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477: Fish oil and the genes that change its effect

Nov 15, 2026 19 min

Ihejirika S et al., Human Genetics and Genomics Advances - This study asks why the same fish oil supplement can shift blood fatty acids differently from person to person. Using a two-stage strategy in UK Biobank participants of European ancestry, the authors first searched the genome for variants linked to the spread, or variance, of 14 plasma polyunsaturated and monounsaturated fatty acid traits, and then tested those variants for interaction with regular fish oil use. Key terms: gene-environment interaction, variance QTL, fish oil supplements, polyunsaturated fatty acids, UK Biobank. Study Highlights: The genome-wide variance scan, in up to 200,736 participants, found 172 variance QTL-trait pairs across the 14 traits, mapping to 46 non-overlapping loci; 16 of them had no detectable effect on the trait mean. In the interaction stage, with 200,060 participants of whom about 31.8% regularly took fish oil, six significant gene-fish oil interactions emerged, in DHA, DHA%, Omega-3, Omega-3%, LA and the Omega-6/Omega-3 ratio. They mapped to the FADS1/2 region, to ZPR1 near the APOA5 apolipoprotein cluster, and to SUGP1/TM6SF2, the last two not detected in the authors' earlier genome-wide interaction scan. Significant interactions were enriched 8.12-fold among variance QTLs compared with ordinary mean-effect loci, with a wide 95% bootstrap confidence interval of 2.26 to 27.07. Conclusion: Screening for variants that change trait variance helped the authors find two additional loci where genotype modifies the association between fish oil use and circulating fatty acids, such as a larger DHA increase with fish oil in carriers of the ZPR1 rs964184 G allele. The findings are associations in participants of European ancestry, fish oil use was a self-reported yes or no without dose or composition, and the mechanisms remain hypotheses that need replication and functional study. Article title: A variance QTL approach to uncover gene-fish oil supplement interaction loci for...

476: One recurring ABI2 change and a thin brain bridge

Nov 12, 2026 10 min

Argilli E et al., The American Journal of Human Genetics - This research letter describes nine unrelated individuals with rare heterozygous missense variants in ABI2, a gene for a cytoskeletal adaptor protein that works in Rac-WAVE signaling and actin remodeling. Seven of them carry the same de novo change, p.Tyr491Cys, in the SH3 domain, and their brain MRIs show a consistent pattern led by a thin corpus callosum, the bundle of fibers that links the two brain hemispheres. Key terms: ABI2, corpus callosum hypoplasia, de novo variant, neurodevelopmental disorder, Rac-WAVE signaling. Study Highlights: Individuals were found through exome or genome sequencing and international data sharing via GeneMatcher, with clinical data from medical records and clinician questionnaires and centrally reviewed brain MRIs. Seven individuals carried the recurrent p.Tyr491Cys variant and two carried distinct de novo variants, p.Val204Met and p.Val463Ala; all variants were absent from gnomAD v4.1. All nine had moderate-to-severe developmental delay and/or intellectual disability, epilepsy occurred in six, and macrocephaly ranging from +2.5 to +4.2 SD was seen in seven of eight individuals. Every individual with p.Tyr491Cys showed marked corpus callosum hypoplasia and periventricular T2-FLAIR hyperintensities, while the two individuals with nonrecurrent variants lacked corpus callosum abnormalities. Conclusion: The authors establish ABI2 as a neurodevelopmental disorder-associated gene and identify the recurrent p.Tyr491Cys variant as defining a distinctive syndrome with corpus callosum hypoplasia and white matter abnormalities, consistent with other Rac-WAVE pathway disorders and with Abi2-deficient mice. The cohort is small, nine individuals, and the mechanism is inferred from structural modeling and prediction tools; the authors state that future functional studies will be needed to explain how the variants cause disease. Article title: Recurrent de novo ABI2 p.Tyr491Cys variant...

