual TAG32 hairpins and KD measurements
Ishiya K et al., PNAS - This episode examines a PNAS study that reports two high-coverage ancient human genomes from mainland Japan (an Initial Jomon >67× and a Middle Yayoi >46×). The genomes enable diploid genotyping, demographic reconstructions, ancestry modeling, and AMY1 copy-number analysis that reshape understanding of Jomon and Yayoi histories. Key terms: ancient DNA, Jomon, Yayoi, AMY1, population history.
Study Highlights: The authors sequenced two low-contamination, high-coverage genomes from mainland Japan (IY1, Initial Jomon; DO, Middle Yayoi) enabling diploid analyses and CNV inference. Demographic reconstructions show divergent post-LGM trajectories: long-term stability with no expansion in the Jomon lineage and gradual sustained growth in the Yayoi-related ancestral population. Admixture and f-statistics indicate substantial continental Northeast Asian ancestry in the Yayoi individual and genetic continuity between the Yayoi and present-day mainland Japanese. High AMY1 copy numbers (~9–10) in both individuals suggest starch-relevant variation existed before large-scale rice farming.
Conclusion: High-coverage ancient genomes from mainland Japan reveal contrasting population histories for Jomon and Yayoi lineages and show that elevated AMY1 copy-number variation relevant to starch consumption predates intensive rice agriculture, refining models of Japanese population formation.
Music: Enjoy the music based on this article at the end of the episode.
Article title: High-coverage ancient genomes reveal divergent population histories and prehistoric starch-related genetic variation in Japan
First author: Ishiya K
Journal: PNAS
DOI: 10.1073/pnas.2606162123
Reference: Ishiya K., Mizuno F., Gojobori J., Kumagai M., et al. High-coverage ancient genomes reveal divergent population histories and prehistoric starch-related genetic variation in Japan. Proc Natl Acad Sci U S A. 2026;123(30):e2606162123. doi:10.1073/pnas.2606162123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-06.
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) sampling of two high-coverage genomes (IY1 and DO), (2) authenticity checks and sequencing depth, (3) demographic inferences (PSMC/SMC++), (4) AMY1 copy-number findings, (5) ancestry and admixture contexts, (6) admixture timing, and (7) the dual-structure model; excluded n - transcript topics: Two high-coverage mainland Japan genomes (IY1 Jomon, DO Yayoi); Petrous bone sampling and ancient DNA authentication; PSMC/SMC++ demographic inferences post-LGM; AMY1 copy-number variation and starch-diet adaptation; Ancestry and continental admixture in Yayoi vs Jomon; Admixture timing via LD decay and related methods
Wu G et al., Proceedings of the National Academy of Sciences - This episode examines a PNAS study that identifies site-specific lactylation of HSP90α as a metabolic signal linking glycolysis to mitochondrial biogenesis in ovarian cells. Lactylation at K58 and K616 modulates HSP90α phosphorylation, enabling nuclear import of PGC1α and LRPGC1, boosting mitochondrial number, cholesterol import, estradiol synthesis, and follicle growth; CREBBP, ACSS2 and GTPSCS participate in the lactylation pathway. Key terms: HSP90α, lactylation, PGC1α, mitochondrial biogenesis, estradiol.
Study Highlights: The authors show that sodium lactate promotes HSP90α lactylation at K58 and K616 via CREBBP and lactyl-CoA synthesis (ACSS2/GTPSCS). K58 lactylation enhances ULK1 recruitment and S39 phosphorylation while K616 lactylation blocks CDK5-mediated S596 phosphorylation, together enabling HSP90α to chaperone PGC1α and LRPGC1 into the nucleus. Nuclear PGC1α/LRPGC1 activate NRF1/2 targets (Tfb1m, Tfb2m, Tfam) to drive mitochondrial biogenesis, increase mitochondrial cholesterol import and raise estradiol production, with in vivo lactate raising ovarian mtDNA, TOM20, estradiol and antral follicle number.
Conclusion: Site-specific lactylation of HSP90α integrates glycolytic flux with chaperone and phosphorylation control to promote PGC1α/LRPGC1 nuclear import, mitochondrial biogenesis and steroidogenic output in ovarian cells, revealing a metabolite-dependent regulatory axis with potential implications for ovarian function and fertility.
