Differences in protein dosage underlie nongenetic differences in traits

Genes and environments do not entirely explain variation in biological traits. Discrete and complex traits manifest distinctly in isogenic organisms in homogenous environments. One cause of variation in traits is variation in the expression of genes. We do not understand how variation in gene expression arises among isogenic individuals, nor do we fully understand the consequences. Here, for the first time in a metazoan, we quantified sources of cell-to-cell variation in gene expression to understand how it arises in the cells of Caenorhabditis elegans . We adapted an experimental approach and analytical framework we used previously in Saccharomyces cerevisiae. We measured cell-to-cell variation in gene expression attributable to: 1) stochastic molecular events in transcription and translation (a.k.a. intrinsic noise) and/or allele access, 2) pathway-specific signaling noise, and 3) general differences in protein dosage resulting from global differences in protein production or turnover. Surprisingly, and in contrast with single celled organisms, in C. elegans cells, general differences in protein dosage constitute the major source of variation. Cells with high protein dosage came from animals with high protein dosage. These differences in protein dosage were consequential. Animals that made more reporter proteins had discrete traits consistent with higher dosage of unrelated neomycin resistance and Ras gain-of-function proteins, consistent with global variation in protein dosage. Our results suggest that the natural axis of protein dosage underlies nongenetic, nonenvironmental differences in complex and discrete traits, including penetrance and expressivity of hypomorphic and hypermorphic alleles. They also raise the possibility that differences in penetrance caused by differences in protein dosage might be responsible for some of the missing heritability in genome wide association studies.