Deep genetics to study and uncover ‘hidden’ biology

Introduction

Human genes are organized in complex networks to produce thousands of proteins that perform a myriad of functions. Whereas we have detailed maps for most biochemical pathways, the wiring of genetic networks in human cells is poorly understood.

Development of Genetic Tools

The development of powerful human genetic tools such as CRISPR, RNAi, and haploid cells, to which I made crucial contributions, has proven invaluable for studying genetic networks. However, these tools face two major limitations:

1. They provide information at the gene level, whereas it would be much more informative to understand genetic regulation at the level of protein domains or individual amino acids.
2. Important biology can be masked, for example, by the cell state or the interfering activity of other genes.

Objectives of DeepGenetics

With DeepGenetics, we aim to bring our understanding of the genetic regulation of cellular phenotypes to the next level and mine ‘hidden biology’ that even impacts well-studied cellular traits. Our specific objectives include:

1. Counterbalancing the use of loss-of-function and gain-of-function genetics to obtain a solid gene-level inventory on the regulation of cellular phenotypes.
2. Identifying genes that ‘mask’ unknown biology and using modifier screens to expose and define these processes, as we have recently exemplified in my group, leading to the discovery of important new cellular pathways.
3. Connecting phenotypes to the functional protein domains and ultimately to the amino acid level.

Conclusion

Thus, DeepGenetics will provide precise views on the regulation of key cellular phenotypes at the amino acid level and will cross the boundaries of our knowledge by exposing ‘hidden biology’.