title: Brain enhancer activities at the gene-poor 5p14.1 autism-associated locus.
abstract: Due to the vast clinical and genetic heterogeneity, identification of causal genetic determinants for autism spectrum disorder (ASD) has proven to be complex. Whereas several dozen 'rare' genetic variants for ASD susceptibility have been identified, studies are still underpowered to analyse 'common' variants for their subtle effects. A recent application of genome-wide association studies (GWAS) to ASD indicated significant associations with the single nucleotide polymorphisms (SNPs) on chromosome 5p14.1, located in a non-coding region between cadherin10 (CDH10) and cadherin9 (CDH9). Here we apply an in vivo bacterial artificial chromosome (BAC) based enhancer-trapping strategy in mice to scan the gene desert for spatiotemporal cis-regulatory activities. Our results show that the ASD-associated interval harbors the cortical area, striatum, and cerebellum specific enhancers for a long non-coding RNA, moesin pseudogene1 antisense (MSNP1AS) during the brain developing stages. Mouse moesin protein levels are not affected by exogenously expressed human antisense RNAs in our transgenic brains, demonstrating the difficulty in modeling rather smaller effects of common variants. Our first in vivo evidence for the spatiotemporal transcription of MSNP1AS however provides a further support to connect this intergenic variant with the ASD susceptibility.
authors: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Ogawahigashi, 4-1-1, Kodaira, Tokyo 187-8502, Japan.
authors: Yukiko U
authors: YU
authors: Inoue
authors: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Ogawahigashi, 4-1-1, Kodaira, Tokyo 187-8502, Japan.
authors: Takayoshi
authors: T
authors: Inoue
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D015820:Cadherins / Q000235:genetics; D022202:Chromosomes, Artificial, Bacterial; D002895:Chromosomes, Human, Pair 5; D019295:Computational Biology; D005821:Genetic Techniques; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: C107751:CDH10 protein, human; C430712:CDH9 protein, human; D015820:Cadherins; D008840:Microfilament Proteins; D016376:Oligonucleotides, Antisense; D062085:RNA, Long Noncoding; C071058:moesin