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Gene Coexpression Networks in Human Brain Developmental Transcriptomes Implicate the Association of Long Noncoding RNAs with Intellectual Disability.

Gudenas BL, Wang L - Bioinform Biol Insights (2015)

Bottom Line: Several ID-associated gene modules were found to be enriched for lncRNAs, known ID genes, and affected biological pathways.Utilizing a list of de novo and pathogenic copy number variants detected in ID probands, we identified lncRNAs overlapping these genetic structural variants.By integrating our results, we have made a prioritized list of potential ID-associated lncRNAs based on the developing brain gene coexpression network and genetic structural variants found in ID probands.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Biochemistry, Clemson University, Clemson, SC, USA.

ABSTRACT
The advent of next-generation sequencing for genetic diagnoses of complex developmental disorders, such as intellectual disability (ID), has facilitated the identification of hundreds of predisposing genetic variants. However, there still exists a vast gap in our knowledge of causal genetic factors for ID as evidenced by low diagnostic yield of genetic screening, in which identifiable genetic causes are not found for the majority of ID cases. Most methods of genetic screening focus on protein-coding genes; however, noncoding RNAs may outnumber protein-coding genes and play important roles in brain development. Long noncoding RNAs (lncRNAs) specifically have been shown to be enriched in the brain and have diverse roles in gene regulation at the transcriptional and posttranscriptional levels. LncRNAs are a vastly uncharacterized group of noncoding genes, which could function in brain development and harbor ID-predisposing genetic variants. We analyzed lncRNAs for coexpression with known ID genes and affected biological pathways within a weighted gene coexpression network derived from RNA-sequencing data spanning human brain development. Several ID-associated gene modules were found to be enriched for lncRNAs, known ID genes, and affected biological pathways. Utilizing a list of de novo and pathogenic copy number variants detected in ID probands, we identified lncRNAs overlapping these genetic structural variants. By integrating our results, we have made a prioritized list of potential ID-associated lncRNAs based on the developing brain gene coexpression network and genetic structural variants found in ID probands.

No MeSH data available.


Related in: MedlinePlus

Characteristics of ID-gene-enriched coexpression modules. (A) The gene expression of lncRNAs from eight weeks postconception to one postnatal year, grouped by module, was normalized and plotted across developmental time using a scatter smoothing function. The shaded adjacent regions represent 95% confidence intervals. (B) Gene functional enrichment was analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID, available at https://david.ncifcrf.gov/), and the top five Gene Ontology terms of biological processes were displayed. The red vertical lines represent the significance threshold of P-value = 0.01.
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f2-bbi-suppl.1-2015-021: Characteristics of ID-gene-enriched coexpression modules. (A) The gene expression of lncRNAs from eight weeks postconception to one postnatal year, grouped by module, was normalized and plotted across developmental time using a scatter smoothing function. The shaded adjacent regions represent 95% confidence intervals. (B) Gene functional enrichment was analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID, available at https://david.ncifcrf.gov/), and the top five Gene Ontology terms of biological processes were displayed. The red vertical lines represent the significance threshold of P-value = 0.01.

Mentions: By mapping the gene sets to the developmental coexpression network, we have identified two out of eight modules that are enriched for ID only genes without also being enriched for ID and ASD genes or ASD genes (Fig. 1 and Supplementary Table S2). These two ID-specific modules are labeled as magenta and turquoise. The highest scoring term of biological processes from the Gene Ontology enrichment analysis for the turquoise module is immune response (P-value <0.001), whereas the magenta module does not show any significant functional term enrichment (Fig. 2B). Interestingly, the blue, black, and purple modules are enriched for all four ID gene sets, in addition to the ASD gene list. These modules are likely involved in core synaptic and regulatory pathways that are affected in both ID and ASD. Gene Ontology functional analysis finds enrichment for transcriptional regulation, synaptic transmission, and protein localization, respectively (Fig. 2B). Furthermore, the blue, black, brown, and turquoise modules possess a significant amount of lncRNAs (Supplementary Table S3) and thus are interesting modules to examine the relationships between lncRNAs and known ID genes.


