Predicting deleterious amino acid substitutions.
Many missense substitutions are identified in single nucleotide polymorphism (SNP) data and large-scale random mutagenesis projects. Each amino acid substitution potentially affects protein function. We have constructed a tool that uses sequence homology to predict whether a substitution affects protein function. SIFT, which sorts intolerant from tolerant substitutions, classifies substitutions as tolerated or deleterious. A higher proportion of substitutions predicted to be deleterious by SIFT gives an affected phenotype than substitutions predicted to be deleterious by substitution scoring matrices in three test cases. Using SIFT before mutagenesis studies could reduce the number of functional assays required and yield a higher proportion of affected phenotypes. may be used to identify plausible disease candidates among the SNPs that cause missense substitutions.
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Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Henikoff
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D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D001426:Bacterial Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D017122:Bacteriophage T4 / Q000201:enzymology / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D017124:Conserved Sequence; D029968:Escherichia coli Proteins; D030342:Genetic Diseases, Inborn / Q000235:genetics; D016333:HIV Protease / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics; D006801:Humans; D056968:Lac Repressors; D007785:Lactose / Q000037:antagonists & inhibitors; D008969:Molecular Sequence Data; D009113:Muramidase; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D011336:Probability; D012097:Repressor Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D012984:Software
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D012097:Repressor Proteins; D009113:Muramidase; D016333:HIV Protease; D007785:Lactose