Autism and Increased Paternal Age Related Changes in Global Levels of Gene Expression Regulation
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{"title"=>"Autism and increased paternal age related changes in global levels of gene expression regulation", "type"=>"journal", "authors"=>[{"first_name"=>"Mark D.", "last_name"=>"Alter", "scopus_author_id"=>"7103262211"}, {"first_name"=>"Rutwik", "last_name"=>"Kharkar", "scopus_author_id"=>"39863023400"}, {"first_name"=>"Keri E.", "last_name"=>"Ramsey", "scopus_author_id"=>"7004911515"}, {"first_name"=>"David W.", "last_name"=>"Craig", "scopus_author_id"=>"56760911500"}, {"first_name"=>"Raun D.", "last_name"=>"Melmed", "scopus_author_id"=>"7004864901"}, {"first_name"=>"Theresa A.", "last_name"=>"Grebe", "scopus_author_id"=>"7004670178"}, {"first_name"=>"R.", "last_name"=>"Curtis Bay", "scopus_author_id"=>"39862870400"}, {"first_name"=>"Sharman", "last_name"=>"Ober-Reynolds", "scopus_author_id"=>"36024084100"}, {"first_name"=>"Janet", "last_name"=>"Kirwan", "scopus_author_id"=>"39863084300"}, {"first_name"=>"Josh J.", "last_name"=>"Jones", "scopus_author_id"=>"39863113600"}, {"first_name"=>"J.", "last_name"=>"Blake Turner", "scopus_author_id"=>"13607421200"}, {"first_name"=>"Rene", "last_name"=>"Hen", "scopus_author_id"=>"7005852886"}, {"first_name"=>"Dietrich A.", "last_name"=>"Stephan", "scopus_author_id"=>"35238808400"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-79951941380", "pui"=>"361318929", "doi"=>"10.1371/journal.pone.0016715", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "sgr"=>"79951941380", "pmid"=>"21379579"}, "id"=>"d431ad2b-e642-31cc-b230-ba60253bab86", "abstract"=>"A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.", "link"=>"http://www.mendeley.com/research/autism-increased-paternal-age-related-changes-global-levels-gene-expression-regulation-3", "reader_count"=>61, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>4, "Librarian"=>1, "Researcher"=>17, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>16, "Student > Postgraduate"=>3, "Student > Master"=>6, "Other"=>1, "Student > Bachelor"=>4, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>4, "Librarian"=>1, "Researcher"=>17, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>16, "Student > Postgraduate"=>3, "Student > Master"=>6, "Other"=>1, "Student > Bachelor"=>4, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Engineering"=>2, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>30, "Medicine and Dentistry"=>6, "Neuroscience"=>3, "Psychology"=>4, "Chemistry"=>2, "Social Sciences"=>1, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Neuroscience"=>{"Neuroscience"=>3}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>30}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>5}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"United States"=>3, "Brazil"=>1, "United Kingdom"=>1, "Germany"=>2, "Croatia"=>1, "India"=>1, "Spain"=>1}, "group_count"=>5}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/797232"], "description"=>"<p>Traditional gene expression analyses were performed. Microarrays were processed and summarized using RMA. Post-summarization gene expression levels were quantile normalization because of the known group level differences at the level of the distribution. Probe sets were filtered for those that were called present in at least 50 of 146 samples. Figure 4a shows that there were more down-regulated than up-regulated genes in the blood of children with autism and children of older fathers when compared to children of younger fathers. 4b shows a very significant overlap (chi-squared  = 2,085, p<.00001) of down-regulated genes in children with autism and children of older fathers. Figure 4c demonstrates that overlapping down-regulated genes are enriched for biological pathways associated with transcription and zinc.</p>", "links"=>[], "tags"=>["genes", "enriched", "pathways", "transcription"], "article_id"=>467590, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Medicine"], "users"=>["Mark D. Alter", "Rutwik Kharkar", "Keri E. Ramsey", "David W. Craig", "Raun D. Melmed", "Theresa A. Grebe", "R. Curtis Bay", "Sharman Ober-Reynolds", "Janet Kirwan", "Josh J. Jones", "J. Blake Turner", "Rene Hen", "Dietrich A. Stephan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016715.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Down_regulated_genes_are_enriched_for_biological_pathways_related_to_transcription_and_zinc_/467590", "title"=>"Down-regulated genes are enriched for biological pathways related to transcription and zinc.