Abstract
Apart from glucose, fatty acid-derived ketone bodies provide metabolic energy for the brain during fasting and neonatal development. We investigated the evolution of HMGCS2, the key enzyme required for ketone body biosynthesis (ketogenesis). Unexpectedly, we found that three mammalian lineages, comprising cetaceans (dolphins and whales), elephants and mastodons, and Old World fruit bats have lost this gene. Remarkably, many of these species have exceptionally large brains and signs of intelligent behavior. While fruit bats are sensitive to starvation, cetaceans and elephants can still withstand periods of fasting. This suggests that alternative strategies to fuel large brains during fasting evolved repeatedly and reveals flexibility in mammalian energy metabolism. Furthermore, we show that HMGCS2 loss preceded brain size expansion in toothed whales and elephants. Thus, while ketogenesis was likely important for brain size expansion in modern humans, ketogenesis is not a universal precondition for the evolution of large mammalian brains.
Highlights
Periods of fasting are a common event for many animals (Secor and Carey, 2016)
We show that in the cetacean and Elephantimorpha clades HMGCS2 was lost before brain size expansion happened, suggesting that the lack of ketogenesis did not prohibit the evolution of large brains in these lineages
We discovered that three independent lineages exhibit large deletions that remove HMGCS2 exons or gene-inactivating mutations that shift the HMGCS2 reading frame and destroy conserved splice site dinucleotides (Figure 1B)
Summary
Periods of fasting are a common event for many animals (Secor and Carey, 2016). Fasting occurs due to natural food scarcity or as part of the life history strategy, for example during hibernation or migration.
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