475: A Cell Line Fitness Score Predicts Cancer Risk in Li-Fraumeni Syndrome

Nov 5, 2026 9 min

Penkert J et al., The American Journal of Human Genetics - Carriers of disease-causing TP53 variants range from mild to severe cancer phenotypes. Using relative fitness scores from a deep CRISPR mutagenesis screen of 9,225 TP53 mutations, this registry study of 437 individuals from 168 families shows that variants scoring 0.673 or higher go with earlier cancer and with full Li-Fraumeni syndrome. Key terms: Li-Fraumeni syndrome, TP53, deep CRISPR mutagenesis, relative fitness score, cancer surveillance. Study Highlights: A previous screen introduced 9,225 TP53 mutations into a colorectal cancer cell line and scored how well each mutant survived TP53 activators, giving a relative fitness score (RFS). The authors linked these scores to 437 individuals from 168 families in the German Cancer Predisposition Syndrome Registry. Carriers of variants with an RFS of 0.673 or higher developed cancer earlier; an RFS below 0.673 had a hazard ratio of 0.41 (95% CI 0.25 to 0.66, p 0.0002) for cancer. The association held among the 407 individuals whose variant is predicted to produce an altered protein, excluding NULL variants (hazard ratio 0.43). Families with a high score met the definition of Li-Fraumeni syndrome in 110 of 148 cases (74.3%), against 3 of 20 (15%) with a low score. Conclusion: Relative fitness scores from deep CRISPR mutagenesis separated TP53 variant carriers with earlier cancer and more severe Li-Fraumeni spectrum phenotypes, which suggests they could feed future variant classification and tailored surveillance. The finding was not validated in an independent cohort, the scores come from a single colorectal cell line, and they exist only for variants in the DNA binding domain. Article title: Deep CRISPR mutagenesis predicts cancer risk in Li-Fraumeni syndrome First author: Penkert J Journal: The American Journal of Human Genetics DOI: 10.1016/j.ajhg.2026.09.016 Reference: Penkert J., Großhennig A., Dutzmann C.M., Ewert A., Zimmer R., Schoene-Bake...

474: Two collagen genes, two different risks

Nov 4, 2026 19 min

Tzoumkas K et al., The American Journal of Human Genetics - COL4A3 and COL4A4 are paralogous genes that build the same collagen IV network in the kidney filter, and variant guidelines have generally treated them as interchangeable. This episode follows a population-scale study in the UK Biobank, replicated in All of Us, showing that truncating and NC1 domain missense variants carry much stronger associations with hematuria and proteinuria in COL4A4 than in COL4A3, while glycine substitutions behave alike in both genes. Key terms: COL4A3, COL4A4, Alport syndrome, hematuria, UK Biobank. Study Highlights: Using whole-genome sequencing from the UK Biobank (n ≈ 500,000) with replication in All of Us (n ≈ 414,000), the authors ran per-variant association tests, gene-based collapsing analyses and phenome-wide association studies across hematuria, proteinuria and chronic kidney disease. They identified 64 COL4A3 and 92 COL4A4 rare variants significantly associated with hematuria or proteinuria. Glycine substitutions in the collagenous domain conferred similar risks in both genes, but truncating and NC1 missense variants were strongly associated with disease only in COL4A4, with proteinuria case rates of 52.7% and 37.2% in COL4A4 compared with 17.1% and 12.1% in COL4A3. The difference persisted after excluding the British founder variant p.Ser969Ter and was independently replicated in All of Us. A genome-wide analysis found the COL4A3 and COL4A4 locus to be the dominant genetic signal for hematuria, accounted for by rare coding variants, with no evidence of independent trans-acting modifiers. Conclusion: The authors conclude that gene identity, not variant class alone, should inform risk stratification, variant interpretation and genetic counseling in collagen IV heterozygotes. The analyses were restricted to individuals of European ancestry, phenotypes came from ICD-10 codes and laboratory data that likely underestimate prevalence, the difference was not extended to sev...

