TY - JOUR T1 - Expanding the Atlas of Functional Missense Variation for Human Genes JF - bioRxiv DO - 10.1101/166595 SP - 166595 AU - Jochen Weile AU - Song Sun AU - Atina G. Cote AU - Jennifer Knapp AU - Marta Verby AU - Joseph Mellor AU - Yingzhou Wu AU - Carles Pons AU - Cassandra Wong AU - Natascha van Lieshout AU - Fan Yang AU - Murat Tasan AU - Guihong Tan AU - Shan Yang AU - Douglas M Fowler AU - Robert Nussbaum AU - Jesse D. Bloom AU - Marc Vidal AU - David E Hill AU - Patrick Aloy AU - Frederick P. Roth Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/07/27/166595.abstract N2 - Although we now routinely sequence human genomes, we can confidently identify only a fraction of the sequence variants that have a functional impact. Here we developed a deep mutational scanning framework that produces exhaustive maps for human missense variants by combining random codon-mutagenesis and multiplexed functional variation assays with computational imputation and refinement. We applied this framework to four proteins corresponding to six human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calmodulin). The resulting maps recapitulate known protein features, and confidently identify pathogenic variation. Assays potentially amenable to deep mutational scanning are already available for 57% of human disease genes, suggesting that DMS could ultimately map functional variation for all human disease genes. ER -