CRISPR screens of population relevant genes governing toxicant resilience

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People vary considerably in their response to and in the effects of exposure to chemical toxicants and biological toxins. As a result, the risk of adverse outcomes associated with exposure for different individuals and populations can be widely divergent. Gene by environment (G x E) interactions likely underlie a significant component of these risk differences. However, we remain largely ignorant of both the key genetic factors and the mechanistic association with specific toxins/toxicants. As a result, our capability to mitigate risk by the identification of susceptible individuals and populations to enable effective preventive efforts remain sorely limited. Current approaches to identify G x E interactions rely on genetic association studies which generally lack sufficient power to identify significant associations, due to the large number of genetic variants and small populations of exposed individuals. We propose, in a fundamentally different approach, to first systematically identify the common human variants which impact the functional response to a specific toxicant/toxin to delineate key candidate G X E interactions for targeted consideration in relevant individuals and populations. We will focus on functional interrogation of 1490 genes, the ToxVar set, which contain an aggregate frequency of loss of function mutations of >0.1% in all human populations assessed to date and previously identified as interacting with one or more toxicant/toxins. We contend that these commonly functionally compromised genes are most likely to impact human response to a toxin/toxicant in a significant proportion of people. We will simultaneously query the impact of functional disruption in each of these 1490 genes on the cellular response to a toxicant using coupled CRISPR screening and single cell toxicologically relevant gene expression targets (scTRGETs). We will evaluate the ToxVar-scTRGET approach to identify functionally relevant and commonly variant genes involved in cellular response to selected toxicants of high human relevance in increasingly physiologically relevant cell models.