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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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Down-regulated genes are enriched for biological pathways related to transcription and zinc.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.
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pone-0016715-g004: Down-regulated genes are enriched for biological pathways related to transcription and zinc.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.

Mentions: Because increased paternal age and autism were both negatively related to overall variance in gene expression, it was predicted that the overall variance in gene expression for children of older fathers would be similar to that in children with autism. To confirm this hypothesis, we performed a median split of subjects by paternal age (median  = 31 years) and assessed for differences in overall variance in gene expression between children with autism and controls in groups of children from older and younger fathers. As predicted, we found that the overall variance was the same in the blood of children from older fathers as in the blood of children with autism from fathers of any age (figure 3b). We found that the association of autism with decreased overall variance was only found in children of younger fathers (p = .0007) (figure 3b). As expected from the negative correlation, in the median split analysis, variance in gene expression in the blood of control children of older fathers was significantly decreased compared to control children of younger fathers (p = .03) (figure 3b).


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)

Down-regulated genes are enriched for biological pathways related to transcription and zinc.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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0016715-g004: Down-regulated genes are enriched for biological pathways related to transcription and zinc.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.
Mentions: Because increased paternal age and autism were both negatively related to overall variance in gene expression, it was predicted that the overall variance in gene expression for children of older fathers would be similar to that in children with autism. To confirm this hypothesis, we performed a median split of subjects by paternal age (median  = 31 years) and assessed for differences in overall variance in gene expression between children with autism and controls in groups of children from older and younger fathers. As predicted, we found that the overall variance was the same in the blood of children from older fathers as in the blood of children with autism from fathers of any age (figure 3b). We found that the association of autism with decreased overall variance was only found in children of younger fathers (p = .0007) (figure 3b). As expected from the negative correlation, in the median split analysis, variance in gene expression in the blood of control children of older fathers was significantly decreased compared to control children of younger fathers (p = .03) (figure 3b).

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