Abstract
In mammals, the master transcription regulator of antioxidant defences is provided by the Nrf2 protein. Phylogenetic analyses of Nrf2 sequences are used here to derive a molecular clock that manifests persuasive evidence that Nrf2 orthologues emerged, and then diverged, at two time points that correlate with well-established geochemical and palaeobiological chronologies during progression of the ‘Great Oxygenation Event’. We demonstrate that orthologues of Nrf2 first appeared in fungi around 1.5 Ga during the Paleoproterozoic when photosynthetic oxygen was being absorbed into the oceans. A subsequent significant divergence in Nrf2 is seen during the split between fungi and the Metazoa approximately 1.0–1.2 Ga, at a time when oceanic ventilation released free oxygen to the atmosphere, but with most being absorbed by methane oxidation and oxidative weathering of land surfaces until approximately 800 Ma. Atmospheric oxygen levels thereafter accumulated giving rise to metazoan success known as the Cambrian explosion commencing at ~541 Ma. Atmospheric O2 levels then rose in the mid Paleozoic (359–252 Ma), and Nrf2 diverged once again at the division between mammals and non-mammalian vertebrates during the Permian-Triassic boundary (~252 Ma). Understanding Nrf2 evolution as an effective antioxidant response may have repercussions for improved human health.
Highlights
Figure 1. displays the Nrf[2] phylogenetic tree relative to atmospheric oxygen levels during the latter period of Earth’s history
The chart presents the traditional “5-stage model” of oxygen evolution constructed from compiled data[1,8,9,10,11,12,13,14,15], with the trend line representing a “best guess” model; Stage 1 represents a period when the atmosphere and oceans were largely anoxic; Stage 2 commences the ‘Great Oxygenation Event’; Stage 3 is the period during which atmospheric oxygen levels remained low due to continued absorption by the oceans and oxidative weathering of the terrestrial crust; Stage 4 is the period after saturation of global oxygen buffers, during which oxygen levels rise towards present (Stage 5) atmospheric levels (PAL)
The results are presented as a phylogenetic tree which was converted to a ‘molecular clock’ using widely accepted paleontological estimates for known splits between major animal phyla
Summary
In order to reconstruct the evolutionary life history of Nrf[2] in response to mounting oxidative stress, a Bayesian phylogenetic analysis of Nrf[2] sequences retrieved from the genome sequences of many diverse taxa was performed together with a prediction of evolutionary pressure as evinced by a calculation of synonymous to non-synonymous nucleotide base substitution rates. According to empirical evidence gained from Drosophila melanogaster[27,28], genomic Keap[1] recruitment occurred in early invertebrates preceding the divergence of the class Insecta after the Cambrian Explosion This time frame coincides with rising levels of atmospheric O2 during Stage 4 of the Earth’s oxygenation and matches the increased evolutionary pressure (measured by Codon-based Z-test of selection, Fig. 2) detected in Nrf[2] sequences from taxa of the early Bilateria. Together, these lines of evidence suggest that rising levels of oxygen led to recruitment of Keap[1] for enhanced regulation of Nrf[2] for the transcription of cytoprotective genes in the response of animals to oxidative stress. This could, in turn, reveal possible new intervention strategies to improve metabolic health in our worldwide ageing population
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