Gene Coexpression Networks in Human Brain Developmental Transcriptomes Implicate the Association of Long Noncoding RNAs with Intellectual Disability.

Gudenas BL, Wang L - Bioinform Biol Insights (2015)

Characteristics of ID-gene-enriched coexpression modules. (A) The gene expression of lncRNAs from eight weeks postconception to one postnatal year, grouped by module, was normalized and plotted across developmental time using a scatter smoothing function. The shaded adjacent regions represent 95% confidence intervals. (B) Gene functional enrichment was analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID, available at https://david.ncifcrf.gov/), and the top five Gene Ontology terms of biological processes were displayed. The red vertical lines represent the significance threshold of P-value = 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4624004&req=5

f2-bbi-suppl.1-2015-021: Characteristics of ID-gene-enriched coexpression modules. (A) The gene expression of lncRNAs from eight weeks postconception to one postnatal year, grouped by module, was normalized and plotted across developmental time using a scatter smoothing function. The shaded adjacent regions represent 95% confidence intervals. (B) Gene functional enrichment was analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID, available at https://david.ncifcrf.gov/), and the top five Gene Ontology terms of biological processes were displayed. The red vertical lines represent the significance threshold of P-value = 0.01.
Mentions: By mapping the gene sets to the developmental coexpression network, we have identified two out of eight modules that are enriched for ID only genes without also being enriched for ID and ASD genes or ASD genes (Fig. 1 and Supplementary Table S2). These two ID-specific modules are labeled as magenta and turquoise. The highest scoring term of biological processes from the Gene Ontology enrichment analysis for the turquoise module is immune response (P-value <0.001), whereas the magenta module does not show any significant functional term enrichment (Fig. 2B). Interestingly, the blue, black, and purple modules are enriched for all four ID gene sets, in addition to the ASD gene list. These modules are likely involved in core synaptic and regulatory pathways that are affected in both ID and ASD. Gene Ontology functional analysis finds enrichment for transcriptional regulation, synaptic transmission, and protein localization, respectively (Fig. 2B). Furthermore, the blue, black, brown, and turquoise modules possess a significant amount of lncRNAs (Supplementary Table S3) and thus are interesting modules to examine the relationships between lncRNAs and known ID genes.

Bottom Line: Several ID-associated gene modules were found to be enriched for lncRNAs, known ID genes, and affected biological pathways.Utilizing a list of de novo and pathogenic copy number variants detected in ID probands, we identified lncRNAs overlapping these genetic structural variants.By integrating our results, we have made a prioritized list of potential ID-associated lncRNAs based on the developing brain gene coexpression network and genetic structural variants found in ID probands.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Biochemistry, Clemson University, Clemson, SC, USA.

ABSTRACT
The advent of next-generation sequencing for genetic diagnoses of complex developmental disorders, such as intellectual disability (ID), has facilitated the identification of hundreds of predisposing genetic variants. However, there still exists a vast gap in our knowledge of causal genetic factors for ID as evidenced by low diagnostic yield of genetic screening, in which identifiable genetic causes are not found for the majority of ID cases. Most methods of genetic screening focus on protein-coding genes; however, noncoding RNAs may outnumber protein-coding genes and play important roles in brain development. Long noncoding RNAs (lncRNAs) specifically have been shown to be enriched in the brain and have diverse roles in gene regulation at the transcriptional and posttranscriptional levels. LncRNAs are a vastly uncharacterized group of noncoding genes, which could function in brain development and harbor ID-predisposing genetic variants. We analyzed lncRNAs for coexpression with known ID genes and affected biological pathways within a weighted gene coexpression network derived from RNA-sequencing data spanning human brain development. Several ID-associated gene modules were found to be enriched for lncRNAs, known ID genes, and affected biological pathways. Utilizing a list of de novo and pathogenic copy number variants detected in ID probands, we identified lncRNAs overlapping these genetic structural variants. By integrating our results, we have made a prioritized list of potential ID-associated lncRNAs based on the developing brain gene coexpression network and genetic structural variants found in ID probands.

No MeSH data available.


Related in: MedlinePlus