PT  - JOURNAL ARTICLE
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
TI  - Expanding the Atlas of Functional Missense Variation for Human Genes
AID  - 10.1101/166595
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 166595
4099  - http://biorxiv.org/content/early/2017/07/27/166595.short
4100  - http://biorxiv.org/content/early/2017/07/27/166595.full
AB  - 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.