Extending the Atlas of Variant Effects in Human Disease Genes

Although we now routinely sequence human genomes, we cannot yet confidently identify functional variants. Here a deep mutational scanning framework is developed that combines random codon-mutagenesis and multiplexed functional variation assays with computational imputation and regularization to yield exhaustive functional maps for human missense variants. The framework is applied to five proteins corresponding to seven human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), NCS1 (neuronal calcium sensor 1), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calmodulin). The resulting functional impact scores correspond to known protein features, and serve to confidently identify pathogenic variation.Ph.D