This is a preprint Journal Club review of Memory sequencing reveals heritable single cell gene expression programs associated with distinct cellular behaviors by Sydney M Shaffer, Benjamin L Emert, Ann E. Sizemore, Rohit Gupte, Eduardo Torre, Danielle S Bassett, and Arjun Raj. The preprint was originally posted on July 27, 2018 (DOI: https://doi.org/10.1101/379016). Dear authors,Thank you for posting your work as a preprint on BioRxiv. We discussed your work at our latest quantitative and systems biology journal club at UCLA. Below is a summary of our feedback containing our main remarks, points of discussion, and suggestions.This study aimed to identify genes and groups of genes that exhibit memory persisting over multiple cell divisions. The authors hypothesized that any such genes would manifest phenotypically as rare cell subsets within a seemingly homogeneous population. To test their hypothesis, they developed a clever new method, termed MemorySeq, which adapts the classic Luria-Delbrück fluctuation experiment to examine gene expression at the genome scale. In this experiment, a clonal population of cells was passed through a bottleneck and gene expression was quantified by RNA sequencing. Genes that exhibited high inter-clonal expression variability were identified as exhibiting multi-generational memory. MemorySeq also allowed them to identify genes that conferred drug resistance, confirming that heritable expression can create specialized cell subsets. In general, the methods were innovative and well-suited to analyze gene expression heritability at the systems scale. The paper was very clearly written and the figures were, for the most part, well-presented. Our comments are outlined below.