**Global analysis of rewiring based on whole-genome predictions in ***S. pombe*. **(a) **Points in the scatter plot each represent groups of between 2 and 22 genes whose protein products are in the same protein complex (Materials and methods). Darker color represents complexes that are predicted to have significant rewiring. Generally, genes in complexes that fall on the diagonal are predicted to have conserved degrees, while those that fall off-diagonal show evidence for large degree differences between the two species. Significantly rewired complexes (at a threshold of 0.05) are labeled by their names. **(b) **To validate our predicted rewired genes, we constructed separate networks of co-expression relationships among genes for each yeast species, then labeled genes according to our rewiring designation. Only one-to-one orthologs that are non-essential in both species were included in the networks. Edges in the co-expression network were classified by whether involved genes were both rewired, only one was rewired, or neither was rewired. We then calculated fractions of conserved co-expression relationships between species within each of these classes. **(c) **There is a clear relationship between these classes of edges and their conservation across the two yeast species. For rewiring at four levels of magnitude, we counted the number of conserved edges (among all edges in the union of the two networks). A conserved edge appears in the networks of both species and a non-conserved edge appears in exactly one. The magnitude of rewiring increases along the x-axis for the rewired class (differences of > 30, > 55, > 80, > 105 interactions), but the non-rewired class is defined as the set of ortholog pairs with less than a 30-edge difference in degree. Edges in the two rewired classes consistently showed significantly lower levels of conservation than edges in the non-rewired class (*P *< 0.01, Fisher's exact test). Error bars show the binomial proportion 95% confidence interval. The dashed line is the expected rate of conservation if edges are randomized in one of the co-expression networks. There are 12,472 edges among 509 genes in the conserved-conserved network. Numbers of edges and genes at rewiring thresholds, in bold, are as follows, where the conserved-rewired case is given as the first pair and the rewired-rewired case is given second: **30: **(14532, 832), (4684, 323); **55: **(8730, 695), (1659, 186); **80: **(5358, 620), (644, 111); **105: **(2822, 565), (176, 56).

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