重复基因中转座元件的偏性外显：来自TIF-IA基因的教训
Biased exonization of transposed elements in duplicated genes: A lesson from the TIF-IA gene
摘要：
背景：基因复制和内含子转座元件的外切是增强基因组多样性的两种机制。我们研究了是否有较少的选择对外显子的转座元件在重复的基因比在单拷贝基因。结果如下：转座元件外显化的全基因组分析显示，相对于单拷贝基因，重复基因内的外显化率更高。TIF-IA基因是一种RNA聚合酶I转录起始因子，经历了类人特异性的三重复制，该基因的所有三个拷贝都具有转录活性，尽管只有一个拷贝保留了产生TIF-IA蛋白的能力。在TIF-IA三重化之前，将Alu元件插入第一内含子中。在其中一个非蛋白质编码拷贝中，该Alu被外显子化。我们确定了一个单一的点突变，导致exonization在一个基因的副本。当这种突变被引入到TIF-IA编码拷贝中时，外显子被激活，蛋白质编码mRNA的水平大幅降低。在正常人细胞中检测到非常低水平的外泌化。然而，这种外泌化在大多数评价的白血病细胞系中是丰富的，尽管与正常细胞相比，这些癌细胞中的基因组序列是不变的。结论：TIF-IA基因中Alu元件作为外显子的定义仅限于某些类型的癌症;该元件在正常人类细胞中不被外显子化。这些结果进一步加深了我们对基因复制和可变剪接之间微妙的相互作用以及导致遗传创新的分子进化机制的理解。这意味着在单拷贝基因中存在针对外显子外切的纯化选择，而重复基因不受这种限制。
英文摘要：
Background: Gene duplication and exonization of intronic transposed elements are two mechanisms that enhance genomic diversity. We examined whether there is less selection against exonization of transposed elements in duplicated genes than in single-copy genes. Results: Genome-wide analysis of exonization of transposed elements revealed a higher rate of exonization within duplicated genes relative to single-copy genes. The gene for TIF-IA, an RNA polymerase I transcription initiation factor, underwent a humanoid-specific triplication, all three copies of the gene are active transcriptionally, although only one copy retains the ability to generate the TIF-IA protein. Prior to TIF-IA triplication, an Alu element was inserted into the first intron. In one of the non-protein coding copies, this Alu is exonized. We identified a single point mutation leading to exonization in one of the gene duplicates. When this mutation was introduced into the TIF-IA coding copy, exonization was activated and the level of the protein-coding mRNA was reduced substantially. A very low level of exonization was detected in normal human cells. However, this exonization was abundant in most leukemia cell lines evaluated, although the genomic sequence is unchanged in these cancerous cells compared to normal cells. Conclusion: The definition of the Alu element within the TIF-IA gene as an exon is restricted to certain types of cancers; the element is not exonized in normal human cells. These results further our understanding of the delicate interplay between gene duplication and alternative splicing and of the molecular evolutionary mechanisms leading to genetic innovations. This implies the existence of purifying selection against exonization in single copy genes, with duplicate genes free from such constrains.
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