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Cell. 2015 Jul 16;162(2):391-402. doi: 10.1016/j.cell.2015.06.037.

Natural Variation in Gene Expression Modulates the Severity of Mutant Phenotypes.

Author information

1
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.
2
Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
3
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.

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.

PMID:
26186192
DOI:
10.1016/j.cell.2015.06.037
[Indexed for MEDLINE]
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