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al., 2002, and Stathopoulos and Levine, 2005.) Yet closer inspection of such diagrams validates the claim. The first of these functional connectivity patterns consists of linear sequences of action between genes, namely genetic pathways. In reality, each gene may (and most do) connect to more than one gene (both upstream and downstream), but if one follows each gene–gene link, from one to the next, a linear sequence of causal activation/inhibition steps is always found (although many gene activations, in particular, require multiple inputs from several gene products). The second set of structural elements are the functional links between the linear segments, the pathways. Again, the connecting links function as either + or − steps. The third class of element is that of feedback loops. These are either positive (+) feed-forward steps or inhibitory (−) negative feedback functions. For both sign types, such feedback loops can either involve a gene product acting on itself (or the encoding gene) or interact with other genes/gene products either upstream or downstream in the sequence.

These two generic properties of networks, namely, the +/− choice at each step and the decomposability into three structural motifs, ensures that if one knows all of the potentially rate-limiting (nonredundant) members of a network/network module, plus all of the relevant inputs (and which ones are being used in a particular developmental process), and, not least, the specific functional relationships (whether + or −) between each pair of interacting genes, one can determine whether a particular set of inputs will trigger a particular set of outputs of the whole functional unit. This principle was first noted by Kauffman (1971), who used the term “forcing structure” to denote this deterministic property of networks, but it has most recently been discussed by Davidson (2006).

This property is most easily illustrated in the abstract for the case of simple, linear pathways. Such sequences always consist of all activating (+) steps, all negative (−) steps (although this group is undoubtedly a minority class), or a mixture of + and − steps (which is almost certainly the most common category of pathways). These are illustrated in Fig. 4.4 for the putative wild-type situation in each case. In addition, the figure shows the effect of a complete loss-of-function mutation in an early (“upstream”) gene of each kind of pathway. For all three pathway types, the effect of such a mutation is the complete reversal of sign of all of the following (“downstream”) gene activities. Thus, not only does the pathway structure allow one to predict outcomes in the wild-type case if one knows which inputs have been applied in any instance, but it also allows you to predict the effect of loss-of-function mutations on pathway/module output. In contrast, the effects of gain-of-function mutations are less predictable, at least where it is a + step that is affected in a pathway that has already been triggered. If, however, the activation step caused by a constitutive gain-



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