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-17 02:06:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/797052"], "description"=>"<p>We used microarrays to measure the expression levels of greater than 47,000 transcripts including 38,500 well-characterized human genes using the Affymetrix Human U133 Plus 2.0 microarray on RNA from peripheral blood lymphocytes from each of 82 children with autism and 64 control subjects. Microarrays showed no group level differences in quality control measures. Microarray expression levels were log-transformed and the overall variance was calculated across the total distribution of expression levels on each microarray. Variance in gene expression was significantly decreased in the blood of children with autism (p = .006). Error bars represent standard error.</p>", "links"=>[], "tags"=>["variance", "peripheral", "lymphocytes", "was", "children"], "article_id"=>467412, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Medicine"], "users"=>["Mark D. Alter", "Rutwik Kharkar", "Keri E. Ramsey", "David W. Craig", "Raun D. Melmed", "Theresa A. Grebe", "R. Curtis Bay", "Sharman Ober-Reynolds", "Janet Kirwan", "Josh J. Jones", "J. Blake Turner", "Rene Hen", "Dietrich A. Stephan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016715.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overall_variance_in_gene_expression_in_peripheral_blood_lymphocytes_PBL_was_decreased_in_children_with_autism_/467412", "title"=>"Overall variance in gene expression in peripheral blood lymphocytes (PBL) was decreased in children with autism.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-17 02:03:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/797118"], "description"=>"<p>Paternal age at birth was found in multiple studies to be a risk factor for autism <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016715#pone.0016715-Reichenberg1\" target=\"_blank\">[26]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016715#pone.0016715-Malaspina2\" target=\"_blank\">[28]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016715#pone.0016715-Saha1\" target=\"_blank\">[34]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016715#pone.0016715-Malaspina3\" target=\"_blank\">[35]</a>. Previous work indicated that factors or interventions that modified mouse hippocampal-dependent behavior also modified the overall variance in gene expression in the predicted direction. In controls (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016715#pone-0016715-g003\" target=\"_blank\">figure 3a</a>) but not in children with autism (not shown), overall variance in log-transformed measures of gene expression was significantly and negatively associated with paternal age at birth (r = -.283, R<sup>2</sup> = .08, p = .03, number of subjects  = 57). For the evaluation of paternal age effects, paternal ages were available for 78 children with autism and 57 control children. To directly compare overall microarray variance in children with autism to children of older fathers, we divided subjects by the median paternal age at birth in our study (31 years) and created 2 groups: 1) children from younger fathers (less than 31 years) (65 subjects: 30 controls and 35 children with autism); and 2) children from older fathers (31 years or older) (70 subjects: 27 controls and 43 children with autism). We compared mean levels of overall variance between children with autism and controls of older and younger fathers. As predicted, we found that overall variance was the same in children of older fathers and children with autism with fathers of any age (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016715#pone-0016715-g003\" target=\"_blank\">figure 3b</a>). We found that the association of autism with decreased overall variance was only found in children of younger fathers and represented a difference of .78 standard deviations within our sample (p = .0007) (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016715#pone-0016715-g003\" target=\"_blank\">figure 3b</a>). Error bars represent standard error.</p>", "links"=>[], "tags"=>["paternal", "negatively", "variance", "peripheral", "lymphocytes"], "article_id"=>467473, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Medicine"], "users"=>["Mark D. Alter", "Rutwik Kharkar", "Keri E. Ramsey", "David W. Craig", "Raun D. Melmed", "Theresa A. Grebe", "R. Curtis Bay", "Sharman Ober-Reynolds", "Janet Kirwan", "Josh J. Jones", "J. Blake Turner", "Rene Hen", "Dietrich A. Stephan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016715.g003", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Increased_paternal_age_at_birth_is_negatively_associated_with_overall_variance_in_gene_expression_in_peripheral_blood_lymphocytes_PBL_of_normal_children_/467473", "title"=>"Increased paternal age at birth is negatively associated with overall variance in gene expression in peripheral blood lymphocytes (PBL) of normal children.