PLOS Genetics：北京大學陸劍課題組揭示果蠅RNA編輯的適應性演化

2017年3月10日，國際知名學術期刊《PLOS genetics》線上發表北京大學生命科學中心陸劍課題組題為“Adaptation of A-to-I RNA editing in Drosophila”的研究論文。論文揭示了果蠅RNA編輯的適應性演化。博士生段元格、生科院博士生竇聖乾、博士後羅詩琦是論文的第一作者，生科院博士生張宏為論文的共同作者，陸劍研究員為論文的通訊作者。

突變是生物體改變性狀以及適應性演化的源泉。在多細胞生物中，非同義DNA突變會在全部細胞中改變蛋白產物。這種“全有或全無”的特性可能會在不同的細胞、組織或器官間產生拮抗作用。因此， DNA突變的多效性會極大地限制生物體的遺傳多樣性，

降低生物體的適合度。腺嘌呤到次黃嘌呤(A-to-I)RNA編輯是動物中廣泛存在的轉錄後修飾，在不改變基因組序列的情況下增加了蛋白產物的多樣性，規避了DNA突變多效性的局限，對生物體的適應性演化可能有重要的作用。

果蠅的RNA編輯主要發生在神經系統，且大量的RNA編輯位元點位於蛋白編碼區。陸劍研究組在黑腹果蠅大腦轉錄組中鑒定到2114個A-to-I編輯位點，其中678個潛在改變蛋白質序列(非同義， Nonsyn)，而且這些Nonsyn編輯位點主要富集在神經功能相關的基因。與同義(Syn)RNA編輯位點相比， Nonsyn位點呈現出非常強的適應性演化信號: 1)Nonsyn位點在mRNA上發生的密度顯著高於中性(隨機)情況下的期望值， 2)Nonsyn比Syn位點有更高的編輯水準。通過對近緣種擬果蠅和擬暗果蠅大腦轉錄組的深度測序及演化基因組學分析，

發現近一半的編輯位點是在演化上保守的。需要指出的是， DNA序列越保守的基因上非同義RNA編輯位元點的密度越高，從而在表觀遺傳學層面拓寬了序列的多樣性。比較基因學分析表明， RNA編輯在演化過程中是高度動態的，新的RNA編輯位點不斷產生，而那些被功能已建立的編輯事件則在漫長演化過程中被自然選擇作用所保留下來。研究還發現在高溫脅迫實驗中，溫度對RNA編輯水準的影響超過了性別因素，揭示了RNA編輯可能參與果蠅的脅迫應答。該研究揭示了果蠅RNA編輯在演化上的適應性，對認識RNA編輯的演化和功能提供了新思路。

同期斯坦福大學Billy Jin Li教授研究組也利用比較基因組學方法在果蠅中發現大量的位於編碼區和非編碼區的RNA編輯事件，

並揭示了順式調控元件對這些編輯位元點演化模式的作用機制。論文題為“Evolutionary analysis reveals regulatory and functional landscape of coding and non-coding RNA editing”。

果蠅腦組織中RNA編輯位元點的鑒定和演化適應性

(A)鑒定黑腹果蠅腦組織RNA編輯位元點的流程;(B)不同果蠅物種的RNA編輯位點的演化關係;(C)RNA編輯位元點的密度與基因/位元點保守性的關係;(D)不同溫度條件下編輯水準的對比;(E)果蠅不同發育階段的RNA編輯酶ADAR與PSEB基因的表達情況。

原文連結：

Adaptation of A-to-I RNAediting in Drosophila

原文摘要：

Adenosine-to-inosine (A-to-I) editing is hypothesized to facilitate adaptive evolution by expanding proteomic diversity through an epigenetic approach. However, it is challenging to provide evidences to support this hypothesis at the whole editome level. In this study, we systematically characterized 2,114 A-to-I RNA editing sites in female and male brains of D.melanogaster, and nearly half of these sites had events evolutionarily conserved acrossDrosophila species. We detected strong signatures of positive selection on the nonsynonymous editing sites in Drosophila brains, and the beneficial editing sites were significantly enriched in genes related to chemical and electrical neurotransmission. The signal of adaptation was even more pronounced for the editing sites located in X chromosome or for those commonly observed across Drosophila species. We identified a set of gene candidates (termed “PSEB” genes) that had nonsynonymous editing events favored by natural selection. We presented evidence that editing preferentially increased mutation sequence space of evolutionarily conserved genes, which supported the adaptive evolution hypothesis of editing. We found prevalent nonsynonymous editing sites that were favored by natural selection in female and male adults from five strains of D. melanogaster. We showed that temperature played a more important role than gender effect in shaping the editing levels, although the effect of temperature is relatively weaker compared to that of species effect. We also explored the relevant factors that shape the selective patterns of the global editomes. Altogether we demonstrated that abundant nonsynonymous editing sites in Drosophila brains were adaptive and maintained by natural selection during evolution. Our results shed new light on the evolutionary principles and functional consequences of RNA editing.

作者：陸劍點擊：次