title: Natural Variation in Gene Expression Modulates the Severity of Mutant Phenotypes.
abstract: Many mutations cause genetic disorders. However, two people inheriting the same mutation often have different severity of symptoms, and this is partly genetic. The effects of genetic background on mutant phenotypes are poorly understood, but predicting them is critical for personalized medicine. To study this phenomenon comprehensively and systematically, we used RNAi to compare loss-of-function phenotypes for ∼1,400 genes in two isolates of C. elegans and find that ∼20% of genes differ in the severity of phenotypes in these two genetic backgrounds. Crucially, this effect of genetic background on the severity of both RNAi and mutant phenotypes can be predicted from variation in the expression levels of the affected gene. This is also true in mammalian cells, suggesting it is a general property of genetic networks. We suggest that differences in the manifestation of mutant phenotypes between individuals are largely the result of natural variation in gene expression.
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Victoria
authors.initials: V
authors.lastname: Vu
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Verster
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Schertzberg
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Tungalag
authors.initials: T
authors.lastname: Chuluunbaatar
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Spensley
authors.affiliation: Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Djina
authors.initials: D
authors.lastname: Pajkic
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: G Traver
authors.initials: GT
authors.lastname: Hart
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: andyfraser.utoronto@gmail.com.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Fraser
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000145:classification / Q000235:genetics*; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D009154:Mutation; D010641:Phenotype; D034622:RNA Interference