Human L1 Transposition Dynamics Unraveled with Functional Data Analysis.
Human L1 Transposition Dynamics Unraveled with Functional Data Analysis.
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DOI：
10.1093/molbev/msaa194
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发表时间：
2020-07
影响因子：
10.7
通讯作者：
Di Chen;Marzia A. Cremona;Zongtai Qi;R. Mitra;Francesca Chiaromonte;K. Makova
中科院分区：
文献类型：
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作者：
Di Chen;Marzia A. Cremona;Zongtai Qi;R. Mitra;Francesca Chiaromonte;K. Makova
长散布元件-1（L1）占人类基因组的17%以上，并且仍然在其中活跃地转座。表征L1在基因组中的转座对于理解基因组进化和体细胞突变至关重要。然而，迄今为止，L1插入和固定模式尚未得到全面研究。为了填补这一空白，我们研究了在不同进化时间整合的三个全基因组L1数据集：17，037个从头L1（来自内部进行的L1插入细胞系实验），以及1，212个多态性和1，205个人类特异性L1（来自公共数据库）。我们鉴定了49个基因组特征，包括染色质可及性、转录活性、复制、重组等。在这些元件的±50 kb侧翼中。使用最先进的功能数据分析（FDA）统计方法，将高分辨率数据视为数学函数，在三个L1数据集和无L1区域之间对比这些特征。我们的研究结果表明，从头，多态性和人类特异性L1被不同的基因组特征包围在特定的位置和规模。这导致了L1转座的整合模型，根据该模型，L1优先整合到富含非B DNA基序的开放染色质区域中，而它们被固定在基本上没有纯化选择耗尽的基因和非编码最保守元件的区域中。有趣的是，我们的研究结果表明，L1插入通过延长CpG甲基化和增加单核苷酸微卫星密度来改变局部基因组景观。总而言之，我们的研究结果大大促进了对L1整合和固定偏好的理解，为揭示它们在衰老和癌症中的作用铺平了道路，并为它们在遗传研究中作为诱变工具提供了信息。
Long Interspersed Elements-1 (L1s) constitute >17% of the human genome and still actively transpose in it. Characterizing L1 transposition across the genome is critical for understanding genome evolution and somatic mutations. However, to date, L1 insertion and fixation patterns have not been studied comprehensively. To fill this gap, we investigated three genome-wide datasets of L1s that integrated at different evolutionary times: 17,037 de novo L1s (from an L1 insertion cell-line experiment conducted in-house), and 1,212 polymorphic and 1,205 human-specific L1s (from public databases). We characterized 49 genomic features-proxying chromatin accessibility, transcriptional activity, replication, recombination, etc.-in the ±50 kb flanks of these elements. These features were contrasted between the three L1 datasets and L1-free regions using state-of-the-art Functional Data Analysis (FDA) statistical methods, which treat high-resolution data as mathematical functions. Our results indicate that de novo, polymorphic and human-specific L1s are surrounded by different genomic features acting at specific locations and scales. This led to an integrative model of L1 transposition, according to which L1s preferentially integrate into open-chromatin regions enriched in non-B DNA motifs, whereas they are fixed in regions largely free of purifying selection-depleted of genes and non-coding most conserved elements. Intriguingly, our results suggest that L1 insertions modify local genomic landscape by extending CpG methylation and increasing mononucleotide microsatellite density. Altogether, our findings substantially facilitate understanding of L1 integration and fixation preferences, pave the way for uncovering their role in aging and cancer, and inform their use as mutagenesis tools in genetic studies.