Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain

• Published in: Neuron (Cambridge, Mass.) Vol. 93; no. 5; pp. 1094 - 1109.e7
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.03.2017; Elsevier Limited
• Subjects: allele-specific expression; Alleles; Animals; autism; behavioral genetics; Brain; Brain - metabolism; brain development; brain epigenetics; Epigenetics; Gene expression; Genetic diversity; Genetic Variation - genetics; Genomes; Genomic Imprinting; Genomics; Genotype; Humans; Imprinting; Intellectual disabilities; Macaca; Mammals; Mental disorders; mental illness; Mice, Transgenic; Monkeys & apes; monoallelic; Mosaics; Mutation; Mutation - genetics; Neonates; Noise; random monoallelic expression; Stem cells; Studies; transcriptome; X Chromosome Inactivation - physiology; brain epigenetics; brain development; behavioral genetics; allele-specific expression; mental illness; monoallelic; transcriptome; genomic imprinting; random monoallelic expression; autism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2017.01.033

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. [Display omitted] •In vivo genome-wide screen uncovers diverse non-genetic allelic effects•Non-genetic allelic effects are prevalent in the neonatal mouse brain•Allelic effects cause mosaics of mutant and wild-type cells for heterozygous mutations•Allelic effects exist in the primate brain and impact genes linked to mental illness Huang and Ferris et al. uncover diverse forms of non-genetic allelic effects in vivo in the mouse and primate brain that can interact with heterozygous mutations to generate mosaics of brain cells that differentially express mutant versus wild-type alleles.