De novo genes with an lncRNA origin encode unique human brain developmental functionality.
De novo genes with an lncRNA origin encode unique human brain developmental functionality.
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DOI：
10.1038/s41559-022-01925-6
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发表时间：
2023-02
影响因子：
16.8
通讯作者：
中科院分区：
文献类型：
--
作者：
人类从头基因可以起源于中性长非编码RNA（lncRNA）基因座，并且通常在进化上具有重要意义，但这种全有或全无的功能转变如何以及为什么发生仍不清楚。在这里，在74个人类/类人猿特异性从头基因中，我们确定了独特的U1元件和RNA剪接相关序列，这些序列负责RNA核输出，区分mRNA和lncRNA，并驱动从头基因从lncRNA位点的起源。通过调节核输出促进lncRNA-mRNA转换的多态性位点被选择性地限制，保持区分mRNA和lncRNA的边界。因此，活跃地通过它的功能性新基因表现出一种适应前起源的模式，因为它们沿着其编码潜能的实现而获得功能。作为概念的证明，我们验证了剪接和U1识别对这些基因之一ENSG 00000205704在人类神经祖细胞中的核输出效率的调节。值得注意的是，在人胚胎干细胞中敲除或过表达该基因分别加速或延迟皮质类器官的神经元成熟。异位表达ENSG 00000205704的转基因小鼠显示出大脑扩大，皮质扩张。因此，我们证明了核输出在从头基因起源中的关键作用。这些新产生的基因应该反映了人类大脑发育的独特性。通过研究源自长链非编码RNA的人类特异性从头基因，作者揭示了促进这些年轻基因核输出的分子机制，并为此类基因在大脑发育中的作用提供了实验证据。
Human de novo genes can originate from neutral long non-coding RNA (lncRNA) loci and are evolutionarily significant in general, yet how and why this all-or-nothing transition to functionality happens remains unclear. Here, in 74 human/hominoid-specific de novo genes, we identified distinctive U1 elements and RNA splice-related sequences accounting for RNA nuclear export, differentiating mRNAs from lncRNAs, and driving the origin of de novo genes from lncRNA loci. The polymorphic sites facilitating the lncRNA–mRNA conversion through regulating nuclear export are selectively constrained, maintaining a boundary that differentiates mRNAs from lncRNAs. The functional new genes actively passing through it thus showed a mode of pre-adaptive origin, in that they acquire functions along with the achievement of their coding potential. As a proof of concept, we verified the regulations of splicing and U1 recognition on the nuclear export efficiency of one of these genes, the ENSG00000205704, in human neural progenitor cells. Notably, knock-out or over-expression of this gene in human embryonic stem cells accelerates or delays the neuronal maturation of cortical organoids, respectively. The transgenic mice with ectopically expressed ENSG00000205704 showed enlarged brains with cortical expansion. We thus demonstrate the key roles of nuclear export in de novo gene origin. These newly originated genes should reflect the novel uniqueness of human brain development. Studying human-specific de novo genes originated from long non-coding RNA, the authors reveal molecular mechanisms that facilitate nuclear export of these young genes, and show experimental evidence for the role of one such gene in brain development.
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DOI：
10.1261/rna.053561.115
发表时间：
2016-06
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Carlevaro-Fita J;Rahim A;Guigó R;Vardy LA;Johnson R
通讯作者：
Johnson R
DOI：
10.1126/science.1260793
发表时间：
2015-02-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Battle A;Khan Z;Wang SH;Mitrano A;Ford MJ;Pritchard JK;Gilad Y
通讯作者：
Gilad Y
影响因子：
3.3
作者：
Begun, David J.;Lindfors, Heather A.;Jones, Corbin D.
通讯作者：
Jones, Corbin D.
影响因子：
3.6
作者：
Berthelot, K;Muldoon, M;McCarthy, JEG
通讯作者：
McCarthy, JEG
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS