Systems biology of SNPs

Abstract

Genome-scale networks can now be reconstructed based on high-throughput data sets. Mathematical analyses of these networks are used to compute their candidate functional or phenotypic states. Analysis of functional states of networks shows that the activity of biochemical reactions can be highly correlated in physiological states, forming so-called co-sets representing functional modules of the network. Thus, detrimental sequence defects in any one of the genes encoding members of a co-set can result in similar phenotypic consequences. Here we show that causal single nucleotide polymorphisms in genes encoding mitochondrial components can be classified and correlated using co-sets.

Figure 1

Relating SNPs, diseases, and correlated reaction sets. (A) Functional metabolic network analysis results in correlated reaction sets. Causal SNPs in any of the genes encoding proteins in the reaction sets are expected to have similar phenotypic states. (B) Examples of the different classes of genotype–phenotype relationships in the context of metabolic networks. Each sub-panel exemplifies a type of co-set represented by colored arrows and circles (non-black). The circles represent the protein subunits of a particular enzyme. Each enzyme is the same color. Red triangles represent altered protein subunits due to causal SNPs. Each group of colored circles (enzyme) corresponds to the same colored reaction flux in the pathway. SNPs in the gene coding for the protein subunits that catalyze the transformation from one metabolite to another will result in a phenotype that is unable to produce that particular product (Type A co-set). Type B co-sets function in an analogous manner, where causal SNPs affecting a reaction that is part of a correlated reaction set (a linear chain of reactions) will result in a phenotype characterized by an inability to produce the end point of the chain. More complex schemes may also occur in which the correlated reaction set is not a linear pathway (Type C co-set).

Figure 2

Map of mitochondrial metabolism with SNP-associated co-sets. The co-sets are color-coded according to the legend at the bottom of the figure. An example of each type of co-set (Type A: TCA cycle; Type B: Heme biosynthesis; Type C: Urea cycle) has a summary chart that includes the following information: gene abbreviation, gene IDs, MIMs, and SNP-associated signs or symptoms, respectively column-wise.