Hasty leads a team of researchers at UCSD that will report in a Dec. 21 advanced online publication by Nature a mathematical description of “extrinsic noise,” an even larger component of variation in gene expression. This second type of noise results because no two genetically identical cells can keep the same time. The measurement of extrinsic noise was based on experiments involving baker's yeast, Saccharomyces cerevisiae, but the phenomenon and the way it is described mathematically would apply to other types of cells and other species.
Intrinsic noise resulting from low copy numbers of molecules has been the focus of earlier studies by Hasty’s group. Its Nature paper focuses on extrinsic noise, an even larger source of variation between identical cells growing side-by-side in identical conditions. “This extrinsic noise originates from cells being out of phase in their growth cycle,” said Hasty. “It’s unavoidable. This study also established an ‘extrinsic-noise floor’ in 11 genes for which intrinsic noise is negligible.”
The group measured the noise floor by used genetically engineered strains of yeast with a green fluorescence marker linked to a gene involved in the metabolism of the sugar galactose. The galactose gene and 10 others were chosen because they are expressed in yeast cells in high copy numbers, a feature that makes intrinsic noise in their expression statistically insignificant. By making cell-to-cell comparisons of the activation of the galactose-fluorescence gene pair in experiments with one to five copies of the gene pair per cell, the team was able to measure the extrinsic-noise floor, a parameter that is needed to create a mathematical algorithm describing gene-expression variation in yeast.
“This may sound relatively straightforward: extrinsic variability is due to individual cells growing out of phase with one another,” said Hasty. “However, this study is the first rigorous description of this variability, which will be very helpful to researchers eager to account for variations in gene expression as they build rigorous, comprehensive models of this and other types of cells.”"
Dimitri Volfson, Jennifer Marciniak, William J. Blake, Natalie Ostroff, Lev S. Tsimring, and Jeff Hasty, "Origins of extrinsic variability in eukaryotic gene expression" (2005). Nature. doi: 10.1038/nature04281.