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Media type:
E-Article
Title:
The Putatively Functional Mkrn1-p1 Pseudogene Is Neither Expressed nor Imprinted, nor Does It Regulate Its Source Gene in Trans
Contributor:
Gray, Todd A.;
Wilson, Alison;
Fortin, Patrick J.;
Nicholls, Robert D.
imprint:
National Academy of Sciences, 2006
Published in:Proceedings of the National Academy of Sciences of the United States of America
Language:
English
ISSN:
0027-8424
Origination:
Footnote:
Description:
<p>A recently promoted genome evolution model posits that mammalian pseudogenes can regulate their founding source genes, and it thereby ascribes an important function to "junk DNA." This model arose from analysis of a serendipitous mouse mutant in which a transgene insertion/deletion caused severe polycystic kidney disease and osteogenesis imperfecta with ≈80% perinatal lethality, when inherited paternally [Hirotsune, S., et al. (2003) Nature 423, 91-96]. The authors concluded that the transgene reduced the expression of a nearby transcribed and imprinted pseudogene, Mkrnl-pl. This reduction in chromosome 5-imprinted Mkrnl-pl transcripts was proposed to destabilize the cognate chromosome 6 Mkrnl source gene mRNA, with a partial reduction in one Mkrnl isoform leading to the imprinted phenotype. Here, we show that 5' Mkrnl-pl is fully methylated on both alleles, a pattern indicative of silenced chromatin, and that Mkrnl1-pl is not transcribed and therefore cannot stabilize Mkrnl transcripts in trans. A small, truncated, rodent-specific Mkrn I transcript explains the product erroneously attributed to Mkrnl-pl. Additionally, Mkrnl expression is not imprinted, and 5' Mkrnl is fully unmethylated. Finally, mice in which Mkrnl has been directly disrupted show none of the phenotypes attributed to a partial reduction of Mkrnl. These data contradict the previous suggestions that Mkrnl1-pl is imprinted, and that either it or its source Mkrnl gene relates to the original imprinted transgene phenotype. This study invalidates the data upon which the pseudogene trans-regulation model is based and therefore strongly supports the view that mammalian pseudogenes are evolutionary relics.</p>