473: Sixty years of cells that stop dividing

Nov 3, 2026 19 min

Klaver M et al., The EMBO Journal - In 1961, Hayflick and Moorhead showed that normal human fibroblasts divide only a finite number of times. This episode follows a review of the six decades since, as senescence moved from a cell-culture limit to a tumor-suppressive stress response, a tissue-remodeling program, a contributor to aging and disease, and a target for therapy. Key terms: cellular senescence, SASP, senolytics, senomorphics, aging. Study Highlights: This review traces cellular senescence from the Hayflick limit of 1961 through telomere shortening, biomarkers and oncogene-induced senescence. The senescence-associated secretory phenotype revealed that senescent cells actively communicate with their tissues, and later work showed there is no single universal SASP. Genetic ablation in mice showed that senescent cells can contribute causally to age-related decline, while other studies showed roles in wound healing, development and tissue repair, and one p16-lineage study reported detrimental effects on the liver. Senolytics such as dasatinib plus quercetin and senomorphics followed, but UBX0101 failed to show significant benefit in Phase 2 and UBX1325 missed its Phase 2b primary endpoint. The authors identify the lack of validated biomarkers of target engagement as the major bottleneck in clinical senotherapy. Conclusion: The authors conclude that senescence is neither inherently beneficial nor inherently detrimental, and that its consequences depend on context, which senescent cells are involved, and how long they persist. This is a narrative review, not a new experiment, and much of the causal evidence comes from mouse models, with human trials so far early, limited by size or design, or unsuccessful. Article title: Cellular senescence: six decades of discovery and reinvention First author: Klaver M Journal: The EMBO Journal DOI: 10.1038/s44318-026-00922-w Reference: Klaver M., Steeneken L.S., Veeningen N., Altulea A., Demaria M. Cellular senesc...

472: 490,319 genomes that fill the gaps in genetic studies

Nov 2, 2026 17 min

Wienbrandt L et al., Nature Genetics - Most genetic studies read only a fraction of the genome and infer the rest from a reference panel. This episode covers a new panel built from whole-genome sequencing of 490,319 UK Biobank participants, benchmarked against the TOPMed r3 panel across 35 datasets and used to reanalyze COVID-19 association studies from four European countries. Key terms: genotype imputation, haplotype reference panel, UK Biobank, EagleImp, COVID-19 GWAS. Study Highlights: Researchers phased whole-genome data from 490,319 UK Biobank participants into reference panels of more than 361 million variants and extended EagleImp to run on a standalone server and inside the UK Biobank Research Analysis Platform. Compared with the TOPMed r3 panel of 133,597 individuals, the UK Biobank panel achieved lower phasing switch error rates for all superpopulations except AMR and for 25 of 26 1000 Genomes subpopulations. Mean absolute error improved for 4 of 5 superpopulations and 12 subpopulations, while TOPMed performed better across all frequency categories in AFR. Estimated R2 improved across all 5 superpopulations and 22 subpopulations for variants down to 0.01% frequency, with the largest gain, +24.39%, in East Asian samples. Reimputing an Italian severe COVID-19 study of 835 cases and 1,255 controls yielded a genome-wide significant association at 3p21.31 and a new lead SNP, rs73064425, that matched three independent studies. Conclusion: The authors conclude that the UK Biobank panel is the most suitable panel for imputing worldwide populations when no population-specific panel is available, and that common-variant imputation is not yet saturated in the European populations tested. The benchmark has limits: estimated imputation R2 stays low for most subpopulations below 0.01% frequency, truth-based measures may be inaccurate at low frequencies, and TOPMed r3 still performed better in AFR on mean absolute error and holds more panel-specific variants. Arti...

471: How cancer treatment picks winners among mutant clones in the normal esophagus

Oct 30, 2026 17 min

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...

470: The hidden swaps CRISPR leaves between sister chromosomes

Oct 29, 2026 17 min

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 universal...

469: What the shape of a face reveals about cleft risk

Oct 27, 2026 18 min

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...

468: When a splicing factor breaks in different ways

Oct 25, 2026 17 min

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 prote...

467: Finding mutations carried by fewer than 1 in 100 cells

Oct 18, 2026 18 min

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...

466: A quieter MECP2 switch and the male bias in autism

Oct 16, 2026 18 min

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 modes...

465: When a lysosomal storage gene shows up only in the retina

Oct 11, 2026 20 min

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...

464: Burning fat while sparing muscle on GLP-1 drugs, in mice

Oct 6, 2026 18 min

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 las...

463: Why brain traits leave faint, common genetic signals

Oct 4, 2026 18 min

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 selectio...

462: A vessel gene tied to AMD dims low-light vision in mice

Sep 30, 2026 20 min

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-ves...

