Function and Regulation of AUTS2, a Gene Implicated in Autism and Human Evolution
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{"title"=>"Function and Regulation of AUTS2, a Gene Implicated in Autism and Human Evolution", "type"=>"journal", "authors"=>[{"first_name"=>"Nir", "last_name"=>"Oksenberg", "scopus_author_id"=>"26023675900"}, {"first_name"=>"Laurie", "last_name"=>"Stevison", "scopus_author_id"=>"6504611122"}, {"first_name"=>"Jeffrey D.", "last_name"=>"Wall", "scopus_author_id"=>"7201352010"}, {"first_name"=>"Nadav", "last_name"=>"Ahituv", "scopus_author_id"=>"8510545900"}], "year"=>2013, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"368295382", "pmid"=>"23349641", "scopus"=>"2-s2.0-84873506311", "sgr"=>"84873506311", "isbn"=>"10.1371/journal.pgen.1003221", "issn"=>"15537390", "doi"=>"10.1371/journal.pgen.1003221"}, "id"=>"9e95e4cb-6c3b-348c-ae63-4ef0b05dcd5c", "abstract"=>"Nucleotide changes in the AUTS2 locus, some of which affect only noncoding regions, are associated with autism and other neurological disorders, including attention deficit hyperactivity disorder, epilepsy, dyslexia, motor delay, language delay, visual impairment, microcephaly, and alcohol consumption. In addition, AUTS2 contains the most significantly accelerated genomic region differentiating humans from Neanderthals, which is primarily composed of noncoding variants. However, the function and regulation of this gene remain largely unknown. To characterize auts2 function, we knocked it down in zebrafish, leading to a smaller head size, neuronal reduction, and decreased mobility. To characterize AUTS2 regulatory elements, we tested sequences for enhancer activity in zebrafish and mice. We identified 23 functional zebrafish enhancers, 10 of which were active in the brain. Our mouse enhancer assays characterized three mouse brain enhancers that overlap an ASD-associated deletion and four mouse enhancers that reside in regions implicated in human evolution, two of which are active in the brain. Combined, our results show that AUTS2 is important for neurodevelopment and expose candidate enhancer sequences in which nucleotide variation could lead to neurological disease and human-specific traits.", "link"=>"http://www.mendeley.com/research/function-regulation-auts2-gene-implicated-autism-human-evolution", "reader_count"=>118, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>20, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>33, "Student > Postgraduate"=>5, "Student > Master"=>11, "Other"=>10, "Student > Bachelor"=>21, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>20, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>33, "Student > Postgraduate"=>5, "Student > Master"=>11, "Other"=>10, "Student > Bachelor"=>21, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Agricultural and Biological Sciences"=>57, "Arts and Humanities"=>1, "Business, Management and Accounting"=>1, "Computer Science"=>1, "Engineering"=>1, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>12, "Medicine and Dentistry"=>21, "Neuroscience"=>8, "Design"=>1, "Sports and Recreations"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>1, "Psychology"=>6, "Social Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>21}, "Social Sciences"=>{"Social Sciences"=>1}, "Sports and Recreations"=>{"Sports and Recreations"=>2}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>6}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Arts and Humanities"=>{"Arts and Humanities"=>1}, "Design"=>{"Design"=>1}, "Engineering"=>{"Engineering"=>1}, "Neuroscience"=>{"Neuroscience"=>8}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>57}, "Computer Science"=>{"Computer Science"=>1}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>12}}, "reader_count_by_country"=>{"Netherlands"=>2, "South Korea"=>1, "United States"=>5, "Luxembourg"=>1, "Brazil"=>2, "United Kingdom"=>1, "France"=>2, "Germany"=>1}, "group_count"=>6}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/276420", "https://ndownloader.figshare.com/files/276447", "https://ndownloader.figshare.com/files/276482", "https://ndownloader.figshare.com/files/276518", "https://ndownloader.figshare.com/files/276637", "https://ndownloader.figshare.com/files/276693", "https://ndownloader.figshare.com/files/276710", "https://ndownloader.figshare.com/files/276811"], "description"=>"<div><p>Nucleotide changes in the <em>AUTS2</em> locus, some of which affect only noncoding regions, are associated with autism and other neurological disorders, including attention deficit hyperactivity disorder, epilepsy, dyslexia, motor delay, language delay, visual