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Ramírez Renta GM et al., The American Journal of Human Genetics - GALS survey of >4,000 US respondents (GenPop and SPARK) shows confidence in genetic knowledge predicts Familiarity, Knowledge, and Skills, explaining ~25% of variance. Study Highlights: Using the Genetic and Autism Literacy Survey (GALS) in two US samples (GenPop and SPARK; n>4,000), the authors measured three genetic literacy components: Familiarity, Knowledge, and Skills via subjective familiarity ratings, objective true/false items, and a comprehension task. They modeled associations between these subscales and identity/belief measures including perceived importance, confidence, religiosity, religious affiliation, and political belief using linear regression adjusted for education and population. Confidence in one’s genetic knowledge was the strongest predictor, accounting for roughly 25% of variance in Familiarity and Knowledge and substantially improving model R2; perceived importance had a positive but smaller effect while religious and political measures showed mixed associations. The finding implies improving individuals’ confidence in genetic knowledge, alongside tailored communication strategies, could support better comprehension and uptake of genetics and genomics services. Conclusion: Confidence in one’s genetic knowledge, after education, is the largest modifiable predictor of genetic literacy and should be a focus for interventions to improve comprehension and uptake of genetics services. Music: Enjoy the music based on this article at the end of the episode. Reference: Ramírez Renta GM, Little ID, Koehly LM, et al. Interaction of identity and beliefs with genetic literacy. The American Journal of Human Genetics. 2026;113:16–28. https://doi.org/10.1016/j.ajhg.2025.11.014 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/genetic-literacy-confidence-gals

Ramírez Renta GM et al., The American Journal of Human Genetics - GALS survey of >4,000 US respondents (GenPop and SPARK) shows confidence in genetic knowledge predicts Familiarity, Knowledge, and Skills, explaining ~25% of variance. Study Highlights: Using the Genetic and Autism Literacy Survey (GALS) in two US samples (GenPop and SPARK; n>4,000), the authors measured three genetic literacy components: Familiarity, Knowledge, and Skills via subjective familiarity ratings, objective true/false items, and a comprehension task. They modeled associations between these subscales and identity/belief measures including perceived importance, confidence, religiosity, religious affiliation, and political belief using linear regression adjusted for education and population. Confidence in one’s genetic knowledge was the strongest predictor, accounting for roughly 25% of variance in Familiarity and Knowledge and substantially improving model R2; perceived importance had a positive but smaller effect while religious and political measures showed mixed associations. The finding implies improving individuals’ confidence in genetic knowledge, alongside tailored communication strategies, could support better comprehension and uptake of genetics and genomics services. Conclusion: Confidence in one’s genetic knowledge, after education, is the largest modifiable predictor of genetic literacy and should be a focus for interventions to improve comprehension and uptake of genetics services. Music: Enjoy the music based on this article at the end of the episode. Reference: Ramírez Renta GM, Little ID, Koehly LM, et al. Interaction of identity and beliefs with genetic literacy. The American Journal of Human Genetics. 2026;113:16–28. https://doi.org/10.1016/j.ajhg.2025.11.014 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/?episode=283-confidence-in-genetic-knowledge-drives-familiarity-knowl-17ljvj2

Liang Y et al., The American Journal of Human Genetics. 113 ( - TWAS using genetically predicted expression exhibit polygenicity-driven inflation that increases with GWAS sample size and heritability; a gene-specific variance-control correction yields calibrated p values. Study Highlights: The authors evaluated TWAS and related xWAS using simulated polygenic null traits and UK Biobank genotypes with predicted mediators including gene expression, metabolites, and brain features. They combined large-scale simulations, theoretical derivations, and empirical regression of mean Z2 on N*h2δ to estimate a gene-specific inflation slope Φ and applied corrections with S‑PrediXcan/PrediXcan across 110 GWAS traits. They show analytically and empirically that Var(Z) ≈ 1 + N*h2δ*Φ, observe a cohort-level slope around 4.2×10^-5, and demonstrate that dividing Z by sqrt(1+N*h2δ*Φ) restores calibration. Applying the variance-control correction yields well-calibrated p values, reduces false positives for highly polygenic traits, and improves precision with minimal loss of power. Conclusion: A gene-specific variance-control correction based on an empirically estimated inflation slope Φ corrects polygenicity-driven inflation in TWAS/xWAS and yields calibrated false-positive rates in simulations and real GWAS analyses. Music: Enjoy the music based on this article at the end of the episode. Reference: Liang Y, Nyasimi F, Im HK. A gene-specific variance-control approach corrects polygenicity-driven inflation observed in transcriptome-wide association studies. The American Journal of Human Genetics. 113 (2026) 276-290. https://doi.org/10.1016/j.ajhg.2025.12.014 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/twas-variance-control-inflation

