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Autism and increased paternal age related changes in global levels of gene expression regulation.

Alter MD, Kharkar R, Ramsey KE, Craig DW, Melmed RD, Grebe TA, Bay RC, Ober-Reynolds S, Kirwan J, Jones JJ, Turner JB, Hen R, Stephan DA - PLoS ONE (2011)

Bottom Line: This premise can be tested by evaluating for changes in the overall distribution of gene expression levels.Variance in the distribution of gene expression levels from each microarray was compared between groups of children.Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. markalter1968@gmail.com

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.

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Related in: MedlinePlus

Schematic for determining the large-scale organization of gene expression in the blood of children with autism and controls.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.
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pone-0016715-g001: Schematic for determining the large-scale organization of gene expression in the blood of children with autism and controls.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.

Mentions: In the current study, we used our previously established strategy of studying the overall pattern of the gene expression distribution to test the hypothesis that autism would be associated with alterations in global levels of gene expression regulation. To do this, we compared the pattern of the gene expression distributions, as assessed by variance across the total gene expression distribution, in the blood of children with autism and controls (schematic in figure 1). Further, since multiple studies associated increased paternal age with increased rates of autism and other neurodevelopmental disorders [21], [22], [23], [24], [25], [26], [27], [28], we performed a secondary analysis to address the hypothesis that paternal age would be associated with changes in the pattern of the gene expression distribution. Finally, we used traditional approaches to gene expression analysis to examine for biological pathways that might be causally related to changes global levels of gene expression regulation.


Autism and increased paternal age related changes in global levels of gene expression regulation.

Alter MD, Kharkar R, Ramsey KE, Craig DW, Melmed RD, Grebe TA, Bay RC, Ober-Reynolds S, Kirwan J, Jones JJ, Turner JB, Hen R, Stephan DA - PLoS ONE (2011)

Schematic for determining the large-scale organization of gene expression in the blood of children with autism and controls.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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040743&req=5

pone-0016715-g001: Schematic for determining the large-scale organization of gene expression in the blood of children with autism and controls.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.
Mentions: In the current study, we used our previously established strategy of studying the overall pattern of the gene expression distribution to test the hypothesis that autism would be associated with alterations in global levels of gene expression regulation. To do this, we compared the pattern of the gene expression distributions, as assessed by variance across the total gene expression distribution, in the blood of children with autism and controls (schematic in figure 1). Further, since multiple studies associated increased paternal age with increased rates of autism and other neurodevelopmental disorders [21], [22], [23], [24], [25], [26], [27], [28], we performed a secondary analysis to address the hypothesis that paternal age would be associated with changes in the pattern of the gene expression distribution. Finally, we used traditional approaches to gene expression analysis to examine for biological pathways that might be causally related to changes global levels of gene expression regulation.

Bottom Line: This premise can be tested by evaluating for changes in the overall distribution of gene expression levels.Variance in the distribution of gene expression levels from each microarray was compared between groups of children.Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. markalter1968@gmail.com

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.

Show MeSH
Related in: MedlinePlus