Chapter 10 PART II: Concepts in Molecular Biology and Genetics Integrative Systems Biology: Implications for the Understanding of Human Disease Companion site for Molecular Pathology Author: William B. Coleman and Gregory J. Tsongalis

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 2 Example of an approximately 40,000 probe spotted oligonucleotide microarray with enlarged inset to show detail (Image from Wikimedia Commons). FIGURE 10.1

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 3 Omics technologies gather data on numerous levels. Various "omics" fields are displayed here along with the laboratory techniques used to generate the data, as well as the relationship of data from one level to another. Adapted from [25]. FIGURE 10.2

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 4 Example of a control module. This module represents a simple feedback loop, with output from the sensor either upregulating or downregulating the process that converts the input into output. FIGURE 10.3

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 5 The iterative nature of systems biology research. Note that every refinement of the model needs additional data generation for retesting of specific hypotheses. Adopted from [26]. FIGURE 10.4

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 6 Hypothesis of etiology-defined pathways to pancreatic fibrosis. Hypothetical influence diagram illustrating pathologic pathways linking proximal factor (Factor A and B) to PSC (pancreatic stellate cell) and fibrosis through multiple steps (a1, a2, a3). Etiological factors of type B activate trypsinogen to trypsin, and therefore their pathologic pathway to the PSC can be interrupted by SPINK1. Etiological factors of type A are independent of trypsin, and therefore will not be influenced by variations in SPINK1 expression or function. FIGURE 10.5

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 7 Disease gene network. Each node is a single gene, and any two genes are connected if implicated in the same disorder. In this network map, the size of each node is proportional to the number of specific disorders in which the gene is implicated. Reproduced with permission from [24]. FIGURE 10.6