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.

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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

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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.

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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

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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.

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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

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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.

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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

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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.

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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

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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.

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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

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Palacio T et al., PNAS - Reconstituted Saccharomyces cerevisiae mismatch repair shows the Mlh1–Pms1 endonuclease directly generates single-strand gaps to excise mispairs independent of Exo1 and Rad27.

Study Highlights:
We reconstituted Saccharomyces cerevisiae mismatch repair with purified Msh2–Msh6 or Msh2–Msh3, Mlh1–Pms1, PCNA, RFC, RPA, and DNA polymerases and analyzed products by restriction mapping, Mung Bean nuclease, electron microscopy, and APOBEC3A deamination. The Mlh1–Pms1 endonuclease, activated by RFC-loaded PCNA and Mn2+, generates strand-specific single-strand gaps on the preexisting nicked strand. Electron microscopy and deamination mapping revealed a broad distribution of gap sizes with a peak around 128 ± 17 nucleotides and most gaps under 500 nucleotides. These gaps can be filled by DNA Polε or low levels of DNA Polδ, providing an Exo1- and Rad27-independent route for mispair excision and explaining redundancy among excision pathways.

Conclusion:
Mlh1–Pms1 catalyzes strand-specific single-strand gap formation that mediates Exo1- and Rad27-independent mispair excision in reconstituted S. cerevisiae mismatch repair.

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Reference:
Palacio T, Calil FA, Bowen N, Griffith JD, Putnam CD, Kolodner RD. DNA mismatch repair mediated by Mlh1–Pms1 endonuclease-catalyzed mispair excision. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2528670122. https://doi.org/10.1073/pnas.2528670122

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Cail RC et al., PNAS - Recombinant human β-cardiac myosin M493I studied by optical trapping and stopped-flow kinetics disrupts the super-relaxed state and increases actin attachment and contractile force.

Study Highlights:
System: recombinant human β-cardiac heavy meromyosin (cHMM) expressed in C2C12 cells. Methods: ensemble actin gliding, stopped-flow kinetics, NADH ATPase, mantATP single-turnover, and single-molecule three-bead optical trap assays. Main results: M493I preserves Pi release and the two-step 4.7–5 nm working stroke but slows ADP release ~5-fold, doubles steady-state ATPase Vmax, reduces SRX occupancy (KSRX/DRX from ~0.33 to ~0.53), and prolongs actin attachment with increased high-force, long-duration interactions. Functional implication: the combined increase in DRX head availability and prolonged AM·ADP lifetimes produce higher sustained force and faster actin reattachment consistent with a mechanism for HCM hypercontractility and impaired relaxation.

Conclusion:
The M493I relay-helix mutation disrupts the SRX off state and, together with slowed ADP release and prolonged actin attachment, increases myosin head availability and force production, explaining its hypercontractile HCM phenotype.

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Reference:
Cail RC, Barua B, Báez-Cruz FA, Winkelmann DA, Goldman YE, Ostap EM. A myosin hypertrophic cardiomyopathy mutation disrupts the super- relaxed state and boosts contractility by enhanced actin attachment. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2521561122. https://doi.org/10.1073/pnas.2521561122

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Englander SW et al., PNAS - Hydrogen exchange (H-T and NMR H-H) on DNA and RNA reveals two distinct base-pair opening modes: single-base microsecond openings and multi-base millisecond soliton-like loops.

Study Highlights:
Systems studied include long polynucleotides (DNA, duplex RNA, synthetic long duplexes) and short oligonucleotides; key methods are H-T (tritium) exchange, stopped-flow H-D, and NMR H-H (water relaxation) measurements. H-T exchange of long polymers reports opening-limited EX1 imino exchange with kop ~1/s, reclosing kcl ~20/s and Kop ~10^-2 consistent with multi-base open loops with ms lifetimes. NMR H-H on short oligos reports catalyzable EX2 behavior dominated by single base-pair openings with kcl ~10^6/s and Kop ~10^-6 and microsecond lifetimes. The selective detection implies short oligonucleotides cannot host extensive loops while multi-base soliton-like loops in polynucleotides could dynamically expose sequences for protein or nucleic acid recognition.

Conclusion:
Both H-T and NMR H-H exchange provide accurate but complementary views: long polynucleotides exhibit frequent multi-base, ms-lived open loops (Kop ~10^-2, kcl ~20/s) while short oligonucleotides reveal rare single-base, μs-lived openings (Kop ~10^-6, kcl ~10^6/s).

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Reference:
Englander SW. Nucleic acid base pair open states by hydrogen exchange. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2520855122. https://doi.org/10.1073/pnas.2520855122

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Vatsa A et al., PNAS - In HPV31-positive keratinocytes (CIN612), TOP1α and TOP3β are upregulated and required for viral transcription and replication, acting via distinct effects on R-loop accumulation and topoisomerase-mediated DNA breaks.

Study Highlights:
Using HPV31-positive CIN612 cells and primary HFK controls, the authors applied ChIP, RADAR, DRIP, alkaline COMET, RNA-seq, and shRNA knockdown to map topoisomerase binding and function. They found TOP1α and TOP3β, but not TOP3α, are elevated in HPV-positive cells and bind the viral URR, and that shRNA depletion of TOP1α or TOP3β reduced episomal viral DNA and early viral transcripts. Knockdown decreased DNA breaks (~50% reduction in COMET tail formation and reduced γH2AX) and altered R-loop levels differentially, with TOP1α depletion increasing viral R-loops by ~50% and TOP3β depletion causing >3-fold R-loop accumulation at viral and cellular loci. Transcriptome changes included reduced IL6/STAT3-AKT signaling after TOP1α loss and marked downregulation of EGR3 (>5-fold) after TOP3β loss, linking distinct mechanistic effects to impaired viral replication.

Conclusion:
TOP1α and TOP3β are differentially required for maintenance of HPV episomes and viral gene expression through distinct regulation of DNA breaks, R-loop dynamics, and specific host signaling pathways.

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Reference:
Vatsa A, Templeton CW, Laimins L. Differential roles of type I topoisomerases in regulating HPV pathogenesis. Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2526296123. https://doi.org/10.1073/pnas.2526296123

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