Music: Enjoy the music based on this article at the end of the episode.
Journal: Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2528979123
Reference: Wu G., Li H., He T., et al. HSP90α lactylation orchestrates PGC1α and LRPGC1 nuclear translocation driving mitochondrial biogenesis. PNAS. 2026;123(30):e2528979123. doi:10.1073/pnas.2528979123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the main mechanistic narrative from lactate signaling to HSP90α lactylation, ULK1/CDK5-regulated phosphorylation, nuclear import of PGC1α/LRPGC1, NRF1/2-driven transcription, mitochondrial biogenesis, cholesterol import, and in vivo hormonal/follicle outcomes. - transcript topics: Lactate as signaling molecule and lactylation concept; HSP90α lactylation at K58 and K616; CREBBP as the lactyltransferase and lactyl-CoA synthesis pathway; ULK1 and CDK5 regulation of S39 and S596 phosphorylation; HSP90α-mediated nuclear import of PGC1α and LRPGC1; NRF1/NRF2 target gene activation (TFB1M, TFB2M, Tfam) and mitochondrial biogenesis
432: Echovirus 18: Capsid opening releases the genome
23 Jul 2026
00:18:29
Mukhamedova L et al., Proceedings of the National Academy of Sciences - Using cryo-electron tomography and single-particle cryo-EM of infected Cos-7 cells, the authors show that echovirus 18 (E18) releases its RNA in vivo by capsid opening with loss of one to three pentamers. Binding to the neonatal Fc receptor (FcRn) expels VP1 pocket factors and primes particles for uncoating. Activated intermediates were not detected in cells, indicating rapid genome release. Key terms: echovirus 18, enterovirus, genome release, capsid opening, FcRn.
Study Highlights: Cryo-EM/ET of infected cells resolved genome-containing E18 particles to 4.3 Å and imaged empty and open capsids in situ. Binding of E18 to FcRn induces partial expulsion of VP1 pocket factors, consistent with receptor- triggered priming. Empty capsids observed inside cells lack one to three pentamers of capsid proteins, providing direct evidence of capsid opening as the genome release mechanism. Activated particles were not detected in cells, implying these intermediates are short- lived and genome release is rapid.
Conclusion: Capsid opening is the physiological uncoating mechanism of echovirus 18 in infected cells: receptor (FcRn) binding expels pocket factors and primes particles, and genome release occurs rapidly via loss of one to several pentamers with empty, incomplete capsids observed in situ.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Particles of echovirus 18 open to release their genomes in vivo
First author: Mukhamedova L
Journal: Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2601182123
Reference: Mukhamedova L., Buchta D., Hrebík D., et al. Particles of echovirus 18 open to release their genomes in vivo. PNAS. 2026;123(30):e2601182123. https://doi.org/10.1073/pnas.2601182123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript sections describing E18 structure, FcRn binding and pocket-factor expulsion, endosomal acidification and detachment, in vivo evidence of empty/open capsids, and the genome release mechanism. - transcript topics: Echovirus 18 capsid structure and pocket factor; FcRn receptor binding and pocket-factor expulsion; Endocytosis and endosomal acidification as uncoating trigger; In vivo evidence: genome-containing particles lack pocket factors; Capsid opening with loss of one to three pentamers; Endosome rupture and cytoplasmic delivery of RNA
Factual Items Audited: - In vivo, echovirus 18 genome release...
431: KIAP4 and the ARND family: essential proteins for Leishmania–sand fly adhesion
23 Jul 2026
00:21:33
Owino BO et al., Proceedings of the National Academy of Sciences - TurboID proximity labeling and proteomics identify KIAP4 as the canonical member of a conserved Adhesion Related NTPase-like Domain (ARND) family that localizes to the Leishmania adhesion plaque. KIAP4 deletion disrupts haptomonad adhesion and prevents stomodeal valve colonization in sand flies. Key terms: Leishmania, adhesion, KIAP4, ARND family, vector colonization.
