Erwin Jennifer A, Paquola Apuã C M, Singer Tatjana, Gallina Iryna, Novotny Mark, Quayle Carolina, Bedrosian Tracy A, Alves Francisco I A, Butcher Cheyenne R, Herdy Joseph R, Sarkar Anindita, Lasken Roger S, Muotri Alysson R, Gage Fred H
The Salk Institute for Biological Studies, La Jolla, California, USA.
Department of Cellular &Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, California, USA.
Nat Neurosci. 2016 Dec;19(12):1583-1591. doi: 10.1038/nn.4388. Epub 2016 Sep 12.
The healthy human brain is a mosaic of varied genomes. Long interspersed element-1 (LINE-1 or L1) retrotransposition is known to create mosaicism by inserting L1 sequences into new locations of somatic cell genomes. Using a machine learning-based, single-cell sequencing approach, we discovered that somatic L1-associated variants (SLAVs) are composed of two classes: L1 retrotransposition insertions and retrotransposition-independent L1-associated variants. We demonstrate that a subset of SLAVs comprises somatic deletions generated by L1 endonuclease cutting activity. Retrotransposition-independent rearrangements in inherited L1s resulted in the deletion of proximal genomic regions. These rearrangements were resolved by microhomology-mediated repair, which suggests that L1-associated genomic regions are hotspots for somatic copy number variants in the brain and therefore a heritable genetic contributor to somatic mosaicism. We demonstrate that SLAVs are present in crucial neural genes, such as DLG2 (also called PSD93), and affect 44-63% of cells of the cells in the healthy brain.
健康的人类大脑是一个由不同基因组组成的镶嵌体。已知长散在核元件-1（LINE-1或L1）逆转录转座通过将L1序列插入体细胞基因组的新位置来产生镶嵌性。使用基于机器学习的单细胞测序方法，我们发现体细胞L1相关变体（SLAVs）由两类组成：L1逆转录转座插入和逆转录转座非依赖性L1相关变体。我们证明，一部分SLAVs包括由L1内切酶切割活性产生的体细胞缺失。遗传L1中的逆转录转座非依赖性重排导致近端基因组区域的缺失。这些重排通过微同源性介导的修复得以解决，这表明L1相关基因组区域是大脑中体细胞拷贝数变体的热点，因此是体细胞镶嵌性的可遗传遗传因素。我们证明，SLAVs存在于关键神经基因中，如DLG2（也称为PSD93），并影响健康大脑中44%-63%的细胞。
