Naturally occurring human genetic variants provide “experiments of nature” that can directly inform on the function of human genes. In addition to providing novel insight into human biology, they can aid in the identification and validation of genes that would be powerful and well-tolerated targets for therapeutic inhibition in both rare and common diseases.
The Broad's Human Knockout Project is a series of pilot experiments designed to provide proof-of-concept for the use of a specific kind of genetic variation — variants predicted to cause the complete disruption of protein-coding genes, termed loss-of-function (LoF) variants — to identify “human knockouts” who completely lack the functional expression of genes of interest. The effort aims to:
- Develop the first comprehensive catalog of human LoF variants.
- Leverage both previously generated and new functional genomic data to validate an important subset of these variants.
- Perform genotype-based recall and deep phenotyping of knockout humans.