Kano Hiroki, Kurahashi Hiroki, Toda Tatsushi
Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19034-9. doi: 10.1073/pnas.0705483104. Epub 2007 Nov 5.
Dactylaplasia, characterized by missing central digital rays, is an inherited mouse limb malformation that depends on two genetic loci. The first locus, Dac, is an insertional mutation around the dactylin gene that is inherited as a semidominant trait. The second locus is an unlinked modifier, mdac/Mdac, that is polymorphic among inbred strains. Mdac dominantly suppresses the dactylaplasia phenotype in mice carrying Dac. However, little is known about either locus or the nature of their interaction. Here we show that Dac is a LTR retrotransposon insertion caused by the type D mouse endogenous provirus element (MusD). This insertion exhibits different epigenetic states and spatiotemporally expresses depending on the mdac/Mdac modifier background. In dactylaplasia mutants (Dac/+ mdac/mdac), the LTRs of the insertion contained unmethylated CpGs and active chromatin. Furthermore, MusD elements expressed ectopically at the apical ectodermal ridge of limb buds, accompanying the dactylaplasia phenotype. On the other hand, in Dac mutants carrying Mdac (Dac/+ Mdac/mdac), the 5' LTR of the insertion was heavily methylated and enriched with inactive chromatin, correlating with inhibition of the dactylaplasia phenotype. Ectopic expression was not observed in the presence of Mdac, which we refined to a 9.4-Mb region on mouse chromosome 13. We report a pathogenic mutation caused by MusD. Our findings indicate that ectopic expression from the MusD insertion correlates with the dactylaplasia phenotype and that Mdac acts as a defensive factor to protect the host genome from pathogenic MusD insertions.
以中央指骨射线缺失为特征的并指畸形是一种遗传性小鼠肢体畸形，它取决于两个基因位点。第一个位点Dac是指蛋白基因周围的插入突变，以半显性性状遗传。第二个位点是一个不连锁的修饰基因mdac/Mdac，在近交系中具有多态性。Mdac在携带Dac的小鼠中显性抑制并指畸形表型。然而，对于这两个位点及其相互作用的本质知之甚少。在这里，我们表明Dac是由D型小鼠内源性前病毒元件（MusD）引起的LTR逆转座子插入。这种插入表现出不同的表观遗传状态，并根据mdac/Mdac修饰基因背景在时空上表达。在并指畸形突变体（Dac/+ mdac/mdac）中，插入的LTR包含未甲基化的CpG和活性染色质。此外，MusD元件在肢芽的顶端外胚层嵴异位表达，伴随着并指畸形表型。另一方面，在携带Mdac的Dac突变体（Dac/+ Mdac/mdac）中，插入的5' LTR高度甲基化并富含无活性染色质，这与并指畸形表型的抑制相关。在存在Mdac的情况下未观察到异位表达，我们将其定位到小鼠13号染色体上的一个9.4 Mb区域。我们报告了由MusD引起的致病突变。我们的研究结果表明，MusD插入的异位表达与并指畸形表型相关，并且Mdac作为一种防御因子保护宿主基因组免受致病性MusD插入的影响。
