Huang Wei-Chao, Ferris Elliott, Cheng Tong, Hörndli Cornelia Stacher, Gleason Kelly, Tamminga Carol, Wagner Janice D, Boucher Kenneth M, Christian Jan L, Gregg Christopher
Departments of Neurobiology & Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Department of Psychiatry, UT Southwestern, Dallas, TX 75390-9127, USA.
Neuron. 2017 Mar 8;93(5):1094-1109.e7. doi: 10.1016/j.neuron.2017.01.033. Epub 2017 Feb 23.
Interactions between genetic and epigenetic effects shape brain function, behavior, and the risk for mental illness. Random X inactivation and genomic imprinting are epigenetic allelic effects that are well known to influence genetic architecture and disease risk. Less is known about the nature, prevalence, and conservation of other potential epigenetic allelic effects in vivo in the mouse and primate brain. Here we devise genomics, in situ hybridization, and mouse genetics strategies to uncover diverse allelic effects in the brain that are not caused by imprinting or genetic variation. We found allelic effects that are developmental stage and cell type specific, that are prevalent in the neonatal brain, and that cause mosaics of monoallelic brain cells that differentially express wild-type and mutant alleles for heterozygous mutations. Finally, we show that diverse non-genetic allelic effects that impact mental illness risk genes exist in the macaque and human brain. Our findings have potential implications for mammalian brain genetics. VIDEO ABSTRACT.
基因效应与表观遗传效应之间的相互作用塑造了脑功能、行为以及精神疾病风险。随机X染色体失活和基因组印记是表观遗传等位基因效应，它们对遗传结构和疾病风险的影响广为人知。而对于小鼠和灵长类动物大脑中其他潜在表观遗传等位基因效应的性质、普遍性和保守性，我们了解得较少。在此，我们设计了基因组学、原位杂交和小鼠遗传学策略，以揭示大脑中并非由印记或基因变异引起的多种等位基因效应。我们发现了等位基因效应具有发育阶段和细胞类型特异性，在新生大脑中普遍存在，并且会导致单等位脑细胞镶嵌体，这些镶嵌体对于杂合突变会差异表达野生型和突变等位基因。最后，我们表明猕猴和人类大脑中存在影响精神疾病风险基因的多种非遗传等位基因效应。我们的发现对哺乳动物脑遗传学具有潜在意义。视频摘要。