Di Donato N et al., The American Journal of Human Genetics. 113:324-341 ( - Analysis of 290 individuals with ACTB and ACTG1 variants defines eight distinct non-muscle actinopathies and links BWCFF-causing variants to altered actin polymerization dynamics. Study Highlights: The study assembled a clinical-genomic cohort of 290 individuals with P/LP ACTB or ACTG1 variants and used expert phenotyping plus GestaltMatcher facial analysis to delineate eight distinct non-muscle actinopathies. Complementary methods included patient-derived fibroblast transcriptomics, recombinant actin production, differential scanning fluorimetry, and pyrene-based polymerization/depolymerization assays. BWCFF-associated missense variants (e.g., ACTB:R196H, ACTG1:T203M) produced decreased polymerization rates and faster depolymerization, whereas selected ACTB missense or in-frame variants impaired folding or thermal stability consistent with loss-of-function. These mechanistic stratifications support improved diagnostic classification, prognostication, and selection of functional assays for variant interpretation. Conclusion: Variant-level analysis of 290 individuals delineates eight distinct non-muscle actinopathies and shows that BWCFF-linked missense variants disrupt actin polymerization while select ACTB variants cause protein instability consistent with loss-of-function. Music: Enjoy the music based on this article at the end of the episode. Reference: Di Donato N, NMA Consortium, et al. Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies. The American Journal of Human Genetics. 113:324-341 (2026). https://doi.org/10.1016/j.ajhg.2025.12.007 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/actb-actg1-non-muscle-actinopathies

Yan X et al., The American Journal of Human Genetics, Corrected proof - In 569 TwinsUK subcutaneous adipose biopsies, twin models and GWAS identify SCD, FADS and 3p25.2 (PPARG) loci regulating fatty acid levels and conversions. Study Highlights: System and sample: 569 female TwinsUK subcutaneous adipose biopsies with matched serum, RNA-seq and 450K methylation data were analyzed. Key methods: gas chromatography fatty acid profiling, ACE twin heritability models, GWAS of 18 fatty acids and 15 product-to-precursor ratios, colocalization with adipose eQTLs and meQTLs, and polygenic score analysis. Main quantitative results: heritability of individual fatty acids ranged from 5%–59% while 15 fatty acid ratios were heritable and GWAS identified 10 genome-wide significant loci including SCD and FADS with the SCD lead variant explaining ~7–11% of variance and ratios showing heritability up to ~54%. Functional implication: colocalizations with adipose-specific eQTLs and meQTLs and associations between metabolic polygenic scores and fatty acid levels link local genetic regulation in adipose tissue to renal and cardio-metabolic phenotypes. Conclusion: Local genetic variation in adipose tissue, including SCD, FADS and a 3p25.2 locus near PPARG, regulates fatty acid composition and conversion and is connected to renal and cardio-metabolic traits. Music: Enjoy the music based on this article at the end of the episode. Reference: Yan X., Roberts A.L., El-Sayed Moustafa J.S., Villicaña S., Al-Hilal M., Tomlinson M., Menni C., Sanders T.A.B., Freidin M.B., Bell J.T., Small K.S., Genetic regulation of fatty acid content in adipose tissue. The American Journal of Human Genetics 113, 1–18, February 5, 2026. https://doi.org/10.1016/j.ajhg.2025.12.008 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/scd-fads-pparg-adipose

