LATE ORIGIN OF OXYGEN REGULATION IN ANIMALS

It remains unclear whether low and unstable marine oxygen levels contributed to the billion-year gap separating the first crown-eukaryotes (ca. 1.9 Ga) from the first crown-metazoans (ca. 855 Ma). Settling this issue depends, in part, on reconstructing how the metazoan last common ancestor responded to environmental oxygen availability. Today, hypoxia-inducible factors (HIFs), transcriptional factors activated by low levels of cellular oxygen, are considered the canonical regulators of oxygen homeostasis in animals, playing key roles in development, blood vessel formation, and metabolic adaptation to low environmental oxygen levels. While the HIF pathway is found in bilaterians, cnidarians, and placozoans, it has not been explored in the two remaining non-bilaterian phyla, ctenophores and sponges. Using comparative genomics, we show that both ctenophores and sponges lack key components of the HIF pathway, and that HIF is not a universal metazoan feature, as previously thought. We support this conclusion with experimental data showing that sponges maintain normal transcription down to oxygen concentrations <1% of modern atmospheric saturation (AS). As sponges and ctenophores represent the earliest-branching extant animal phyla, the last common ancestor of metazoans likely lacked the HIF pathway as well. Together, this evidence suggests that the metazoan last common ancestor could have respired aerobically at oxygen levels <1% AS, and did not need to regulate its gene expression in response to oxygen availability. The evolution of the HIF pathway ca. 845 Ma potentially reflects the advent of more metabolically demanding animals requiring a higher degree of oxygen regulation for life in low-oxygen environments.