A new role for expressed pseudogenes as ncRNA: regulation of mRNA stability of its homologous coding gene

Abstract

We have earlier generated a mutant mouse in a course of making a transgenic line that exhibited interesting heterozygote phenotypes, which exhibited failure to thrive, severe bone deformities, and polycystic kidneys. This mutant mouse provided a clue to uncover a unique role of expressed pseudogenes. In this mutant the transgene was integrated into the vicinity of the expressing pseudogene of Makorin1 called Makorin1-p1. This insertion reduced transcription of the Makorin1-p1, resulting in destabilization of the Makorin1 mRNA in trans via a cis-acting RNA decay element within the 5' region of Makorin1 that is homologous between Makorin1 and Makorin1-p1. These findings demonstrate a novel and specific regulatory role of an expressed pseudogene as well as functional significance for noncoding RNAs. Next, we developed an original algorithm to determine how many pseudogenes are expressed. Based on our examination 2-3% of human processed pseudogenes are expressed using the most strict criteria. Interestingly, the mouse has a much smaller proportion of expressed pseudogenes (0.5-1%). Pseudogenes are functionally less constrained, and have accumulated more mutations than translated genes. If they have some functions in gene regulation, this property would allow more rapid functional diversification than protein-coding genes. In addition, some genetic phenomena that exhibit incomplete penetrance might be attributed to "mutation" or "variation" of pseudogenes.

Eukaryotic regulatory RNAs: an answer to the ‘genome complexity’ conundrum

“…Interestingly, this mouse line died shortly after birth from multiorgan failure, suggesting an important role for Makorin1-p1. From these results Yano et al (2004) have proposed that the Makorin1-p1 RNA functions to stabilize the Makorin1 mRNA. However, a recent study by Nicholls and colleagues (Gray et al 2006) challenged the role of Makorin1-p1 in regulating Makorin1 mRNA stability.…”

“…Most of these pseudogene sequences are the result of LINE1-mediated retrotransposition (processed pseudogene) or genome duplication (duplicated pseudogene). The human genome is estimated to contain up to 20,000 pseudogenes, and it has been predicted that ∼3% of them are transcribed (Yano et al 2004;Zhang et al 2006). Pseudogenes are important, as they may represent genomic fossils that can be used to infer the ancestral sequence and evolutionary history of present day genes (Zhang et al 2006) and/or they may represent a means for additional levels of gene regulation.…”

“…Recent studies have suggested the importance of pseudogene transcripts in gene regulation (Hirotsune et al 2003;Lee 2003;Yano et al 2004). Hirotsune et al (2003) reported the unprecedented finding that a mouse not expressing the Makorin1-p1 pseudogene due to a gene insertion at the Makorin1-p1 chromosomal locus shows abnormal expression of the functional protein-coding Makorin1 gene located elsewhere in the genome.…”

The putatively functional Mkrn1-p1 pseudogene is neither expressed nor imprinted, nor does it regulate its source gene in trans

“…We also show that mice in which Mkrn1 has been directly disrupted do not display any of the phenotypes that were attributed to a partial down-regulation of this gene (6). Combined, our data invalidate the experimental evidence that formed the basis of the paradigm-shifting, mammalian pseudogene trans-stabilization model (6)(7)(8)(9).…”

“…Recently, however, the established paradigm that pseudogenes are ''junk DNA'' has been challenged by a model suggesting that some pseudogenes can regulate their respective source genes (6)(7)(8)(9). This provocative model, summarized in Fig.…”