Context-aware simulation enables systematic optimization of long-read mapping parameters

Long-read mapping performance is critical for downstream genomic analyses but remains sensitive to parameter selection. We present CycSim, a context-aware long-read simulator that learns sequence-context-dependent error profiles from empirical data and generates realistic simulated reads. CycSim more faithfully recapitulated real long-read characteristics than existing simulators, providing a high-fidelity simulation framework with known ground truth. Using this framework, we identified a Cyclone-specific parameter set that achieved 2.78-fold faster mapping than an ONT-oriented baseline while maintaining comparable variant-calling performance. For SV-oriented optimization, CycSim-guided refinement improved mapping efficiency by 8.14-34.16% across ONT, HiFi, and Cyclone HG002 datasets; increased SV F1 scores by 0.57-1.75 percentage points; and showed consistent improvements across independent benchmark datasets and different SV callers. Together, these results demonstrate the utility of CycSim for platform- and analysis-goal-specific algorithm development, benchmarking, and parameter optimization.