Study Highlights: Using TurboID-tagged KIAP3 and mass spectrometry, the authors identified KIAP4 and multiple ARND family paralogs enriched at the adhered flagellum. KIAP4 localizes to the adhesion plaque alongside KIAP3 and accumulates during haptomonad differentiation. KIAP4 deletion severely reduces in vitro adhesion and abolishes stomodeal valve colonization in Lutzomyia longipalpis, while ARND paralogs are conserved and localize to adhered flagella in Trypanosoma congolense. Phylogenetic analysis shows ancient duplications and lineage-specific expansions of the ARND family across kinetoplastids.
Conclusion: KIAP4 is a foundational adhesion-plaque protein and founding member of a conserved ARND family required for Leishmania haptomonad adhesion and sand fly stomodeal valve colonization, making ARND proteins candidate targets for transmission-blocking strategies.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Identification of a conserved gene family with an essential role in Leishmania parasite–insect vector adhesion
First author: Owino BO
Journal: Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2603653123
Reference: Owino BO, Yanase R, Pruzinovac K, Farr H, Lopez Y, Marron AO, Vaughan S, Volf P, Sunter JD. Identification of a conserved gene family with an essential role in Leishmania parasite–insect vector adhesion. Proc Natl Acad Sci U S A. 2026;123(30):e2603653123. doi:10.1073/pnas.2603653123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited spoken sections covering (1) identification of KIAP4 as the canonical ARND member and its adhesion-plaque localization, (2) TurboID proximity labeling methodology and protein enrichment results, (3) KIAP4 functional analyses including in vitro adhesion and in vivo valve colonization, (4) ARND conservation acros - transcript topics: KIAP4 and ARND identification in Leishmania; TurboID proximity labeling workflow and enrichment of adhesion-plaque components; Localization of KIAP4 and KIAP3 within the adhesion plaque; KIAP4 knockout effects on haptomonad adhesion and sand fly stomodeal valve colonization; ARND conservation across kinetoplastids (Trypanosoma congolense; T. brucei cross-species data); Inactive Walker A motif in ARND proteins (NTPase-like domains)
430: Proterozoic Rise: Steady Diversification of Crown Eukaryotes
23 Jul 2026
00:25:20
Sandin MM et al., Proceedings of the National Academy of Sciences - Molecular clocks and diversification models applied to a 75,975-OTU rDNA dataset, including long-read environmental sequences and 77 fossil calibrations, indicate crown-group eukaryotes diversified steadily from the mid‑Proterozoic with Archaeplastida dominating early diversity. Key terms: eukaryote evolution, Proterozoic diversification, Archaeplastida, molecular clock, environmental sequencing.
Study Highlights: The study assembled 75,975 nonredundant rDNA OTUs combining long-read environmental metabarcoding and reference sequences and calibrated 32 timetrees with 77 fossil constraints. Molecular dating places LECA at ~1775 Ma and finds most eukaryotic supergroups originating across the Mesoproterozoic. Diversification analyses (ClaDS, BAMM) show steady accumulation of crown-group diversity through the Proterozoic, with Archaeplastida exhibiting an early rapid diversification likely tied to plastid endosymbiosis. Results suggest crown eukaryotes were ecologically and taxonomically diverse long before clear crown-group fossils appear.
Conclusion: Integrating extensive environmental sequencing with molecular dating and diversification models reveals that crown-group eukaryotes were diversifying steadily from the mid‑Proterozoic, overturning the notion of a biologically stagnant “boring billion” and indicating early ecological interactions and endosymbioses drove diversification.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Environmental phylogenetics supports a steady diversification of crown eukaryotes starting from the mid-Proterozoic
First author: Sandin MM
Journal: Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2600283123
Reference: Sandin MM, Burki F, Cohen PA, Morlond H (2026) Environmental phylogenetics supports a steady diversification of crown eukaryotes starting from the mid-Proterozoic. PNAS 123(29):e2600283123. doi:10.1073/pnas.2600283123
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript segments covering LECA dating and molecular clock; environmental sequencing (OTUs and 18S-28S rDNA); Archaeplastida endosymbiosis and early diversification; Proterozoic diversification dynamics and the 'boring billion' reinterpretation; predator–prey dynamics and fossil evidence; and limitations/samp - transcript topics: LECA dating and molecular clock; Environmental metabarcoding and OTU dataset (75,975 OTUs); Archaeplastida diversification and plastid endosymbiosis; Proterozoic diversification vs. 'boring billion' narrative; Predation, defense, and ecosystem dynamics (fossil evidence); Sampling limitations and diversification modeling (ClaDS, BAMM)
QC Summary: - factual score: 10/10 - met...
