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We propose a peak calling algorithm, Weighted Analysis of ChIP-seq (WACS), which is an extension of the well-known peak caller MACS2. There are two main steps in WACS First, weights are estimated for each control using non-negative least squares regression. The goal is to customize controls to model the noise distribution for each ChIP-seq experiment. This is then followed by peak calling. We demonstrate that WACS significantly outperforms MACS2 and AIControl, another recent algorithm for generating smart controls, in the detection of enriched regions along