Since the advent of molecular biology, considerable progress has been made in the quest to understand the mechanisms that underlie human disease, particularly for genetically inherited disorders. Genotype-phenotype relationships, as summarized in the Online Mendelian Inheritance in Man (OMIM) database (Amberger et al., 2009
), include mutations in more than 3,000 human genes known to be associated with one or more of over 2,000 human disorders. This is a truly astounding number of genotype-phenotype relationships considering that a mere three decades have passed since the initial description of Restriction Fragment Length Polymorphisms (RFLPs) as molecular markers to map genetic loci of interest (Botstein et al., 1980
), only two decades since the announcement of the first positional cloning experiments of disease-associated genes using RFLPs (Amberger et al., 2009
), and just one decade since the release of the first reference sequences of the human genome (Lander et al., 2001
; Venter et al., 2001
). For complex traits, the information gathered by recent Genome Wide Association studies suggests high-confidence genotype-phenotype associations between close to 1,000 genomic loci and one or more of over one hundred diseases, including diabetes, obesity, Crohn s disease and hypertension (Altshuler et al., 2008
). The discovery of genomic variations involved in cancer, inherited in the germline or acquired somatically, is equally striking, with hundreds of human genes found linked to cancer (Stratton et al., 2009
). In light of new powerful technological developments such as next-generation sequencing, it is easily imaginable that a catalog of nearly all human genomic variations, whether deleterious, advantageous, or neutral, will be available within our lifetime.
Despite the natural excitement emerging from such a huge body of information, daunting challenges remain. Practically, the genomic revolution has thus far seldom translated directly into the development of new therapeutic strategies, and the mechanisms underlying genotype-phenotype relationships remain only partially explained. Assuming that with time most human genotypic variations will be described together with phenotypic associations, there would still be major problems to fully understand and model human genetic variations and their impact on diseases.
To understand why, consider the “one-gene/one-enzyme/one-function” concept originally framed by Beadle and Tatum (Beadle and Tatum, 1941
), which holds that simple, linear connections are expected between the genotype of an organism and its phenotype. But the reality is that most genotype-phenotype relationships arise from a much higher underlying complexity. Combinations of identical genotypes and nearly identical environments do not always give rise to identical phenotypes. The very coining of the words “genotype” and “phenotype” by Johannsen more than a century ago derived from observations that inbred isogenic lines of bean plants grown in well-controlled environments give rise to pods of different size (Johannsen, 1909
). Identical twins, although strikingly similar, nevertheless often exhibit many differences (Raser and O'Shea, 2005
). Likewise, genotypically indistinguishable bacterial or yeast cells grown side-by-side can express different subsets of transcripts and gene products at any given moment (Elowitz et al., 2002
; Blake et al., 2003
; Taniguchi et al., 2010
). Even straightforward Mendelian traits are not immune to complex genotype-phenotype relationships. Incomplete penetrance, variable expressivity, differences in age of onset, and modifier mutations are more frequent than generally appreciated (Perlis et al., 2010
We argue, along with others, that the way beyond these challenges is to decipher the properties of biological systems, and in particular, those of molecular networks taking place within cells. As is becoming increasingly clear, biological systems and cellular networks are governed by specific laws and principles, the understanding of which will be essential for a deeper comprehension of biology (Nurse, 2003
; Vidal, 2009
Accordingly, our goal is to review key aspects of how complex systems operate inside cells. Particularly, we will review how by interacting with each other, genes and their products form complex networks within cells. Empirically determining and modeling cellular networks for a few model organisms and for human has provided a necessary scaffold towards understanding the functional, logical and dynamical aspects of cellular systems. Importantly, we will discuss the possibility that phenotypes result from perturbations of the properties of cellular systems and networks. The link between network properties and phenotypes, including susceptibility to human disease, appears to be at least as important as that between genotypes and phenotypes ().
Perturbations in biological systems and cellular networks may underlie genotype-phenotype relationships