Guest, O et al., Zenodo (2025) - Position piece urging universities to resist uncritical adoption of AI technologies such as LLMs and chatbots because they undermine academic freedom, integrity, and pedagogical skills. Study Highlights: A co-authored open letter, conceptual analysis, and literature synthesis drawing on historical and contemporary sources. The authors analyse how AI industry marketing, ambiguous jargon, closed-source models, and extractive data and labour practices create institutional dependencies and conflicts of interest. They show this structural entanglement erodes research integrity, deskills students and staff, and produces environmental and social harms. As a functional implication they call for principled refusal, transparency, critical AI literacy, and policy measures to protect academic freedom and the ecosystem of human knowledge. Conclusion: Universities must reject the uncritical adoption of AI technologies and take active measures to safeguard critical thinking, expertise, academic freedom, and scientific integrity. Music: Enjoy the music based on this article at the end of the episode. Reference:  Against the Uncritical Adoption of 'AI' Technologies in Academia. Zenodo. (2025) https://doi.org/10.5281/zenodo.17065099  License: CC BY 4.0 Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/universities-resist-ai-adoption

Rashid AI et al., The American Journal of Human Genetics - US antitrust shifts in human genetic technologies: FTC scrutiny of Illumina’s acquisition of Grail alters NGS market oversight and could affect spin-offs and startups. Study Highlights: This perspective examines the US legal and regulatory landscape for human genetic and genomic technologies, focusing on FTC and DOJ policy changes and enforcement habits. Using a case-study approach centered on Illumina’s proposed acquisition and eventual divestiture of Grail, the authors review updated merger guidelines, non-compete rule developments, and exclusive-dealing concerns. They report that the 2023 merger guidelines lowered thresholds for presumed anti-competitiveness and that the FTC’s challenge emphasized risks to nascent mult-cancer early detection competitors that rely on next-generation sequencing platforms. The authors conclude that heightened vertical-merger scrutiny may reduce spin-offs and early-stage acquisitions, prompting firms to favor in-house R&D or alternate collaboration models. Conclusion: Heightened scrutiny of vertical mergers and attention to nascent competition in US antitrust policy is likely to reshape biotechnology strategies by reducing spin-offs and encouraging in-house development. Music: Enjoy the music based on this article at the end of the episode. Reference: Rashid AI, Rincon NA, Rihani N, Wagner JK. Competition in human genetic technologies: The current US legal landscape. The American Journal of Human Genetics. 2026;113:1–10. https://doi.org/10.1016/j.ajhg.2025.12.012 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/illumina-grail-vertical-mergers

Morsy H et al., The American Journal of Human Genetics - Exome sequencing identifies homozygous MDGA2 loss-of-function variants in nine individuals and functional neuronal assays show impaired MDGA2 trafficking with disrupted Nlgn1-dependent excitatory synapse regulation causing DEE. Study Highlights: Exome sequencing of consanguineous families identified seven distinct homozygous MDGA2 loss-of-function variants in nine individuals with severe developmental and epileptic encephalopathy. Functional evaluation used mammalian expression in HEK293T cells, heterologous synapse-formation assays, cultured hippocampal neurons, and electrophysiology. Representative nonsense variants abolished MDGA2 surface trafficking, disrupted MDGA2–Nlgn1 binding, failed to suppress excitatory synapse density, and did not reduce AMPAR- and NMDAR-mediated synaptic responses. These synaptic deficits imply disruption of excitatory-inhibitory balance, providing a mechanistic link to early-onset intractable seizures and progressive neurodevelopmental impairment. Conclusion: Homozygous MDGA2 loss-of-function variants cause an autosomal-recessive developmental and epileptic encephalopathy by impairing MDGA2 trafficking and Nlgn1-dependent suppression of excitatory synapses. Music: Enjoy the music based on this article at the end of the episode. Reference: Morsy H, Kim H, Jang G, et al. MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy. The American Journal of Human Genetics. 2026;113:1–12. https://doi.org/10.1016/j.ajhg.2025.12.015 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/mdga2-loss-of-function-dee

