14-3-3. Pseudogenes: Physiologically and powerful evolutionary forces in the genome

Abstract Contrary to the rigid dogma ruling out the phenotypic relevance of pseudogenes, recent RNA-seq and meta-analyses indicate that 10% of all pseudogenes are transcribed, and 40% of those pseudogenes are translated into protein. This investigation unpackages the 14-3-3ζ (YWHAZ) gene, which has been shown to regulate cytokine signaling, induce antibody response, and reduce inflammation in rats with rheumatoid arthritis. The original YWHAZ gene is located on the 8 thhuman chromosome. Our detailed investigation in the human genome shows that there are ten pseudogenes of YWHAZ. Located across the human genome, these pseudogenes display unique properties, such as having allelic SNPs for Body Mass Index, Prostatic Neoplasms, and Macular Degeneration. Diverse mRNA expression profiles skewed towards reproductive organs and an unusually high transcription rate (9 of 10 being actively transcribed) suggest a strong physiological relevance. Additionally, contrary to the prevailing pseudogene formation theory where all exons are transcribed, YWHAZ pseudogenes have omitted the sixth exon’s UTR region, resulting in a more compact, equally functional gene structure. The evolution of the YWHAZ pseudogene from the parent gene’s framework, combined with some pseudogenes having allelic properties, demonstrates how pseudogenes may be the body’s way to repackage and repurpose parent genes for a more diverse genome and proteome.