Deep genetics to study and uncover ‘hidden’ biology

Human genes are organized in complex networks, to produce thousands of proteins to 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 powerful human genetic tools (CRISPR, RNAi, haploid cells), to which I made crucial contributions, have proven invaluable to study genetic networks. However, they face two major limitations.

First, they provide information at the gene level, whereas it will be much more informative to understand genetic regulation at the level of protein domains or individual amino acids.

Second, important biology can be masked – for example, by the cell state or interfering activity of other genes.With DeepGenetics we will bring our understanding of the genetic regulation of cellular phenotypes to the next level and mine ‘hidden biology’ that even impacts on well-studied cellular traits.

We will (i) counterbalance the use of loss-of-function and gain-of-function genetics to obtain a solid gene-level inventory on the regulation of cellular phenotypes; (ii) identify genes that ‘mask’ unknown biology and use 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, and (iii) connect phenotypes to the functional protein domains and ultimately to the amino acid level.

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’.