429: Validating the EAGL genetic literacy measure
23 Jul 2026
00:23:49
Barna LS et al., Human Genetics and Genomics Advances - We summarize a psychometric validation of the EAGL measure using US adult online samples. The study produced a validated 17-item EAGL-short that captures three core genetic literacy constructs and can be used to assess and target genetic communication and education. Key terms: genetic literacy, EAGL, psychometrics, knowledge comprehension, autism.
Study Highlights: The authors administered the EAGL across three online US samples (combined N ≈ 2,708) and used exploratory and confirmatory factor analyses to refine the instrument. The final EAGL-short contains 17 items loading on three factors: subjective knowledge, knowledge comprehension, and conceptual (objective) knowledge, with CFA fit indices showing excellent model fit (CFI = 0.996, RMSEA = 0.031, SRMR = 0.080). Regression analyses found numeracy to be the strongest predictor across subscales, a personal connection to autism raised subjective familiarity but not comprehension or conceptual knowledge, and metropolitan vs non-metropolitan status showed no main effects. An interaction between education and connection to autism was observed for knowledge comprehension, highlighting education as a moderator.
Conclusion: The EAGL-short is a psychometrically sound, 17-item tool that measures subjective knowledge, knowledge comprehension, and conceptual genetic knowledge in US adults; it enables more precise assessment of genetic literacy and the design of targeted educational interventions, though further validation in other languages and settings is recommended.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Psychometric validation of the education and assessment of genetic literacy or the EAGL measure
First author: Barna LS
Journal: Human Genetics and Genomics Advances
DOI: 10.1016/j.xhgg.2026.100651
Reference: Barna LS, Liao Y, Wierzbicki MR, Ramírez-Renta GM, Kaphingst KA, Gunter C. Psychometric validation of the education and assessment of genetic literacy or the EAGL measure. Human Genetics and Genomics Advances. 2026;7:100651. doi:10.1016/j.xhgg.2026.100651.
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantive auditing covered the EAGL-short validation narrative, the three constructs, the autism infographic comprehension exercise, numeracy as predictor, autism connection effects, geography/metropolitan status findings, and the education-autism interaction implications as presented in the transcript. - transcript topics: EAGL-short three-factor structure; Autism infographic used for knowledge comprehension; Numeracy as predictor of genetic literacy; Autism connection influencing subjective knowledge; Geography/metro status effects on literacy; Education by autism interaction affecting knowledge comprehension
QC Summary:
428: Genetic regulation of plasma metabolites in people with HIV
23 Jul 2026
00:28:03
Ait Oumelloul M et al., Human Genetics and Genomics Advances - Untargeted plasma metabolomics (1,930 features) in 1,244 participants of the Swiss HIV Cohort Study were paired with genome-wide genotypes to map genetic influences on metabolite levels, test colocalization with eQTLs, and apply Mendelian randomization to probe causal links with aging-related biomarkers and diseases. Key terms: HIV, metabolomics, GWAS, Mendelian randomization, NAT8.
Study Highlights: The study performed GWAS on 1,930 putative plasma metabolites measured by untargeted mass spectrometry in 1,244 people with HIV and identified 27 metabolites associated with 12 genetic loci, including NAT8, FUT2, PYROXD2, and FADS. Colocalization analyses found that 24 of the 27 metabolite loci overlapped with tissue eQTLs, linking genetic variants to gene expression and metabolite variation. Mendelian randomization using MR-link-2 provided evidence for putative causal relationships, notably genetically higher N-acetylcitrulline associated with lower serum creatinine (protective for kidney function) and chorismate linked to higher cholesterol and triglycerides. Sensitivity analyses across ancestries and sex and partial replication in non-HIV data supported the robustness of key signals.
