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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

Overall variance in gene expression in peripheral blood lymphocytes (PBL) was decreased in children with autism.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.
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pone-0016715-g002: Overall variance in gene expression in peripheral blood lymphocytes (PBL) was decreased in children with autism.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.

Mentions: An internet based 2×2 chi square contingency table (http://www.graphpad.com/quickcalcs/contingency1.cfm) was used to assess for a significant overlap between gene lists. A chi-square with Yates correction was used to calculate chi squared and a two-tailed p-value.


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)

Overall variance in gene expression in peripheral blood lymphocytes (PBL) was decreased in children with autism.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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0016715-g002: Overall variance in gene expression in peripheral blood lymphocytes (PBL) was decreased in children with autism.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.
Mentions: An internet based 2×2 chi square contingency table (http://www.graphpad.com/quickcalcs/contingency1.cfm) was used to assess for a significant overlap between gene lists. A chi-square with Yates correction was used to calculate chi squared and a two-tailed p-value.

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