impairment, microcephaly, and alcohol consumption. In addition, <em>AUTS2</em> contains the most significantly accelerated genomic region differentiating humans from Neanderthals, which is primarily composed of noncoding variants. However, the function and regulation of this gene remain largely unknown. To characterize <em>auts2</em> function, we knocked it down in zebrafish, leading to a smaller head size, neuronal reduction, and decreased mobility. To characterize <em>AUTS2</em> regulatory elements, we tested sequences for enhancer activity in zebrafish and mice. We identified 23 functional zebrafish enhancers, 10 of which were active in the brain. Our mouse enhancer assays characterized three mouse brain enhancers that overlap an ASD–associated deletion and four mouse enhancers that reside in regions implicated in human evolution, two of which are active in the brain. Combined, our results show that <em>AUTS2</em> is important for neurodevelopment and expose candidate enhancer sequences in which nucleotide variation could lead to neurological disease and human-specific traits.</p> </div>", "links"=>[], "tags"=>["implicated", "autism", "evolution"], "article_id"=>114483, "categories"=>["Neuroscience", "Genetics", "Evolutionary Biology"], "users"=>["Nir Oksenberg", "Laurie Stevison", "Jeffrey D. Wall", "Nadav Ahituv"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003221.s001", "https://dx.doi.org/10.1371/journal.pgen.1003221.s002", "https://dx.doi.org/10.1371/journal.pgen.1003221.s003", "https://dx.doi.org/10.1371/journal.pgen.1003221.s004", "https://dx.doi.org/10.1371/journal.pgen.1003221.s005", "https://dx.doi.org/10.1371/journal.pgen.1003221.s006", "https://dx.doi.org/10.1371/journal.pgen.1003221.s007", "https://dx.doi.org/10.1371/journal.pgen.1003221.s008"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Function_and_Regulation_of_AUTS2_a_Gene_Implicated_in_Autism_and_Human_Evolution__/114483", "title"=>"Function and Regulation of <em>AUTS2</em>, a Gene Implicated in Autism and Human Evolution", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-01-17 01:14:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/505093"], "description"=>"<p>Human accelerated sequences are shown as blue lines above the gene <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Green1\" target=\"_blank\">[17]</a>–<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Prabhakar1\" target=\"_blank\">[19]</a>. Structural variants <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Sultana1\" target=\"_blank\">[4]</a>–<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Talkowski1\" target=\"_blank\">[12]</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Elia1\" target=\"_blank\">[14]</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Mefford1\" target=\"_blank\">[15]</a> are represented as colored lines (red: deletion, orange: inversion, green: duplication, purple: translocation). The rs6943555 SNP associated with alcohol consumption <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Schumann1\" target=\"_blank\">[16]</a> is shown as a magenta star. Arrows in bars signify that the structural variant extends past the gene in that direction. Exons are depicted as light blue rectangles, as defined by the RefSeq genes track in the UCSC Genome Browser <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Pruitt1\" target=\"_blank\">[52]</a>. Numbers to the left of the lines correspond to a reference number. Human Accelerated Conserved Non-coding Sequence (HACNS), Human Accelerated Region (HAR), developmental delay (DD), intellectual disability (ID), dysmorphic features (DF), seizure disorder (SD), multiple congenital anomalies (MCA), language disability (LD).</p>", "links"=>[], "tags"=>["genomic"], "article_id"=>175611, "categories"=>["Neuroscience", "Genetics", "Evolutionary Biology"], "users"=>["Nir Oksenberg", "Laurie Stevison", "Jeffrey D. Wall", "Nadav Ahituv"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003221.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_of_the_AUTS2_genomic_region_/175611", "title"=>"Schematic of the <i>AUTS2</i> genomic region.