期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 32, 页码 12039-12044出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0602216103
关键词
disease mechanism; gene regulation; imprinting; molecular evolution; transgene
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据