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Haploid Human Cells as Genetic Tool to Identify Genes important for Human Disease Genetics can provide a powerful window on the components that play a role in complex biological processes. However, human lines are refractory to efficient mutagenesis-based genetics due to the diploid nature of their genome. Therefore it remains challenging to apply powerful genetic approaches that were successful in genetic model organisms such as yeast to human cells. Our group recently developed an entirely novel genetic model system based on insertional mutagenesis in haploid human cells. We have shown that this enables the generation of knockouts for most human genes and can be used to pinpoint genes that are involved in phenotypes of interest. Combined with deep sequencing, this yields high-density genetic overviews of genes required for nearly any selectable cell trait. In a variety of genetic screens we have identified host factors required for infection of cells by influenza virus, the first entry receptor for a Clostridium difficile toxin and the cholesterol transporter NPC1 as the long-sought intracellular receptor for Ebola virus. We foresee that yeast-like genetics in haploid human cells can be used to link genes to numerous phenotypes beyond infectious disease.