Single nucleotide variants in transcription factors associate more tightly with phenotype than with gene expression.

Priya Sudarsanam,Barak A Cohen

doi:10.1371/journal.pgen.1004325

Abstract

Mapping the polymorphisms responsible for variation in gene expression, known as Expression Quantitative Trait Loci (eQTL), is a common strategy for investigating the molecular basis of disease. Despite numerous eQTL studies, the relationship between the explanatory power of variants on gene expression versus their power to explain ultimate phenotypes remains to be clarified. We addressed this question using four naturally occurring Quantitative Trait Nucleotides (QTN) in three transcription factors that affect sporulation efficiency in wild strains of the yeast, Saccharomyces cerevisiae. We compared the ability of these QTN to explain the variation in both gene expression and sporulation efficiency. We find that the amount of gene expression variation explained by the sporulation QTN is not predictive of the amount of phenotypic variation explained. The QTN are responsible for 98% of the phenotypic variation in our strains but the median gene expression variation explained is only 49%. The alleles that are responsible for most of the variation in sporulation efficiency do not explain most of the variation in gene expression. The balance between the main effects and gene-gene interactions on gene expression variation is not the same as on sporulation efficiency. Finally, we show that nucleotide variants in the same transcription factor explain the expression variation of different sets of target genes depending on whether the variant alters the level or activity of the transcription factor. Our results suggest that a subset of gene expression changes may be more predictive of ultimate phenotypes than the number of genes affected or the total fraction of variation in gene expression variation explained by causative variants, and that the downstream phenotype is buffered against variation in the gene expression network.

Highlights

Mapping the loci that control quantitative variation is a crucial step towards understanding complex disease [1,2,3]
We find that the amount of variation in gene expression explained by the variants does not correlate with the amount of variation observed in spore formation, which has implications for studies that attempt to infer the effect of a polymorphism on phenotypic variation by studying its effect on gene expression variation
Our analysis reveals that 1) the amount of variation in gene expression explained by a polymorphism is not always correlated with the amount of phenotypic variation explained by that same polymorphism, 2) genetic interactions between variants are responsible for a larger proportion of gene expression variability than phenotypic variability, and 3) that alleles that change either the level or activity of a transcription factor affect expression variation of the same genes to different extents

Summary

Introduction

Mapping the loci that control quantitative variation is a crucial step towards understanding complex disease [1,2,3]. Finding eQTL is a widely accepted strategy for identifying new variants that potentially affect phenotype [15], for screening GWAS alleles to find those that affect disease risk by altering transcription [16], and for uncovering the molecular pathways underlying disease [17]. These studies make a distinction between cis-eQTL (genetic variants that affect the expression of physically linked genes) and trans-eQTL (variants that are physically unlinked from their target gene) [18]. It remains extremely difficult to identify the precise nucleotide variant/s responsible for the changes in gene expression or phenotype, even in model organisms

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Conclusion