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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The putatively functional Mkrn1-p1 pseudogene is neither expressed nor imprinted, nor does it regulate its source gene in trans
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The putatively functional Mkrn1-p1 pseudogene is neither expressed nor imprinted, nor does it regulate its source gene in trans

机译：既定的功能性Mkrn1-p1假基因既不表达也不印迹，也不反过来调节其源基因

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摘要

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 approximate to 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, Mkrn1-p1. This reduction in chromosome 5-imprinted Mkrn1-p1 transcripts was proposed to destabilize the cognate chromosome 6 Mkrn1 source gene mRNA, with a partial reduction in one Mkrn1 isoform leading to the imprinted phenotype. Here, we show that 5' Mkrn1-p1 is fully methylated on both alleles, a pattern indicative of silenced chromatin, and that Mkrn1-p1 is not transcribed and therefore cannot stabilize Mkrn1 transcripts in trans. A small, truncated, rodent-specific Mkrn1 transcript explains the product erroneously attributed to Mkrn1-p1. Additionally, Mkrn1 expression is not imprinted, and 5' Mkrn1 is fully unmethylated. Finally, mice in which Mkrn1 has been directly disrupted show none of the phenotypes attributed to a partial reduction of Mkrnl. These data contradict the previous suggestions that Mkrn1-p1 is imprinted, and that either it or its source Mkrn1 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.
机译：最近推广的基因组进化模型认为，哺乳动物假基因可以调节其起源基因，从而将“垃圾DNA”的重要功能归因于此。该模型源于对意外小鼠突变体的分析，该突变体在父系遗传时转基因插入/缺失引起严重的多囊性肾病和成骨不全症，围产期致死率约为80％[Hirotsune，S.等。 （2003）Nature 423，91-96]。作者得出的结论是，转基因减少了附近转录和印迹的假基因Mkrn1-p1的表达。有人提出减少5号染色体印记的Mkrn1-p1转录本来稳定同源6号染色体Mkrn1源基因的mRNA的稳定性，而一种Mkrn1同工型的部分减少导致了印记的表型。在这里，我们显示5'Mkrn1-p1在两个等位基因上都被完全甲基化，这表明染色质沉默，并且Mkrn1-p1没有被转录，因此不能稳定Mkrn1转录物的反式。一个小的，被截短的，啮齿类动物特异性的Mkrn1转录本解释了该产物错误地归因于Mkrn1-p1。此外，没有印记Mkrn1表达，并且5'Mkrn1完全未甲基化。最后，其中Mkrn1被直接破坏的小鼠没有表现出归因于Mkrnl部分减少的表型。这些数据与先前提出的印迹Mkrn1-p1的建议相矛盾，或者它或其来源Mkrn1基因与原始印迹的转基因表型有关。这项研究使假基因反式调节模型所依据的数据无效，因此有力地支持了哺乳动物假基因是进化遗物的观点。

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