(A) In pteropodids, molecular dating estimates that the loss of HMGCS2 happened 29–18 Mya and thus may overlap the split of the flying foxes and the Egyptian fruit bat. It is not possible to resolve whether gene loss happened before or after the split as HMGCS2 is completely deleted in the Egyptian fruit bat. While horseshoe bats and other insectivorous bat lineages have brains not larger than expected for their body size (encephalization quotient (EQ) <1), brain size has increased in the lineage leading to the fruit bats that have EQ values > 1 (Stephan et al., 1981). Thus, brain size expansion presumably predates the loss of ketogenesis. (B) HMGCS2 was already lost in the cetacean ancestor before the split of toothed and baleen whales ~ 36 Mya, as inferred from shared inactivating mutations in exons 1, 2 and 8. Molecular dating further estimates that the loss of this gene happened early on the cetacean branch 50–47 Mya. The cetacean ancestor had a brain slightly larger than expected for its body size with an EQ of 1.4. While EQ values increased and decreased in several cetacean lineages, brain size has greatly expanded in dolphins, reaching an EQ of 3.7 (Montgomery et al., 2013). Thus, brain size expansion in dolphins occurred after the loss of ketogenesis. (C) Early proboscids such as Moeritherium, an extinct lineage that split from other proboscids ~ 43 Mya, had brains about 20% of the size expected for a mammal of the same body size, and thus an EQ of 0.2 (Shoshani et al., 2006). Exact EQ values of Palaeomastodons are not known; however, fossils have a small braincase, which indicates a low EQ (Sanders et al., 2010; Benoit, 2015). In contrast, mastodons that diverged from elephants ~ 27 Mya had brains about twice as large as expected from their body size (EQ 2.2), similar to extant elephants (Shoshani et al., 2006). This suggests that brain size expansion happened in a period between 37 and 27 Mya. Molecular dating indicates that HMGCS2 loss happened between 45 and 42 Mya, suggesting that the loss of ketogenesis precedes brain size expansion in the elephant lineage. Divergence times of extinct proboscid lineages were taken from (Shoshani and Tassy, 2013) and (Rohland et al., 2007). Supporting Information.