Analysis of LINE-1 Elements in DNA from Postmortem Brains of Individuals with Schizophrenia
Analysis of LINE-1 Elements in DNA from Postmortem Brains of Individuals with Schizophrenia
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DOI：
10.1038/npp.2017.115
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发表时间：
2017-12-01
影响因子：
7.6
通讯作者：
Berrettini, Wade H.
中科院分区：
文献类型：
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作者：
Doyle, Glenn A.;Crist, Richard C.;Berrettini, Wade H.
虽然一些罕见的遗传变异传达了精神分裂症（SZ）的高风险，但传达中度风险的常见等位基因仍然难以捉摸。长散布元件-1（L1）是移动的反转录转座子，其包含约17%的人类基因组。在神经发育过程中，L1反转录转座可通过插入突变引起体细胞嵌合现象。我们假设，与对照组相比，诊断为精神分裂症（PDS）的患者可能有更多的有害L1插入，可能发生从头，在背外侧前额叶皮层（DLPFC）神经元的脑表达基因。神经元和非神经元细胞核分离的荧光激活细胞分选从36 PDS和26年龄匹配的对照组死后DLPFC。从神经元DNA扩增L1的3 '侧侧翼的基因组序列，并对神经元L1文库进行测序。使用定制的生物信息学程序分析比对序列的L1插入。对PDS和对照组中L1破坏的puptide基因列表进行了本体论和途径分析。通过液滴数字PCR或Taqman基因分型评估L1的细胞或群体等位基因频率。我们观察到PDS的DLPFC中基因内新L1的比例在统计学上显著增加。我们发现过度代表性的L1插入内的基因本体“细胞投影”和“突触后膜”的基因列表中来自PDS样本，但不是从控制。检测的L1插入的细胞等位基因频率表明DLPFC细胞基因组中的杂合性。发现ERI 1核糖核酸外切酶家族成员3（ERI 3）内的L1与SZ相关。这些结果扩展了先前的工作，记录了PDS大脑中L1遗传负担的增加，并确定了独特的基因，可能为精神分裂症的病理生理学提供新的见解。
Whereas some rare genetic variants convey high risk for schizophrenia (SZ), common alleles conveying even moderate risk remain elusive. Long interspersed element-1s (L1) are mobile retrotransposons comprising similar to 17% of the human genome. L1 retrotransposition can cause somatic mosaicism during neurodevelopment by insertional mutagenesis. We hypothesized that, compared to controls, patients diagnosed with schizophrenia (PDS) may have increased numbers of deleterious L1 insertions, perhaps occurring de novo, in brain-expressed genes of dorsolateral prefrontal cortex (DLPFC) neurons. Neuronal and non-neuronal nuclei were separated by fluorescence-activated cell sorting from postmortem DLPFC of 36 PDS and 26 age-matched controls. Genomic sequences flanking the 3'-side of L1s were amplified from neuronal DNA, and neuronal L1 libraries were sequenced. Aligned sequences were analyzed for L1 insertions using custom bioinformatics programs. Ontology and pathway analyses were done on lists of genes putatively disrupted by L1s in PDS and controls. Cellular or population allele frequencies of L1s were assessed by droplet digital PCR or Taqman genotyping. We observed a statistically significant increase in the proportion of intragenic novel L1s in DLPFC of PDS. We found over-representation of L1 insertions within the gene ontologies 'cell projection' and 'postsynaptic membrane' in the gene lists derived from PDS samples, but not from controls. Cellular allele frequencies of examined L1 insertions indicated heterozygosity in genomes of DLPFC cells. An L1 within ERI1 exoribonuclease family member 3 (ERI3) was found to associate with SZ. These results extend prior work documenting increased L1 genetic burden in the brains of PDS and also identify unique genes that may provide new insight into the pathophysiology of schizophrenia.