Motifs were compared to a library of search matrices for 9 known Mtb motifs (Acr, Crp, CsoR, DosR, FurA, IdeR, KstR, MprAB, and ZurB), as well as a library of 55 E. coli motifs [98] and 22 Corynebacterial motifs [99] . Comparison of motifs was done using CompareACE [76] . Within each experiment, we extracted a list of genes upregulated 1.5 and 2 standard deviations above the mean. For each category, we considered a gene to be upregulated if it was upregulated in more than 50% of the experiments making up that category. We then searched for genes that were only upregulated under certain conditions or sets of conditions. We looked at the evolution of these sets of Mtb H37Rv genes by taking the other members of their orthogroups across all 31 other organisms. Evolution of these groups can be visualized in our supplementary information http://www.broadinstitute.org/ftp/pub/seq/ msc/pub/SYNERGY/index.html.