461: Adult Ank3 loss quiets neurons and lowers a myelin protein

Sep 24, 2026 24 min

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 selecti...

460: The lupus variant that also sharpens antiviral defense

Sep 21, 2026 24 min

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 t...

459: Cerebral palsy genetics: 515 candidate genes, evidence for 89

Sep 13, 2026 24 min

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 d...

458: Somatic or inherited? Reading TP53 risk from shared DNA

Sep 10, 2026 25 min

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...

457: A deletion that raises Alzheimer risk, a duplication that lowers it

Sep 9, 2026 24 min

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 r...

456: Beyond exons: where heritability hides as traits get more polygenic

Sep 8, 2026 45 min

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...

455: Agentic genomics: the bottleneck moves from code to judgment

Sep 7, 2026 13 min

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...

454: Efavirenz retarda a doença priônica mexendo no colesterol do cérebro [PT]

Sep 2, 2026 17 min

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-hidroxic...

453: Efavirenz slows sCJD progression by reshaping brain cholesterol

Aug 31, 2026 20 min

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 accumulati...

452: Reduzir a PrP funciona em todas as linhagens [PT]

Aug 28, 2026 28 min

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...

451: Prion protein lowering is disease-modifying across stages and strains

Aug 25, 2026 24 min

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: T...

450: ASOs que reduzem PrP prolongam a sobrevida [PT]

Aug 24, 2026 24 min

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 Internation...

449: siRNA divalente para doença priônica [PT]

Aug 24, 2026 28 min

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 don...

448: PrP‑lowering ASOs prolong survival in prion‑infected mice

Aug 23, 2026 25 min

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/...

447: Divalent siRNA for prion disease

Aug 23, 2026 23 min

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 arti...

446: Cilia, Synuclein, and Survival: G51D Mice Reveal a Shared Parkinson’s Pathway

Aug 23, 2026 28 min

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...

445: Why Thymine Survived the UV: Photodamage Pathways Explained

Aug 22, 2026 26 min

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 publishe...

444: Many-eyes or Sentinels? How Cost Curvature Shapes Collective Vigilance

Aug 19, 2026 24 min

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...

443: 5D‑ASO boosts exon 51 skipping and restores dystrophin in DMD models

Aug 18, 2026 19 min

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...

442: When pumps go missing: Ca2+ control of PMCA2 in Tmc1 deafness mutants

Aug 17, 2026 22 min

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: Proce...

441: Evolutionary mapping of Cav1.3 functional sites

Aug 14, 2026 24 min

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...

440: DENV-4: Suppressing DNA Repair and Causing Genome Damage

Aug 12, 2026 23 min

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-f...

439: Coembedding Sequence and Structure: CLSS Maps the Protein Universe

Aug 11, 2026 23 min

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 glob...

438: Mapping AIRE: a proactive atlas of 9,790 missense variants

Aug 10, 2026 24 min

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...

437: Cell villages and Dirichlet modeling map human cell fitness genetics

Aug 9, 2026 28 min

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...

436: KIAP4 and the ARND family: building the Leishmania adhesion plaque

Aug 8, 2026 24 min

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 y...

435: E. coli TGT binds two tRNAs — cryo-EM reveals dual engagement

Aug 7, 2026 19 min

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:e2...

434: High‑coverage genomes recast Japan's prehistoric demography

Aug 6, 2026 27 min

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 ep...

433: Lactate, HSP90α and the Mitochondrial Switch

Jul 23, 2026 23 min

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. Article title: HSP90α lactylation orchestrates PGC1α and LRPGC1 nuclear translocation driving mitochondrial biogenesis First author: Wu G 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. 2...

432: Echovirus 18: Capsid opening releases the genome

Jul 23, 2026 18 min

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) – htt...

431: KIAP4 and the ARND family: essential proteins for Leishmania–sand fly adhesion

Jul 23, 2026 21 min

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 publis...

430: Proterozoic Rise: Steady Diversification of Crown Eukaryotes

Jul 23, 2026 25 min

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....

429: Validating the EAGL genetic literacy measure

Jul 23, 2026 23 min

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 validatio...

428: Genetic regulation of plasma metabolites in people with HIV

Jul 23, 2026 28 min

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.xh...