Characteristics of Transcriptional Activity in Nonlinear Dynamics of Genetic Regulatory Networks

Simon Rosenfeld

doi:10.4137/grsb.s3119

Abstract

Microarray measurements of mRNA abundances is a standard tool for evaluation of transcriptional activity in functional genomics. The methodology underlying these measurements assumes existence of a direct link between transcription levels, that is, gene-specific mRNA copy numbers present in the cell, and transcription rates, that is, the numbers of gene-specific mRNA molecules synthesized per unit of time. In this paper, the question of whether or not such a tight interdependence may exist is examined in the context of nonlinear dynamics of genetic regulatory networks. Using the equations of chemical kinetics, a model has been constructed that is capable of explicitly taking into consideration nonlinear interactions between the genes through the teamwork of transcription factors. Jacobian analysis of stability has shown that steady state equilibrium is impossible in such systems. However, phase space compressibility is found to be negative, thus suggesting that asymptotic stability may exist and assume either the form of limit cycle or of a chaotic attractor. It is argued that in rapidly fluctuating or chaotic systems, direct evaluation of transcription rates through transcription levels is highly problematic. It is also noted that even if a hypothetical steady state did exist, the knowledge of transcription levels alone would not be sufficient for the evaluation of transcription rates; an additional set of parameters, namely the mRNA decay rates, would be required. An overall conclusion of the work is that the measurements of mRNA abundances are not truly representative of the functionality of genes and structural fidelity of the genetic codes.

Highlights

DNA microarray measurements of mRNA abundances are widely recognized as a powerful tool for obtaining the whole-genome information regarding transcriptional activity
A key assumption underlying microarray measurements is that measuring mRNA abundances provides the basis for definitive statements regarding the functionality and integrity of the corresponding genes
In formal terms, such reasoning assumes the existence of a direct link between transcription levels and transcription rates

Summary

Introduction

DNA microarray measurements of mRNA abundances are widely recognized as a powerful tool for obtaining the whole-genome information regarding transcriptional activity. After the introduction of DNA microarrays[1,2,3,4] and the initial rush of enthusiasm and great hopes,[5,6,7] a period of sober evaluation of capabilities and pitfalls has emerged in which reproducibility has become a dominant concern.[8,9] in the editorial preceding,[10] the report summarizing a large-scale Microarray Quality Control Project (MAQC), this period of development is characterized as follows:. After 15 years of research and development, broad consensus is still lacking concerning best practice for experimental design and sample preparation, and for data acquisition, statistical analysis and interpretation. Though problematic for bench research, lack of resolution of these issues continues to even more seriously hamper translation of microarray technology into the regulatory and clinical settings. Microarrays have a long way to go before they can be used to support regulatory decision-making or accurate and consistent prediction of patient outcomes in the clinic.”

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