Avsec et al., Advancing regulatory variant effect prediction with AlphaGenome. Nature 649, 1206–1218 ( - AlphaGenome, a 1 Mb DNA deep‑learning model, predicts base‑pair‑resolution genome tracks (RNA‑seq, splicing, chromatin) and scores variant effects, achieving state‑of‑the‑art performance across modalities. Study Highlights: AlphaGenome is a unified sequence‑to‑function deep learning model trained on human and mouse genomes that consumes 1 Mb of DNA and predicts 5,930 human genome tracks across 11 modalities using a U‑Net‑inspired encoder, transformer tower and decoder. The model was pretrained with fold splits and distilled into a single student model for efficient variant scoring, enabling base‑pair resolution outputs and splice junction prediction alongside splice site usage and RNA‑seq coverage. Quantitatively, AlphaGenome outperformed or matched external models on 22 of 24 genome track tasks and on 25 of 26 variant effect benchmarks, improving eQTL sign prediction and QTL effect correlations. The multimodal outputs enable mechanistic interpretation of variants, for example recapitulating oncogenic TAL1 enhancer mutations and identifying splice‑disrupting variants. Conclusion: AlphaGenome provides a unified 1‑Mb multimodal, base‑resolution sequence model that substantially improves genome track and regulatory variant effect prediction and enables mechanistic, cross‑modality interpretation. Music: Enjoy the music based on this article at the end of the episode. Reference: Avsec, Ž. et al. Advancing regulatory variant effect prediction with AlphaGenome. Nature 649, 1206–1218 (2026). https://doi.org/10.1038/s41586-025-10014-0 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/alphagenome-regulatory-variant-prediction

Sierant MC et al., PNAS - MIPseq and exome sequencing of 11,555 human congenital heart disease probands implicate 60 dominant CHD genes, with NOTCH1 cysteine‑altering and transmitted MYH6 missense variants driving distinct defects. Study Highlights: We analyzed 11,555 human CHD probands from PCGC and PHN using a 248‑gene MIPseq panel and whole‑exome sequencing. A meta‑analysis of de novo and very rare transmitted/unphased damaging variants identified 60 genes with significant burden, accounting for damaging variants in 10.1% of probands with similar DNM and transmitted contributions. Mechanistically, NOTCH1 missense mutations that introduce or remove cysteines in EGF domains were highly enriched in tetralogy of Fallot and conotruncal defects, while transmitted damaging MYH6 missense variants were overtransmitted and contributed to multiple CHD subtypes. Genes with cardiomyocyte‑restricted expression correlated with isolated CHD, whereas broadly brain‑expressed genes correlated with neurodevelopmental delay, supporting genotype‑informed risk assessment. Conclusion: Targeted genomic analysis of 11,555 CHD probands identifies 60 dominant genes accounting for 10.1% of cases and supports molecular diagnosis to stratify cardiac and neurodevelopmental risk. Music: Enjoy the music based on this article at the end of the episode. Reference: Sierant MC, Jin SC, Bilguvar K, Morton SU, López-Giráldez F, Knight JR, Zhao H, Deanfield J, Giardini A, Mital S, Shend Y, Bernstein D, Yost HJ, Lifton RP, Brueckner M, et al. Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2420343122. https://doi.org/10.1073/pnas.2420343122 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/notch1-myh6-chd-genes Chapters (00:00:20) - Deadly heart defect: The genetics of congenital heart disease(00:03:05) - How 60 genes explain the cause of heart defect(00:07:03) - Heart defects and neurodevelopmental delay(00:10:24) - These are the hidden syndromes(00:14:21) - Dazzling Sound

Chandler LC et al., PNAS - AAV-mediated RPE expression of MCT2 in rat and mouse retinitis pigmentosa models increases RPE lactate uptake and prolongs cone photoreceptor survival and function. Study Highlights: Neonatal subretinal AAV8.Best1.MCT2 delivery was tested in multiple RP models (S334ter rats, FVB and P23H mice) and produced a statistically significant increase in surviving cones and transient preservation of optomotor visual acuity. The study combined AAV gene delivery with two-photon fluorescence lifetime imaging microscopy (FLIM) using LiLac and GlucoSnFR-TS biosensors to measure lactate and glucose in RPE tissue. MCT2 localized to apical and basolateral RPE membranes, MCT2-expressing RPE showed higher intracellular lactate and greater glucose accumulation consistent with increased lactate uptake and reduced glycolysis. These metabolic changes correlated with functional cone preservation across distinct genetic causes of RP, supporting a gene-agnostic metabolic rescue strategy. Conclusion: AAV-mediated, RPE-specific expression of MCT2 enhances lactate uptake into the RPE, shifts RPE metabolism toward higher intracellular lactate and glucose, and prolongs cone survival with transient preservation of cone-mediated function in multiple RP models. Music: Enjoy the music based on this article at the end of the episode. Reference: Chandler LC, Gardner A, Cepko CL. RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2421978122. https://doi.org/10.1073/pnas.2421978122 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/rpe-mct2-cone-survival Chapters (00:00:00) - Blending Genomics Into Your Life(00:00:28) - The starvation of RPE(00:02:48) - New science in retinal degeneration(00:03:56) - Gene therapy to save the retina(00:08:04) - Pigmented eyes to help sight?(00:10:25) - Genetics fixes blindness in mice(00:13:47) - A New way to save the brain(00:14:36) - Open the Gate, Let the Sugar Run

