靈長類特有之微小核醣核酸叢集的比較基因體學分析

Abstract

Alu 單元和微小核醣核酸﹝microRNA﹞是兩個截然不同的基因體序列。在近幾年，兩者皆被廣泛研究。Alu 單元是專一出現在靈長類動物的短散布重複因子﹝SINE﹞中佔多數的因子之一，且它們不轉譯出有功能的蛋白質。在最近的研究中指出Alu 單元可能和癌症的產生有所關聯。其他的研究也認為Alu 單元可能影響基因的功能。基於這些發現，可以合理的認為，Alu 單元在靈長類的演化中可能扮演某種很重要的角色。在人類第19 號染色體上的微小核醣核酸叢集﹝C19MC﹞中的Alu 單元和微小核醣核酸，被發現有一種很特殊的位置上的靠近。這個不尋常的片段可能是起因於一連串的複製﹝duplication﹞事件。在這篇研究中，我們分析了這些可能是複製單元的序列，無論是在同物種的同源基因﹝paralogs﹞之間，或是異物種同源基因對﹝ortholog pairs﹞之間，希望能辨識出序列中每個位置所遭受的選擇壓力﹝selection pressure﹞。我們發現在恆河猴C19MC 中的同物種同源基因序列，相對於人類有較高的變異度。同時我們的全面性和區域性的分析也指出，無論在人類或恆河猴的C19MC 中，不同的序列區域遭受到不同的選擇力量。在表現子﹝exon﹞區域有最高的變異性，然而在中間區域靠近微小核醣核酸的週邊，則有較高的保留度。此外，先前的研究指出Alu 可能會被微小核醣核酸所抑制，因為Alu 單元的擴張可能會使基因體受損。在此篇研究的第二部份，我們假設 降低Alu 單元的表現程度，可能會使人類基因體有選擇優勢。因此我們認為在靈長類的演化中，C19MC 可能是主要的防禦機制，用來對抗Alu 單元的擴張。我們初步的結果指出，無論在人類或恆河猴的基因體中，C19MC 中的微小核醣核酸傾向針對AluS 而非AluJ和AluY。這個發現支持了我們的假說，C19MC 的出現可能是在Alu 擴張之後的一種防禦反應。

Alu elements and microRNAs are two different types of genomic sequences. Each of them has been extensively studied in recent years. Alu is one of the most abundant SINEs (short interspersed nuclear element) discovered specifically in primates and it does not encode a functional protein. In recent studies, Alu was reported to be related to cancer. Some other studies further suggested that Alu may influence gene functions. Based on these findings, it is reasonable to speculate that Alu might play some important roles during primate evolution. An unusual cluster of positional proximity of Alu and microRNA was found in human chromosome 19 microRNA cluster (C19MC). This unusual fragment seems to be derived from a serious of duplication events. In this study, we analyzed the sequences of the possible duplication unit either in paralogs within a species or ortholog pairs between species to identify the selection pressures on each nucleotide site. We found that the sequences of rhesus C19MC are more diverged than their paralogs in human. Meanwhile, our global and local analyses revealed that in both human and rhesus C19MC, different regions are under different selection forces. The exons are more diverged, while the internal flanking regions, which are adjacent to microRNAs, are more conserved. In addition, previous studies suggested that Alu elements in human might be repressed by microRNAs, because Alu expansion might damage human genome. In the second part of our study, we hypothesized that reducing the expression level of Alu might have selectively advantage for human genome. We suggested that this C19MC cluster might be a major defender against Alu expansion during primate evolution. Our preliminary results indicate that microRNAs in C19MC tend to target AluS rather than AluJ and AluY in human and macaque genomes. This finding supports the hypothesis that the appearance of C19MC might follow Alu expansion as a response of defense.