The Genomic Landscape of Position Effects on Protein Expression Level and Noise in Yeast

Abstract

SUMMARY Position effect, the influence of the chromosomal location of a gene on its activity, is a fundamental property of the genome. By placing a green florescent protein gene cassette at 482 different locations across all chromosomes in budding yeast, we quantified the position effects on protein expression level and noise at the genomic scale. The position effects are significant, altering the mean protein expression level by up to 15 times and expression noise by up to 20 times. DNA replication timing, three-dimensional chromosomal conformation, and several histone modifications are major covariates of position effects. Essential genes are enriched in genomic regions with inherently low expression noise, supporting the hypothesis that chromosomal clustering of essential genes results from selection against their expressional stochasticity. Position effects exhibit significant interactions with promoters. Together, our results suggest that position effects have shaped the evolution of chromosome organization and should inform future genome engineering efforts.

Chromosome-wide co-fluctuation of stochastic gene expression in mammalian cells

“…4D). Hence, the previous finding that genes encoding members of (usually not the same) protein complexes tend to be clustered is best explained by the fact that certain chromosomal regions have inherently low expression noise and that these regions attract genes encoding protein complex members because stochastic expressions of these genes are especially harmful (i.e., the noise reduction hypothesis) [4,63].…”

Pervasive coexpression of spatially proximal genes is buffered at the protein level

“…Indeed, such a "ripple effect" of transcriptional activation has been observed in yeast and humans (Ebisuya et al, 2008). The noise and expression levels of transgenes also vary with their insertion site, as a result of both domain-wide effects and interference with individual neighbouring genes (Gierman et al, 2007;Chen & Zhang, 2016). Transgenes can also affect the mRNA expression levels of endogenous genes located close to the insertion site (Akhtar et al, 2013).…”

High-throughput creation and functional profiling of eukaryotic DNA sequence variant libraries using CRISPR/Cas9

“…This enables the creation of specific user-defined loss-of-function, gain-of-function, and altered regulation mutants en masse. More importantly, by editing the locus within its native context without the need for exogenous marker genes, we avoid artifacts from using surrogate reporter systems and false positive and negative results due to selection marker-driven positional effects 27 . Furthermore, the fact that our system is highly efficient allows users to simply read the guide+donor sequence present within the plasmid delivered to each cell and, by doing so, identify the cell's genotype.…”