Define protein variant functions with high-complexity mutagenesis libraries and enhanced mutation detection software ASMv1.0
Yang, X.; Hong, A. L.; Sharpe, T.; Giacomelli, A. O.; Lintner, R. E.; Alan, D.; Green, T.; Hayes, T. K.; Piccioni, F.; Fritchman, B.; Kawabe, H.; Sawyer, E.; Sprenkle, L.; Lee, B. P.; Persky, N. S.; Brown, A.; Greulich, H.; Aguirre, A. J.; Meyerson, M.; Hahn, W. C.; Johannessen, C. M.; Root, D. E.
Show abstract
Pooled variant expression libraries can test the phenotypes of thousands of variants of a gene in a single multiplexed experiment. In a library encoding all single-amino-acid substitutions of a protein, each variant differs from its reference only at a single codon-position located anywhere along the coding sequence. Consequently, accurately identifying these variants by sequencing is a major technical challenge. A popular but expensive brute-force approach is to divide the pool of variants into multiple smaller sub-libraries that each contains variants of a small region and that must each be constructed and screened individually, but that can then be PCR-amplified and fully sequenced with a single read to allow direct readout of variant abundance. Here we present an approach to screen very large variant libraries with mutations spanning a wide region in a single pool, including library design criteria and mutant-detection algorithms that permit reliable calling and counting of variants from large-scale sequencing data.
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