Researchers from the UvA and Israel have discovered a mechanism that cells can use to reduce the ‘background noise’ generated by important genes. By effecting a few simple DNA mutations, they were able to show that a gene can be activated using a little – or a lot – of ‘noise’. The results have been published in the leading online journal PLoS Biology.
Their discovery has implications for our understanding of not only what makes cells function efficiently in a highly variable environment but also how known genes can be optimised or designed – for therapeutic treatments – to be impervious to noise and, therefore, more robust (able to function in a highly variable and unpredictable environment).
Cells that are genetically identical to each other nevertheless manifest major differences in their behaviour (phenotype). This can be likened to a kind of ‘background noise’, which is the inherent result of the random nature of all biochemical processes since it is nearly impossible for a cell to determine how much of any given protein it has. Yet, despite this uncertainty, cells are able to function with great efficiency. The researchers (David van Dijk, Peter Sloot and Jaap Kaandorp of the UvA, and Lucas Carey and Eran Segal of the Weizmann Institute of Science in Israel) wanted to know how they are able to do this.
The researchers discovered that while different genes were present in equal numbers, the extent to which they fluctuated from one cell to another varied immensely. During the study, they ensured that the individual genes only differed in terms of the DNA sequence which regulates activity. But then how it is that DNA sequence can modulate noise?
Using a computer model, the researchers simulated the specific biochemical processes that are responsible for translating DNA sequence into protein sequences. They discovered that the same quantity of a protein can be produced with much less background noise if production is switched ‘on’ and then ‘off’ again in quick succession. In addition, the simulations indicated that genes possess a mechanism for shielding themselves from noise in their environment – in other words, of ensuring stable protein production in a highly variable environment. This mechanism works through a process of activation and inhibition by a single molecule (i.e. instead of two different ones), where every random and uncontrolled activation effects an equal but opposite inhibition so that, in the end, no change results.
The simulations predicted that these mechanisms can be switched off by means of a few simple DNA mutations. Lab measurements confirmed this.
Lucas B. Carey, David van Dijk, Peter M. A. Sloot, Jaap A. Kaandorp, Eran Segal: Promoter Sequence Determines the Relationship between Expression Level and Noise. PLoS Biology (2 april 2013).