Gori K et al., PNAS - In canine transmissible venereal tumor (CTVT), deep sequencing and cytogenetics identify a 15‑Mb horizontally transferred nuclear element (N-HT1) acquired ~2,000 years ago that is transcriptionally active. Study Highlights: The authors screened 174 transmissible tumor genomes, focusing on CTVT, DFT1, and DFT2, using deep short-read sequencing, long-read PacBio sequencing, structural variant analysis, and metaphase FISH. In CTVT-A they discovered a 15-Mb dicentric element (N-HT1) assembled from 11 fragments of six chromosomes that forms the short arm of a small submetacentric chromosome after centromeric fusion. Mutation density and CpG-based dating place N-HT1 acquisition about 2,000 years ago, and transcriptome allele deconvolution shows N-HT1 is transcriptionally active and adopts the CTVT expression profile. Functional interrogation found no clear oncogenic drivers on N-HT1, with at least one rescued gene (ARFGEF3) later inactivated, consistent with the element behaving as a likely neutral passenger. Conclusion: A single host-to-tumor nuclear horizontal transfer event was detected in sampled transmissible cancers: CTVT-A acquired a 15-Mb N-HT1 element that is transcriptionally active but shows no clear evidence of positive selection. Music: Enjoy the music based on this article at the end of the episode. Reference: Gori K., Baez-Ortega A., Strakova A., Stammnitz M.R., Wang J., Chan J., Hughes K., et al. Horizontal transfer of nuclear DNA in transmissible cancer. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2424634122. https://doi.org/10.1073/pnas.2424634122 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/ctvt-n-ht1-horizontal-transfer Chapters (00:00:00) - Blast by Bass(00:00:29) - Cancer Has Stealing DNA From Your Body(00:02:41) - Horizontal Transfer of nuclear DNA in transmissible cancer(00:07:24) - The ghost of a dog's genome(00:11:55) - Transmissible DNA in human cancer(00:14:08) - Step, Step, Close Hold

Ju X-C et al., PNAS - Human-specific ADSL A429V substitution and a common regulatory haplotype reduce ADSL activity and raise purine substrates in the brain, altering mouse behavior. Study Highlights: Model: mice humanized for ADSL carrying the modern-human A429V (with R428Q) were compared to wild-type littermates using ultraperformance LC–Orbitrap metabolomics and automated IntelliCage behavioral assays. Mechanistic/quantitative result: SAICAr and S-Ado concentrations increased up to ~2-fold in liver and 1.8–5.4-fold across cerebrum regions, and these increases correlated negatively with Adsl mRNA expression across tissues. Human genetics: a 7.8-kb haplotype (including rs8135371) at >97% carrier frequency is associated with lower ADSL expression, higher S-Ado in cerebrospinal fluid, and signals of positive selection. Functional implication: female humanized mice accessed water more efficiently under restricted conditions, linking reduced ADSL activity to altered behavior. Conclusion: Two genetic changes on the modern human lineage—a nearly fixed A429V amino acid substitution and a common regulatory haplotype—have reduced ADSL activity and expression, increasing purine substrates particularly in the brain and producing measurable behavioral effects in mice. Music: Enjoy the music based on this article at the end of the episode. Reference: Ju X-C, Huttner W, Ågren R, Machado LC, Xing J, Lee S-Y, Siepel A, Azama C, Roy MC, Pääbo S, Endo T, Fukunaga I, Zeberg H. The activity and expression of adenylosuccinate lyase were reduced during modern human evolution, affecting brain and behavior. Proc. Natl. Acad. Sci. U.S.A. 2025.122:e2508540122. https://doi.org/10.1073/pnas.2508540122 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/adsl-a429v-purine-brain

