title: Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain.
abstract: 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.
authors.affiliation: Departments of Neurobiology & Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Departments of Neurobiology & Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Elliott
authors.initials: E
authors.lastname: Ferris
authors.affiliation: Departments of Neurobiology & Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Departments of Neurobiology & Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Cornelia Stacher
authors.initials: CS
authors.lastname: Hörndli
authors.affiliation: Department of Psychiatry, UT Southwestern, Dallas, TX 75390-9127, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Gleason
authors.affiliation: Department of Psychiatry, UT Southwestern, Dallas, TX 75390-9127, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Tamminga
authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Janice D
authors.initials: JD
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Cancer Biostatistics Shared Resource, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boucher
authors.affiliation: Departments of Neurobiology & Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Jan L
authors.initials: JL
authors.lastname: Christian
authors.affiliation: Robertson Neuroscience Investigator, New York Stem Cell Foundation, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Departments of Neurobiology & Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: chris.gregg@neuro.utah.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gregg
mesh_terms: D000483:Alleles; D000818:Animals; D001921:Brain / Q000378:metabolism*; D014644:Genetic Variation / Q000235:genetics*; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D008251:Macaca; D008322:Mammals; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D049951:X Chromosome Inactivation / Q000502:physiology*
keywords: allele-specific expression; autism; behavioral genetics; brain development; brain epigenetics; genomic imprinting; mental illness; monoallelic; random monoallelic expression; transcriptome