Retrotransposed genes such as Frat3 in the mouse Chromosome 7C Prader-Willi syndrome region acquire the imprinted status of their insertion site
Retrotransposed genes such as Frat3 in the mouse Chromosome 7C Prader-Willi syndrome region acquire the imprinted status of their insertion site
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DOI：
10.1007/s00335-001-2083-1
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发表时间：
2001-11-01
期刊：
影响因子：
2.5
通讯作者：
Nicholls, RD
中科院分区：
文献类型：
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作者：
Chai, JH;Locke, DP;Nicholls, RD
Prader-Willi综合征（PWS）是由人类染色体（Chr）15 q11-q13中1.0- 1.5-Mb的印迹、父系表达基因的功能丧失引起的。小鼠Chr 7 C同源区印迹基因表达的缺失导致了相似的新生儿PWS表型。在人类PWS区域中的几个蛋白质编码基因是无内含子的，可能通过反转录转座产生。在这里，我们提出的证据表明，在进化过程中的小鼠PWS区域的基因的持续收购。生物信息学分析确定了BAC含有四个基因，Mkrn 3，Magel 2，Ndn，Frat 3，和Atp 5l-ps1假基因，后两个基因来自最近的L1介导的反转录转座。对8个重叠BAC的分析表明，这些基因在两个近交系中以tel-Atp 51-ps1-Frat 3-Mkrn 3-Magel 2-Ndn-cen的顺序聚集在120 kb内。印迹分析表明，Frat 3是差异甲基化的，并在Angelman综合征的转基因小鼠模型中仅从父系等位基因表达，而在PWS的小鼠模型中没有从母系等位基因表达。因此，Frat 3表达的缺失可能导致PWS小鼠模型的表型。在一个小的基因组间隔的5个内含子的基因的鉴定表明，该地区是易于在生殖细胞或其合子和胚胎细胞前体的逆转录，它允许这些外来序列的后续功能表达。最近的进化收购的基因，采用相同的印记作为旧的，侧翼的基因表明，新获得的基因成为“无辜的旁观者”的主要表观遗传信号造成印记的PWS域。
Prader-Willi syndrome (PWS) results from loss of function of a 1.0- to 1.5-Mb domain of imprinted, paternally expressed genes in human Chromosome (Chr) 15q11-q13. The loss of imprinted gene expression in the homologous region in mouse Chr 7C leads to a similar neonatal PWS phenotype. Several protein-coding genes in the human PWS region are intronless, possibly arising by retrotransposition. Here we present evidence for continued acquisition of genes by the mouse PWS region during evolution. Bioinformatic analyses identified a BAC containing four genes, Mkrn3, Magel2, Ndn, Frat3, and the Atp5l-ps1 pseudogene, the latter two genes derived from recent L1-mediated retrotransposition. Analyses of eight overlapping BACs indicate that these genes are clustered within 120 kb in two inbred strains, in the order tel-Atp5l-ps1-Frat3-Mkrn3-Magel2-Ndn-cen. Imprinting analyses show that Frat3 is differentially methylated and expressed solely from the paternal allele in a transgenic mouse model of Angelman syndrome, with no expression from the maternal allele in a mouse model of PWS. Loss of Frat3 expression may, therefore, contribute to the phenotype of mouse models of PWS. The identification of five intronless genes in a small genomic interval suggests that this region is prone to retroposition in germ cells or their zygotic and embryonic cell precursors, and that it allows the subsequent functional expression of these foreign sequences. The recent evolutionary acquisition of genes that adopt the same imprint as older, flanking genes indicates that the newly acquired genes become 'innocent bystanders' of a primary epigenetic signal causing imprinting in the PWS domain.