The clickable genome: click on any gene and generate a function-phenotype map (i.e., genetic dose-response curve)
[I am an employee of Bristol-Myers Squibb. The views expressed here are my own.]
One of my predictions for the next decade – the “clear view” decade – is that we will have the ability to click on any gene in the human genome to generate function-phenotype maps. These maps should enable drug discovery by informing on mechanism, magnitude and markers of target perturbation. In particular, I have championed an “allelic series” model, whereby genes with a series of alleles are used to derived genetic dose-response curves (see here, here).
During a recent presentation to my former colleagues at the Division of Genetics at Brigham & Women’s Hospital (BHW, slides here), I discussed important assumptions underlying this model:
- Large-scale sequence data will identify a range of protein-coding variants associated with traits of medical interest that are suitable surrogates for drug discovery (allelic series architecture assumption).
- It will be possible to use high-throughput functional assays to interrogate the impact of trait-associated variants on cell physiology for the majority of genes in the genome (functional readout assumption).
- Large-scale biobanks will emerge to enable testing of these same trait-associated variants for pleiotropic effects across a wide-variety of clinical phenotypes in the real world (PheWAS assumption).