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-17 02:04:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/398823", "https://ndownloader.figshare.com/files/398847", "https://ndownloader.figshare.com/files/398909", "https://ndownloader.figshare.com/files/398963", "https://ndownloader.figshare.com/files/399012"], "description"=>"<div><p>A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.</p> </div>", "links"=>[], "tags"=>["autism", "paternal", "changes", "levels"], "article_id"=>138768, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Medicine"], "users"=>["Mark D. Alter", "Rutwik Kharkar", "Keri E. Ramsey", "David W. Craig", "Raun D. Melmed", "Theresa A. Grebe", "R. Curtis Bay", "Sharman Ober-Reynolds", "Janet Kirwan", "Josh J. Jones", "J. Blake Turner", "Rene Hen", "Dietrich A. Stephan"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0016715.s001", "https://dx.doi.org/10.1371/journal.pone.0016715.s002", "https://dx.doi.org/10.1371/journal.pone.0016715.s003", "https://dx.doi.org/10.1371/journal.pone.0016715.s004", "https://dx.doi.org/10.1371/journal.pone.0016715.s005"], "stats"=>{"downloads"=>8, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Autism_and_Increased_Paternal_Age_Related_Changes_in_Global_Levels_of_Gene_Expression_Regulation/138768", "title"=>"Autism and Increased Paternal Age Related Changes in Global Levels of Gene Expression Regulation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-02-17 02:26:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/796960"], "description"=>"<p>The figure displays the steps used to evaluate the large-scale organization of gene expression in the blood of children with autism and controls. Peripheral blood lymphocytes were purified from the blood of children with autism (n = 82) or control subjects (n = 64). Total RNA was extracted for microarray experiments with Affymetrix Human U133 Plus 2.0 3′ Expression Arrays. Array data was pre-processed and summarized using Affymetrix Microarray Analysis Suite 5.0 (MAS 5.0) to obtain 54,675 expression levels for approximately 47,000 unique transcripts including approximately 38,500 human genes. Expression levels were log2 transformed and the variance of log2 transformed expression levels was determined.</p>", "links"=>[], "tags"=>["determining", "large-scale", "children", "autism"], "article_id"=>467319, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Medicine"], "users"=>["Mark D. Alter", "Rutwik Kharkar", "Keri E. Ramsey", "David W. Craig", "Raun D. Melmed", "Theresa A. Grebe", "R. Curtis Bay", "Sharman Ober-Reynolds", "Janet Kirwan", "Josh J. Jones", "J. Blake Turner", "Rene Hen", "Dietrich A. Stephan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016715.g001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_for_determining_the_large_scale_organization_of_gene_expression_in_the_blood_of_children_with_autism_and_controls_/467319", "title"=>"Schematic for determining the large-scale organization of gene expression in the blood of children with autism and controls.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-17 02:01:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/797388"], "description"=>"<p>Gene expression data from a publically available dataset show that treatment of a lung cancer cell line with actinomycin D and a high dose of sapphyrin results in decreased variance in gene expression compared to treatment with mannitol or a low dose of sapphyrin. Error bars represent standard error.</p>", "links"=>[], "tags"=>["inhibitors", "variance"], "article_id"=>467748, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Medicine"], "users"=>["Mark D. Alter", "Rutwik Kharkar", "Keri E. Ramsey", "David W. Craig", "Raun D. Melmed", "Theresa A. Grebe", "R. Curtis Bay", "Sharman Ober-Reynolds", "Janet Kirwan", "Josh J. Jones", "J. Blake Turner", "Rene Hen", "Dietrich A. Stephan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016715.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcription_inhibitors_lead_to_decreased_variance_in_gene_expression_/467748", "title"=>"Transcription inhibitors lead to decreased variance in gene expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-17 02:09:08"}

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