Evidence for conservation of a primordial 12-hour ultradian gene program in humans

While circadian rhythms are entrained to the once daily light-dark cycle of the sun, many marine organisms exhibit ~12h ultradian rhythms corresponding to the twice daily movement of the tides. Although human ancestors emerged from circatidal environment millions of years ago, direct evidence of the existence of ~12h ultradian rhythms in humans are lacking. Here, we performed prospective, temporal transcriptome profiling of peripheral white blood cells and identified robust ~12h transcriptional rhythms from three healthy subjects. Pathway analysis implicated ~12h rhythms effecting RNA and protein metabolism, with strong homology to the circatidal gene programs previously identified in Cnidarian marine species. We further observed ~12h rhythms of intron retention events of genes involved in MHC class I antigen presentation in all three subjects, synchronized to those of mRNA splicing gene expressions in each individual. Gene regulatory network inference revealed XBP1, GABPA and KLF7 as putative transcriptional regulators of human ~12h rhythms. These results thus establish human ~12h biological rhythms have a primordial evolutionary origin and are likely to have far-reaching implications in human health and disease.