Conclusion: Integrating untargeted metabolomics with GWAS, eQTL colocalization, and MR in people with HIV revealed host genetic regulation of plasma metabolites, identified colocalized expression signals, and suggested causal links between specific metabolites and kidney and lipid biomarkers, highlighting targets for follow-up and the utility of multi-omics for precision comorbidity research in this population.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Genome-wide association study of untargeted plasma metabolomic profiles identifies host genetic regulation in people with HIV
First author: Ait Oumelloul M
Journal: Human Genetics and Genomics Advances
DOI: 10.1016/j.xhgg.2026.100635
Reference: Ait Oumelloul M, van der Graaf A, Tang S, Thorball CW, Labarile M, Saadat A, Timonina V, Schöpf IC, Wandeler G, Nemeth J, Cavassini M, Calmy A, Schmid P, Stöckle M, Elzi L, Zamboni N, Kouyos RD, Tarr PE, Fellay J; Swiss HIV Cohort Study. Genome-wide association study of untargeted plasma metabolomic profiles identifies host genetic regulation in people with HIV. Human Genetics and Genomics Advances. 2026;7:100635. https://doi.org/10.1016/j.xhgg.2026.100635
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited portions include study design and population, untargeted metabolomics, GWAS of metabolites, eQTL colocalization, Mendelian randomization analyses, and key metabolite–gene–disease links (NAT8/N-acetylcitrulline, chorismate, F11/5-HTP), along with limitations and clinical implications discussed in the transcrip...
427: When Genes Talk to Gut: Microbiome as Mediator of Metabolic Risk
23 Jul 2026
00:25:13
Simpson RC et al., Trends in Genetics - This forum reviews evidence that host genetic variants associated with metabolic disease often overlap with loci that shape gut microbiome composition and function. Examples include LCT/MCM6 linking Bifidobacterium to reduced T2D risk, defensin locus variants affecting DEFA26 and Akkermansia abundance, and rs7133214 associating with HbA1c. The authors outline mechanisms, analytic tools, and experimental strategies to resolve causality and call for centralized microbiome–genetic resources. Key terms: gut microbiome, genetics, type 2 diabetes, defensins, bile acids.
Study Highlights: The authors compile microbial GWAS loci and perform phenome-wide scans using the Synteny tool, revealing significant overlaps between microbe-associated SNPs and metabolic traits including obesity, HDL, blood glucose, and T2D. Case studies highlight loci such as LCT/MCM6, defensin genes (DEFA26–Akkermansia), and rs7133214 (methionine pathway) as examples of microbiome-mediated effects. Mechanisms likely include immune-mediated (Paneth cell defensins, NOD2, FUT2) and substrate/metabolite-mediated (lactose metabolism, bile acids, polyamines) pathways. The paper advocates integrated multi-omic studies, Mendelian randomisation, and human–mouse syntenic mapping, and emphasizes the need for a centralized database to enable causal inference.
Conclusion: Host genetic control of the gut microbiome is widespread and may mediate many genetic links to metabolic disease; resolving causality will require integrated multi-omic datasets, improved causal-mapping tools, standardized databases, and complementary human and controlled mouse studies.
Music: Enjoy the music based on this article at the end of the episode.
Article title: The gut microbiome as an effector of metabolic disease gene variants
First author: Simpson RC
Journal: Trends in Genetics
DOI: 10.1016/j.tig.2026.03.011
Reference: Simpson RC, Cutler HB, James DE, Masson SWC. The gut microbiome as an effector of metabolic disease gene variants. Trends in Genetics. 2026;42(7):585-588. https://doi.org/10.1016/j.tig.2026.03.011
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantively audited portions covering: (1) host genetic regulation of the gut microbiome and immune barrier, (2) specific gene–microbiome examples (LCT/MCM6, defensin locus, TCF7L2), (3) methodological approach (Synteny, CNV/MR concepts), (4) overlaps between microbial SNPs and human metabolic traits (HbA1c, HDL, obe - transcript topics: Gut microbiome as metabolic organ governed by host genetics; Lactase persistence (LCT/MCM6) and T2D risk via microbial metabolism; Defensin locus variants and Akkermansia muciniphila in mice; TCF7L2's role in Paneth cell development and dysbiosis; Synteny tool, microbial GWAS, and Mendelian randomisation conce...
