Human testis-specific TTRP regulates circadian clock as an evolutionarily young natural antisense transcript of PER2

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The circadian clock orchestrates a variety of physiological and behavioral processes, endowing the ability to adapt to the cycling environment. Here, we report the identification of TTRP, a TDP-43 pseudogene that emerged in higher Hominoidea species ~8.6 Mya. TTRP is a human testis-specific gene that overlaps with the clock gene PER2 and interferes with PER2 transcription. TTRP encodes a protein that interacts with the clock proteins PER2, BMAL1, and CRY2, and promotes PER2 and CRY1 turnover. The expression of gorilla and bonobo TTRP proteins changes the period and amplitude of circadian rhythms in human cells. Knock-in and expression of human TTRP in mouse testes prolong the brood-interval time and increase the ratio of sperm with high motility. These findings highlight the functional importance of TTRP as a regulator of the circadian clock and suggest that the human circadian clock may be undergoing continuous evolution through the recruitment of novel factors. TTRP is an evolutionarily novel gene in higher Hominoidea that has been recruited to regulate the human circadian clock. As an antisense gene to PER2, TTRP modulates circadian rhythms through both transcriptional interference and its encoded protein.

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