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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.