Expanding the Atlas of Functional Missense Variation for Human Genes
By
Jochen Weile,
Song Sun,
Atina G. Cote,
Jennifer Knapp,
Marta Verby,
Joseph Mellor,
Yingzhou Wu,
Carles Pons,
Cassandra Wong,
Natascha van Lieshout,
Fan Yang,
Murat Tasan,
Guihong Tan,
Shan Yang,
Douglas M. Fowler,
Robert Nussbaum,
Jesse Bloom,
Marc Vidal,
David E. Hill,
Patrick Aloy,
Frederick P. Roth
Posted 27 Jul 2017
bioRxiv DOI: 10.1101/166595
(published DOI: 10.15252/msb.20177908)
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.
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