Figure 4. Pairwise epistatic interactions in the TEM extended-spectrum community either previously described in the literature or identified in our experiments [19] , [79]–[83].

Network is represented as in Figure 2. The subcommunity containing the active-site residue 238 is light blue and the subcommunity containing the active-site residue 164 is dark blue. Node size is proportional to weighted degree centrality (Methods). Link thickness indicates how frequently two residues (nodes) are mutated in the same sequence, normalized by the number of sequences in which only one or the other position is mutated (Methods). (A) Black links indicate positive epistatic interactions. (B) Red links indicate negative epistatic interactions. Because the network is constructed from co-occurring mutated residue pairs, negative-epistatic pairs may be underrepresented in or absent from the network, e.g. 39 and 173. Image created with CytoScape [78].