Evrony Gilad D, Lee Eunjung, Mehta Bhaven K, Benjamini Yuval, Johnson Robert M, Cai Xuyu, Yang Lixing, Haseley Psalm, Lehmann Hillel S, Park Peter J, Walsh Christopher A
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
Neuron. 2015 Jan 7;85(1):49-59. doi: 10.1016/j.neuron.2014.12.028.
Somatic mutations occur during brain development and are increasingly implicated as a cause of neurogenetic disease. However, the patterns in which somatic mutations distribute in the human brain are unknown. We used high-coverage whole-genome sequencing of single neurons from a normal individual to identify spontaneous somatic mutations as clonal marks to track cell lineages in human brain. Somatic mutation analyses in >30 locations throughout the nervous system identified multiple lineages and sublineages of cells marked by different LINE-1 (L1) retrotransposition events and subsequent mutation of poly-A microsatellites within L1. One clone contained thousands of cells limited to the left middle frontal gyrus, whereas a second distinct clone contained millions of cells distributed over the entire left hemisphere. These patterns mirror known somatic mutation disorders of brain development and suggest that focally distributed mutations are also prevalent in normal brains. Single-cell analysis of somatic mutation enables tracing of cell lineage clones in human brain.
体细胞突变发生在大脑发育过程中，并且越来越多地被认为是神经遗传疾病的一个病因。然而，体细胞突变在人类大脑中的分布模式尚不清楚。我们对一名正常个体的单个神经元进行了高覆盖度的全基因组测序，以识别自发的体细胞突变作为克隆标记，从而追踪人类大脑中的细胞谱系。在整个神经系统的30多个位置进行的体细胞突变分析确定了多个细胞谱系和亚谱系，这些谱系由不同的LINE-1（L1）逆转录转座事件以及随后L1内多聚腺苷微卫星的突变所标记。一个克隆包含数千个局限于左额中回的细胞，而另一个不同的克隆包含数百万个分布在整个左半球的细胞。这些模式反映了已知的大脑发育体细胞突变疾病，并表明局灶性分布的突变在正常大脑中也很普遍。体细胞突变的单细胞分析能够追踪人类大脑中的细胞谱系克隆。
