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Jae Lab - Research

Genome-wide Loss-of-Function Genetics

Virtually every form of human disease is shaped by the individual or concerted action of genes. Incredibly successful work in model organisms – most importantly in yeast – has paved the way to build genetic wiring diagrams of the eukaryotic cell (for a recent example see Costanzo et al., Science, 2016). However, strategies for comparable experiments in a human system have long been hindered by the diploid nature of the human genome, which buffers against individual genetic insults. With the advent of haploid mutagenesis in human cells (Carette et al., Science, 2009) and repurposing of CRISPR-Cas (Jinek et al., Science, 2012) we can finally embark on similar genetic expeditions in the human system.

Fitness assessment of mutants subjected to certain types of stress, such as infection with a pathogen, can help elucidate how these insults are processed by the cell (e.g. Jae et al., Science, 2013; 2014; Pillay et al., Nature, 2016Raaben et al., Cell Host Microbe, 2017). Mapping genetic interactions through knock-out genetics is a remarkably useful tool in the mechanistic dissection of complex cellular phenomena, but it can also aid the annotation of orphan genes and potentially reveal new strategies to therapeutically combat disease states (Blomen*, Májek*, Jae* et al., Science, 2015). Phenotypic profiling of ultra-complex mutant libraries using flow cytometry can readily point out the genetic wiring maps underlying signal transduction, organelle fidelity, and other cellular programs (Brockmann et al., Nature, 2017; Mezzadra*, Sun*, Jae* et al., Nature, 2017).

 

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Workflow and applications of haploid genome mutagenesis.