Morris TT et al., PNAS - EA and cognition polygenic indexes (PGIs) in three British birth cohorts show EA PGI associations with years of education increased from 1946–1970 and were strongest in advantaged socioeconomic backgrounds. Study Highlights: Using three nationally representative British birth cohorts born 1946, 1958, and 1970, the authors analyzed polygenic indexes for educational attainment (EA) and cognition. They generated PGIs with clumping-and-thresholding (PRSice2) and LDpred2, used multiple imputation and inverse probability weighting, and estimated linear models including cohort-by-PGI interactions. EA PGI associations increased from approximately 0.44 to 0.67 years of education per 1-SD and incremental R2 rose from 3.5% to 5.1% across cohorts, while cognition PGI associations were broadly stable. There was strong evidence of gene–environment interaction: returns to EA genetic liability were disproportionately larger among those born into more advantaged socioeconomic backgrounds. Conclusion: Across three British birth cohorts born 1946–1970, genetic liability indexed by an EA PGI became more predictive of years of completed education while cognition PGI prediction remained stable, and EA PGI effects were amplified in advantaged socioeconomic contexts. Music: Enjoy the music based on this article at the end of the episode. Reference: Morris TT, Wright L, Shireby G, Bann D. Genetic associations with education have increased and are patterned by socioeconomic context: Evidence from 3 studies born 1946–1970. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2516460123. https://doi.org/10.1073/pnas.2516460123 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/ea-pgi-cohort-socioeconomic-interaction Chapters (00:00:00) - Genetics and the socioeconomic gap(00:04:36) - The genetic link between school and success(00:07:42) - Genetics and educational success(00:11:42) - The Wealthy Kids and the Poor(00:12:56) - The genetics of intelligence and personality(00:15:38) - Open Access: Science Podcast(00:16:31) - Inheritance

Spakmana D et al., H., Hickson I. D., Peterman E. J. G., Wuite G. J. L., King G. A. Mechanistic basis for relaxation of DNA supercoils by human topoisomerase IIIα–RMI1–RMI2. Proc. Natl. Acad. Sci. U.S.A - Optical tweezers and fluorescence imaging show human Topoisomerase IIIα–RMI1–RMI2 (TRR) processively relaxes highly negatively supercoiled DNA faster than PICH loops. Study Highlights: Using torsionally constrained end-closed λ-DNA in a multichannel flow cell, the authors combined Optical DNA Supercoiling (ODS), dual-trap optical tweezers, and fluorescence imaging to measure supercoiling density and visualize TRR binding in real time. They find TRR relaxes hyper-negatively supercoiled DNA in a highly processive manner, with single TRR complexes performing thousands (>3,000) of strand-passage reactions and exhibiting a force-dependent rate described by an Arrhenius relation (δ ≈ 1.1–1.4 nm in ensemble and single-molecule fits). Ensemble TRR activity was ~10-fold lower than E. coli TopoI under the same conditions, while single- complex rates indicate a single TRR can relax PICH-generated negative loops within the reported loop lifetime. These results support a mechanistic role for TRR in relaxing PICH-generated negative supercoils that could facilitate ultrafine anaphase bridge resolution. Conclusion: Human topoisomerase IIIα–RMI1–RMI2 (TRR) relaxes highly negatively supercoiled DNA in a force-dependent, highly processive manner and can act within the lifetime of PICH-generated negative loops, supporting a role in ultrafine anaphase bridge resolution. Music: Enjoy the music based on this article at the end of the episode. Reference: Spakmana D., Biebricher A. S., Bizard A. H., Hickson I. D., Peterman E. J. G., Wuite G. J. L., King G. A. Mechanistic basis for relaxation of DNA supercoils by human topoisomerase IIIα–RMI1–RMI2. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2406949123. Published January 23, 2026. https://doi.org/10.1073/pnas.2406949123 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/trr-supercoil-relaxation-optical-tweezers Chapters (00:00:00) - The Great Divide: When will the bridge break?(00:02:41) - Deep Dive: The mechanism of DNA supercoils by human to(00:03:49) - The Hidden Story of DNA(00:08:02) - How fast does TRR work on DNA?(00:12:40) - Why TRR Stuck to the DNA(00:17:30) - Who is the bouncer of DNA?