Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
PLoS One. 2012;7(8):e44017. doi: 10.1371/journal.pone.0044017. Epub 2012 Aug 30.
Stochastic processes and imprinting, along with genetic factors, lead to monoallelic or allele-biased gene expression. Stochastic monoallelic expression fine-tunes information processing in immune cells and the olfactory system, and imprinting plays an important role in development. Recent studies suggest that both stochastic events and imprinting may be more widespread than previously considered. We are interested in allele-biased gene expression occurring in the brain because parent-of-origin effects suggestive of imprinting appear to play a role in the transmission of schizophrenia (SZ) and autism spectrum disorders (ASD) in some families. In addition, allele-biased expression could help explain monozygotic (MZ) twin discordance and reduced penetrance. The ability to study allele-biased expression in human neurons has been transformed with the advent of induced pluripotent stem cell (iPSC) technology and next generation sequencing. Using transcriptome sequencing (RNA-Seq) we identified 801 genes in differentiating neurons that were expressed in an allele-biased manner. These included a number of putative SZ and ASD candidates, such as A2BP1 (RBFOX1), ERBB4, NLGN4X, NRG1, NRG3, NRXN1, and NLGN1. Overall, there was a modest enrichment for SZ and ASD candidate genes among those that showed evidence for allele-biased expression (chi-square, p = 0.02). In addition to helping explain MZ twin discordance and reduced penetrance, the capacity to group many candidate genes affecting a variety of molecular and cellular pathways under a common regulatory process - allele-biased expression - could have therapeutic implications.
随机过程和印迹与遗传因素一起导致单等位基因或等位基因偏向的基因表达。随机单等位基因表达精细调节免疫细胞和嗅觉系统中的信息处理，印迹在发育中起着重要作用。最近的研究表明，随机事件和印迹可能比以前认为的更为普遍。我们对大脑中发生的等位基因偏向的基因表达感兴趣，因为暗示印迹的亲本来源效应似乎在某些家庭中精神分裂症 (SZ) 和自闭症谱系障碍 (ASD) 的传播中起作用。此外，等位基因偏向的表达可以帮助解释同卵 (MZ) 双胞胎的不一致和降低的外显率。随着诱导多能干细胞 (iPSC) 技术和下一代测序技术的出现，研究人类神经元中等位基因偏向表达的能力发生了转变。使用转录组测序 (RNA-Seq)，我们在分化神经元中鉴定出 801 个以等位基因偏向方式表达的基因。其中包括一些假定的 SZ 和 ASD 候选基因，如 A2BP1 (RBFOX1)、ERBB4、NLGN4X、NRG1、NRG3、NRXN1 和 NLGN1。总的来说，在表现出等位基因偏向表达证据的基因中，SZ 和 ASD 候选基因适度富集 (卡方，p = 0.02)。除了帮助解释 MZ 双胞胎的不一致和降低的外显率之外，将影响多种分子和细胞途径的许多候选基因分组到一个共同的调节过程——等位基因偏向表达——下的能力可能具有治疗意义。