426: ProtoCloud — Prototypical self-explaining model for single-cell analysis
23 Jul 2026
00:16:53
Guo K et al., Cell Genomics - ProtoCloud is a self-explaining deep generative model that embeds single cells around cell-type-specific prototypes to deliver accurate, uncertainty-aware cell type annotation and gene-level explanations from raw UMI counts. Key terms: single-cell, explainable AI, prototypical models, cell type annotation, uncertainty estimation.
Study Highlights: ProtoCloud achieves accurate and efficient annotation of single-cell data, including improved detection of rare cell types, by organizing embeddings around learned prototypes. A disentangled latent space separates biological identity from batch and nuisance variation, improving robustness and label transfer. Built-in uncertainty quantification based on cell–prototype similarity identifies and enables correction of misannotations. Prototypical relevance propagation backpropagates similarity to highlight genes driving classification for instant gene‑level explainability.
Conclusion: By combining a decomposed VAE, learnable prototypes, PRP-based gene relevance, and calibrated similarity-based uncertainty, ProtoCloud provides accurate, interpretable, and robust single-cell annotations that detect rare states, correct label errors, and nominate marker genes to support atlas construction and disease studies.
Music: Enjoy the music based on this article at the end of the episode.
Article title: ProtoCloud: A prototypical self-explaining model for single-cell analysis
First author: Guo K
Journal: Cell Genomics
DOI: 10.1016/j.xgen.2026.101217
Reference: Guo K. & Ding J. ProtoCloud: A prototypical self-explaining model for single-cell analysis. Cell Genomics 6, 101217 (2026). doi:10.1016/j.xgen.2026.101217
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
Factual Items Audited: - ProtoCloud uses six prototypes per cell type by default - Latent space is partitioned into two components: z1 for cell-type identity and z2 for batch/noise factors - PRP identifies gene-level relevance and HRGs (e.g., CD79B, LY9)...
425: BEAM: Bayesian reconstruction of metastatic migration histories
23 Jul 2026
00:23:31
Staklinski SJ et al., Cell Genomics 6, 101193 (2026) - This episode explores BEAM, a Bayesian framework built on BEAST 2 that jointly infers cell-lineage phylogenies and tissue-migration graphs from CRISPR-based lineage-tracing data. The method quantifies uncertainty, improves reconstruction versus parsimony-based approaches, and supports Bayes-factor hypothesis testing of migration models. Applications to simulated data and mouse lung and prostate datasets reveal complex migration patterns and highlight limits imposed by sparse mutational signal. Key terms: Bayesian inference, metastasis, lineage tracing, phylogenetics, BEAM.
Study Highlights: BEAM jointly samples lineage trees and tissue-migration histories, producing posterior distributions over migration graphs and timing. In simulations BEAM outperforms existing parsimony-based methods across a range of mutation and migration regimes and is robust to missing barcode data. Applied to mouse lung and prostate datasets, BEAM uncovers complex, heterogeneous migration patterns and provides conservative estimates of metastasis-to-metastasis and primary-reseeding events. The framework also implements Bayes-factor tests to assess dataset informativeness and to compare competing migration models.
Conclusion: BEAM provides a fully Bayesian approach that integrates lineage-tree and migration-graph inference, quantifies uncertainty, and enables formal hypothesis testing; it improves accuracy in many simulated regimes and reveals richer metastatic histories in real datasets, while its utility is constrained by sparse mutational information and current scalability limits.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Bayesian inference of tissue-migration histories in metastatic cancer from cell-lineage tracing data
First author: Staklinski SJ
Journal: Cell Genomics 6, 101193 (2026)
DOI: 10.1016/j.xgen.2026.101193
Reference: Staklinski SJ, Scheben A, Brault LM, Hassett R, Serio RN, Xing J, Nowak DG, Siepel A. Bayesian inference of tissue-migration histories in metastatic cancer from cell-lineage tracing data. Cell Genomics. 2026;6:101193. doi:10.1016/j.xgen.2026.101193
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript's substantive claims about BEAM's methodology, benchmarking against parsimony methods, simulated performance, real-data findings (lung and prostate), Bayes-factor testing, and limitations/future directions; compared against the canonical article text. - transcript topics: BEAM Bayesian joint inference on BEAST 2; Two-step parsimony methods and their limitations; Simulation benchmarks and edgewise performance; Real-data analyses: lung cancer migration histories; Prostate cancer migration histories and data informativeness; Bayesian hypothesis testing and Bayes fac...