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-17 01:33:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/505183"], "description"=>"<p>(A) Fish injected with the 5 base-pair translational MO mismatch control have similar morphology as wild type fish. Injection of the <i>auts2</i> translational MO results in fish with a stunted development phenotype that includes a smaller head, eyes, body and fins. (B) HuC-GFP fish injected with the 5 bp control MO display normal levels of developing neurons in the brain. HuC-GFP translational MO injected fish display considerably less developing neurons in the optic tectum (ot), retina (ret), and cerebellum (ce). (C) 5 bp mismatch control injected fish have little to non-observable apoptosis in the brain as observed by TUNEL staining, while translational MO injected fish display high levels of apoptosis, primarily in the midbrain (mb) and hindbrain (hb). (D) PCNA cell proliferation assay in the 5 bp MO control injected fish shows lower levels of cell proliferation in the brain compared to the translational MO injected fish. (E) Tg(mnx1∶GFP) fish injected with the 5 bp MO control display normal levels of motor neurons versus the <i>auts2</i> translational MO injected fish which have fewer motor neurons in the spinal cord (sc). In addition, motor neuron projections (mnp) are weaker and more perpendicular to the spinal cord. (F) Translational MO injected fish display fewer Rohon-Beard cells (arrowheads) in the spinal cord than morphants. All morphant fish are scaled to their 5 bp control counterparts.</p>", "links"=>[], "tags"=>["48", "hpf", "morphant"], "article_id"=>175703, "categories"=>["Neuroscience", "Genetics", "Evolutionary Biology"], "users"=>["Nir Oksenberg", "Laurie Stevison", "Jeffrey D. Wall", "Nadav Ahituv"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003221.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_auts2_48_hpf_morphant_phenotype_/175703", "title"=>"<i>auts2</i> 48 hpf morphant phenotype.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-17 01:35:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/505300"], "description"=>"<p>Three positive enhancers (AEC27, 29, 32) show positive enhancer activity in zebrafish (24 or 48 hpf) and in mice (E11.5 or 12.5). AEC27 shows enhancer expression in the somitic muscle in zebrafish, while in mouse at E11.5 (hs658; <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Visel3\" target=\"_blank\">[34]</a>) it is active in the midbrain, medulla, and neural tube at E11.5. The histological section below shows its enhancer activity in the pretectum and the pons. At E12.5, AEC29 shows enhancer activity in the olfactory epithelium (arrows in histological section) similar to zebrafish and in addition also displays enhancer expression in the eye. AEC32 recapitulates the zebrafish enhancer expression displaying strong enhancer activity in the midbrain (tectum) and hindbrain and in addition also displays enhancer expression in the forebrain at E12.5. Histological sections of AEC32 show enhancer activity in the mouse cerebellum (red arrowheads).</p>", "links"=>[], "tags"=>["intronic", "deletion"], "article_id"=>175825, "categories"=>["Neuroscience", "Genetics", "Evolutionary Biology"], "users"=>["Nir Oksenberg", "Laurie Stevison", "Jeffrey D. Wall", "Nadav Ahituv"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003221.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Enhancers_within_an_ASD_associated_AUTS2_intronic_deletion_5_/175825", "title"=>"Enhancers within an ASD–associated <i>AUTS2</i> intronic deletion [<b>5</b>].", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-17 01:37:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/505401"], "description"=>"<p>At E12.5, AEC10 shows zebrafish and mouse enhancer expression in the midbrain and eye. The histological section below highlights its expression in the tectum. AEC13, is expressed in the otic vesicle both in zebrafish and E11.5 mouse embryos (hs1660 ; <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Visel3\" target=\"_blank\">[34]</a>). AEC21 is expressed in the spinal cord in zebrafish, while in the mouse it showed midbrain expression at E11.5 (hs1425; <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003221#pgen.1003221-Visel3\" target=\"_blank\">[34]</a>). Histological sections below show its expression in the pretectum of the midbrain. AEC24 was expressed in the spinal cord and hindbrain in zebrafish and in the eye in mouse at E12.5.</p>", "links"=>[], "tags"=>["zebrafish", "enhancers", "regions", "implicated"], "article_id"=>175917, "categories"=>["Neuroscience", "Genetics", "Evolutionary Biology"], "users"=>["Nir Oksenberg", "Laurie Stevison", "Jeffrey D. Wall", "Nadav Ahituv"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003221.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Four_positive_zebrafish_and_mouse_enhancers_in_regions_implicated_in_human_evolution_/175917", "title"=>"Four positive zebrafish and mouse enhancers in regions implicated in human evolution.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-17 01:38:37"}

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