What are positive and negative CRISPR library screens?

In simple terms, positive screens are used to determine genes that accumulate in a population because of a treatment and negative screens determine genes that are lost from the population.
Positive screens identify genes that are sensitive to the selection mechanism, such that when these genes are knocked out, the cells survive the selection. In this type of a screen, most cells are lost and only cells that contain sgRNAs knocking out genes which make the cell sensitive to the selection agent will survive. The expected result is that the remaining cells will be enriched for these sgRNAs. In these types of screens, it is essential to culture the cells long enough to allow for the loss of the edited targets and manifestation of the resulting phenotype before sequencing. In our experience, ten days to two weeks is generally sufficient. Because these types of screens can be rather robust, a typical recommended NGS read depth is ~1 x 10⁷ reads.
Negative screens identify genes that are essential for survival under the selective pressure provided by the screening conditions. Cells expressing sgRNAs that trigger null or loss-of-function edits in these genes will be lost from the population upon application of screening conditions, such that the cells expressing other sgRNAs are overrepresented. These types of screens are often more challenging, as most cells survive the screen, and parameters need to be tightly controlled to ensure that statistically significant changes can be detected. For the detection of subtle changes in sgRNA representation in these negative screens, NGS analysis may require read depths of up to ~1 x 10⁸ reads.

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