Myers, M. A.; Satas, G.; Shah, S.; Mcpherson, A.

Correctly inferring copy-number aberrations from single-cell DNA sequencing data requires estimating cell DNA content, which is unidentifiable from read counts alone. In tagmentation-based sequencing, sequence fragments are distinct DNA molecules, thus overlap counts are directly linked to copy number. We present a theoretical model of fragment overlaps as a function of copy number and coverage and introduce scPlOver, a method that uses this model to infer DNA content. scPlOver outperforms existing methods on simulated and experimental data and identifies thousands of ovarian cancer cells with higher DNA content than previously estimated across a cohort of 41 patients.