Essel Arthur, K. | bioRxiv Science

bioRxiv2025

Ancestry-Aware Modeling of Dark Cyclobutane Pyrimidine Dimer Formation Integrating GTEx Skin Transcriptomes and Evolutionary Genomics

Ultraviolet (UV) radiation induces cyclobutane pyrimidine dimers (CPDs) in DNA, initiating mutagenic cascades that underlie photocarcinogenesis. Even hours after irradiation, dark-CPDs photoproducts generated via melanin-mediated chemiexcitation continue to form in melanocytes (4-6). While melanin confers photoprotection, its oxidative by-products can paradoxically extend DNA damage. Here we empirically validate an ancestry-aware computational framework coupling population pigmentation genetics with transcriptional regulation of DNA-repair pathways using Genotype-Tissue Expression (GTEx v9) skin RNA-seq data. We analyzed 604 GTEx donors from sun-exposed and non-exposed skin (lower leg, suprapubic) across inferred ancestry axes. Expression modules for melanin synthesis (TYR, TYRP1, SLC24A5, MC1R) and nucleotide-excision/oxidative-repair (XPC, DDB2, POLH, OGG1) were examined through differential expression, random-forest modeling, and 1,000-fold bootstrap uncertainty quantification. POLH and DDB2 were significantly upregulated in sun-exposed tissue (log2FC = 0.88 +/- 0.12 and 0.64 +/- 0.18; FDR < 0.05), whereas SLC24A5 and TYR displayed ancestry-linked gradients consistent with prior GWAS (8-10, 15, 16). Predictive modeling of a composite dark-CPD index achieved mean R^2 = 0.62 +/- 0.04 and RMSE = 0.21 +/- 0.03 (95 % CI), highlighting SLC24A5 (27 %) and XPC (19 %) as major contributors. These results empirically demonstrate co-regulation between pigmentation and repair pathways within realistic transcriptomic uncertainty bounds. Our integrative approach provides a reproducible, ancestry-aware platform for equitable dermatogenomic risk assessment and mechanistic insight into delayed UV mutagenesis.

genomics↗

bioRxiv2025

Targeted Enzymatic Fragmentation of Lipoprotein(a) via Kringle IV Domains: A Novel Therapeutic Approach for Cardiovascular Disease.

BackgroundElevated lipoprotein(a) [Lp(a)] is an independent, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD). Its unique apolipoprotein(a) [apo(a)] component contains variable Kringle IV (KIV) domain repeats that influence secretion, thrombosis, and atherogenesis. Current therapies antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) suppress hepatic production and achieve up to 80-98% Lp(a) reduction. However, mechanisms for enhancing clearance remain underexplored. ObjectiveWe propose a biologic approach to actively accelerate Lp(a) removal. Specifically, we design an antibody-drug conjugate (ADC) that binds conserved KIV9/10 domains and delivers a protease to fragment apo(a) into kidney-excretable fragments, complementing existing production inhibitors. MethodsThe therapeutic is designed as a monoclonal antibody directed at KIV9/10 fused via a cleavable linker to a site-specific protease (e.g., IdeS-like) engineered for conditional activity. Kringle domains were modeled with graph neural networks trained on plasminogen homologs to predict epitope accessibility and binding affinity. A one-compartment, first-order elimination model was used to illustrate potential clearance acceleration, with normal Lp(a) clearance modeled at rate constant k = 0.05 h-1 enhanced clearance at k = 0.10 h-1 CKD at k=0.03 h-1 and CKD+enhanced at k=0.06 h-1. ResultsSimulated concentration-time curves showed that doubling the clearance rate could shorten Lp(a) half-life from [~]13.9 to [~]6.9 h (normal vs. enhanced) and from [~]23.1 to [~]11.6 h (CKD vs. CKD+enhanced). Starting at 100 mg/dL, normal clearance reached [~]9.07 mg/dL by 48 h, while enhanced reached [~]0.82 mg/dL; CKD reached [~]23.69 mg/dL, restored to [~]5.61 mg/dL with enhancement. Acute 50-70% lowering was predicted within 24 h, potentially enabling infrequent dosing and synergy with production inhibitors. ConclusionsEnzymatic fragmentation of Lp(a) at KIV domains is a novel clearance-enhancing paradigm. By generating <100 kDa fragments suitable for renal excretion, this strategy could complement ASO/siRNA therapies, particularly in patients with residual high Lp(a) or impaired kidney function. Further work should validate protease specificity, safety, and in vivo efficacy in animal models before clinical translation.

biochemistry↗