simPIC: flexible simulation of single-cell ATAC-seq paired-insertion counts from individuals to populations

Abstract

Single-cell Assay for Transposase Accessible Chromatin (scATAC-seq) is increasingly used at population scale to study how genetic variation shapes chromatin accessibility. Method development is limited by the lack of flexible simulation tools with known ground truth. Here, we present simPIC, a fast, memoryefficient framework for simulating realistic single-cell ATAC-seq count data across individuals and populations. simPIC models cell groups, batch effects, and genotype-dependent accessibility variation, enabling controlled evaluation of population-scale methods, including chromatin accessibility quantitative traits locus (QTL) mapping. Across multiple datasets and cell types, simPIC closely matches real data distributions while scaling to cohort sizes impractical for current tools.