Chapters
(00:00:02) - Papercast: The Science of Genomics
(00:00:29) - How does cancer spread? The '
(00:05:55) - Bayesian Analysis of Cancer metastasis
(00:10:55) - Beme the Better Way to Map Prostate Cancer?
(00:15:16) - Beme the computational lung cancer model
424: LECA's Ancient Interactome and Modern Disease
23 Jul 2026
00:12:03
Cox RM et al., Cell Genomics 6, 101254 - Cox et al. reconstruct a conserved protein interaction network for the last eukaryotic common ancestor using >26,000 mass spectrometry experiments across 31 species and demonstrate how the ancient interactome predicts and explains modern human disease mechanisms. Key terms: LECA, protein interactome, co-fractionation mass spectrometry, ciliopathy, V-ATPase.
Study Highlights: The authors inferred a core LECA gene set and integrated ∼26,000 mass spectrometry experiments from 31 eukaryotes to reconstruct a conserved interactome of 109,466 pairwise interactions among 3,193 orthogroups. The map recovers known complexes (e.g., ARP2/3, TRAPP, V-ATPase, HOPS/CORVET) and reveals unexpected ancient interactions and lineage-specific losses. Network propagation on this interactome predicted novel gene-disease links validated experimentally: EFHC2 mislocalization linked to ciliopathic renal failure, ATP6V1A implicated in osteopetrosis with corresponding increased bone density in mouse knockouts, and GLG1 disruption impairing IFT and ciliation relevant to SRTD. The dataset supports a complex LECA capable of cell projection machinery and provides a framework for linking deep conservation to medical phenotypes.
Conclusion: An experimentally reconstructed LECA interactome defines deeply conserved macromolecular assemblies that have persisted for nearly two billion years and can predict modern disease mechanisms, as shown by validated links to ciliopathies, osteopetrosis, and short-rib thoracic dysplasia.
Music: Enjoy the music based on this article at the end of the episode.
Article title: A protein interactome for the last eukaryotic common ancestor illuminates the biochemical basis of modern genetic diseases
First author: Cox RM
Journal: Cell Genomics 6, 101254
DOI: 10.1016/j.xgen.2026.101254
Reference: Cox RM, Papoulas O, Shril S, et al. A protein interactome for the last eukaryotic common ancestor illuminates the biochemical basis of modern genetic diseases. Cell Genomics. 2026;6:101254. https://doi.org/10.1016/j.xgen.2026.101254
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantively audited transcript sections: LECA concept and health relevance; CFMS data integration across 31 species; conserved vesicle tethering complexes and actin cytoskeleton in LECA; primordial origins of cell projection/phagocytosis; EFHC2 ciliopathy mechanism; ATP6V1A osteopetrosis; GLG1 in ciliogenesis and SRT - transcript topics: LECA concept and health relevance; CFMS data integration across 31 species; Conserved vesicle tethering complexes (TRAPP, GARP/COG, HOPS); Actin cytoskeleton and ARP2/3 in LECA; Primordial origins of cell projection and phagocytosis; EFHC2 ciliary mechanism in renal disease
(00:00:20) - Papercast: Dating the genetics of humans
(00:01:29) - Machine-learning maps the interactions of a billion year old cell
(00:04:44) - Could the LECA Intersectome Identify Human Diseases?
423: How GRN Topology Shapes the Genetic Architecture of Expression
22 Jul 2026
00:25:10
Aguirre M et al., Cell Genomics - Aguirre et al. use simulated gene regulatory networks and a linear structural equation model to show how sparsity, modularity, and hub regulators shape the genome-wide distribution of cis- and trans-heritability of gene expression. Their results indicate gene expression is less polygenic but more pleiotropic than previously thought. Key terms: gene regulatory networks, trans-eQTL, cis-heritability, modularity, hub regulators.
Study Highlights: The authors model local motifs, modular group structure, and global hub regulators to study their effects on cis- and trans-acting genetic variance. They show that sparsity, modularity, and hub-like out-degree distributions together best reproduce the observed distribution of cis-heritability in human whole-blood data. Hub regulators shorten network paths and concentrate trans-acting variance at pleiotropic loci. Local motifs mediate much of the effect of modular groups on trans-heritability.
