Co-option of the lineage-specific LAVA retrotransposon in the gibbon genome[RNA-Seq]

Co-option of transposable elements (TEs) to become part of existing or new enhancers is an important mechanism for evolution of gene regulation. However, contributions of lineage-specific TE insertions to recent regulatory adaptations remain poorly understood. Gibbons present a suitable model to study these contributions as they have evolved a lineage-specific TE called LAVA (LINE-AluSz-VNTR-AluLIKE), which is still active in the gibbon genome. The LAVA retrotransposon is thought to have played a role in the emergence of the highly rearranged structure of the gibbon genome by disrupting transcription of cell cycle genes. In this study, we investigated whether LAVA may have also contributed to the evolution of gene regulation by adopting enhancer function. We characterized fixed and polymorphic LAVA insertions across multiple gibbons and found 96 LAVA elements overlapping enhancer chromatin states. Moreover, LAVA was enriched in multiple transcription factor binding motifs, was bound by an important transcription factor (PU.1), and was associated with higher levels of gene expression in cis. We found gibbon-specific signatures of purifying/positive selection at 27 LAVA insertions. Two of these insertions were fixed in the gibbon lineage and overlapped with enhancer chromatin states, representing putative co-opted LAVA enhancers. These putative enhancers were located within genes encoding SETD2 and RAD9A, two proteins that facilitate accurate repair of DNA double-strand breaks and prevent chromosomal rearrangement mutations. Co-option of LAVA in these genes may have influenced regulation of processes that preserve genome integrity. Our findings highlight the importance of considering lineage-specific TEs in studying evolution of gene regulatory elements. RNA-seq data was collected from EBV-transformed lymphocyte cell lines established from 9 different Nomascus leucogenys gibbons

转座元件（transposable elements, TEs）被共选择为现有或新型增强子的组成部分，是基因调控进化的重要机制。然而，谱系特异性转座元件插入对近期调控适应的贡献仍不甚明晰。长臂猿是研究此类贡献的理想模型，其演化出了一种名为LAVA（LINE-AluSz-VNTR-AluLIKE）的谱系特异性转座元件，该元件在长臂猿基因组中仍具有转座活性。研究认为，LAVA反转录转座子通过干扰细胞周期基因的转录，在长臂猿基因组高度重排结构的形成过程中发挥了作用。本研究旨在探讨LAVA是否可通过获得增强子功能，参与基因调控的进化过程。我们对多只长臂猿中的固定型与多态型LAVA插入位点进行了系统表征，发现共有96个LAVA元件与增强子染色质状态存在重叠。此外，LAVA富集多种转录因子结合基序，可被关键转录因子PU.1结合，并与顺式基因的更高表达水平显著相关。我们在27个LAVA插入位点中检测到了长臂猿特异性的纯化选择/正向选择信号。其中两个插入位点在长臂猿谱系中已固定，且与增强子染色质状态重叠，属于推定的共选择LAVA增强子。这些推定增强子位于SETD2与RAD9A编码基因内部，这两种蛋白可促进DNA双链断裂的精准修复，并抑制染色体重排类突变的发生。这些基因中LAVA的共选择事件，可能影响了维持基因组完整性的相关调控过程。本研究结果凸显了在基因调控元件进化研究中纳入谱系特异性转座元件的重要性。本研究的转录组测序（RNA-seq）数据，采集自9只不同的白颊长臂猿（Nomascus leucogenys）建立的EBV转化淋巴细胞系。