Conclusion: Network topology constrains the genetic architecture of gene expression: realistic GRNs are sparse, modular, and hub-rich, leading to fewer regulators per gene but more repeated use of the same regulators across genes. These findings suggest model and inference biases toward sparse, modular, hub-containing networks and support aggregation strategies to improve trans-eQTL discovery.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Regulatory network topology and the genetic architecture of gene expression
First author: Aguirre M
Journal: Cell Genomics
DOI: 10.1016/j.xgen.2026.101219
Reference: Aguirre M, Spence JP, Sella G, Pritchard JK. Regulatory network topology and the genetic architecture of gene expression. Cell Genomics. 2026;6:101219. doi:10.1016/j.xgen.2026.101219.
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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-22.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantively audited sections covering cis- and trans-heritability, the two-part GRN modeling (graph-generating model + SEM), motifs and hubs, modular structure, and limitations of the approach. - transcript topics: cis- and trans-eQTLs and their effect sizes; twin-study heritability and cis/trans fractions; graph-based GRN generation: planted partition model (PPM) and modularity; linear structural equation modeling (SEM) of gene expression; hub regulators and heavy-tailed out-degree distributions; network motifs: triangle and diamond (bi-parallel) motifs
Factual Items Audited: - cis-eQTL median effect size = 0.14; trans-eQTL median e...
Chapters
(00:00:20) - Understanding the genetic architecture of gene expression
(00:02:29) - The hidden genetics of genomics
(00:08:34) - The Hidden Networks of Human Biology
(00:14:21) - Do regulatory hubs make the human genome fragile?
(00:15:54) - Genomic Networks: Less Polygenic, More Pleiotropic
(00:22:23) - A network of signals in the dark
422: Germline rDNA Variants and Human Complex Traits
22 Jul 2026
00:20:13
Rodriguez-Algarra F et al., Cell Genomics - This episode examines a large-scale analysis of germline ribosomal DNA (rDNA) variation in ~500,000 UK Biobank genomes that identifies high-confidence rDNA SNVs and indels associating with human complex traits, notably a cluster in the 28S expansion segment ES15L linked to body-size measures. Key terms: ribosomal DNA, rRNA variants, UK Biobank, ES15L expansion segment, complex traits.
Study Highlights: The authors derived a stringent set of 378 rDNA variants from UK Biobank whole-genome sequencing and tested intragenomic variant frequencies (IGFs) for association with 419 traits. They report 34 associations at global FDR < 0.01 concentrated in the 28S, with a cluster in ES15L associating with height, weight, and related measures. ES15L variant combinations are predicted to alter rRNA secondary structure and are expressed and incorporated into actively translating ribosomes. rDNA copy number and sequence variation influence overlapping traits but act independently.
Conclusion: Germline sequence variation within human rDNA is a reproducible and trait-relevant source of genetic variation, with species-specific ES15L variants likely altering rRNA structure and ribosome composition and contributing to variation in body-size and other complex traits.
Music: Enjoy the music based on this article at the end of the episode.
Article title: Germline sequence variation within the ribosomal DNA is associated with human complex traits
First author: Rodriguez-Algarra F
Journal: Cell Genomics
DOI: 10.1016/j.xgen.2026.101213
Reference: Rodriguez-Algarra F., Whittaker E., Cooper M., et al. Germline sequence variation within the ribosomal DNA is associated with human complex traits. Cell Genomics. 2026;6:101213. https://doi.org/10.1016/j.xgen.2026.101213
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/
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On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-22.
QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript for core scientific claims about ES15L rDNA variants: their clustering and trait associations, mechanistic interpretation (RNA structure, translation), evolutionary specificity, and independence from copy number, as presented in the article. - transcript topics: ES15L expansion segment 15L variants in the 28S subunit; Association of ES15L variants with body-size traits (height, weight, birth weight, waist circumference); Evolutionary and primate comparison of ES15L haplotypes; Polysome-seq evidence for ES15L variant expression and incorporation into translating ribosomes; RNA secondary structure modeling of ES15L variants; Independence of ES15L variant effects from total rDNA copy number