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miRNA and miRNA target genes in copy number variations occurring in individuals with intellectual disability.

Qiao Y, Badduke C, Mercier E, Lewis SM, Pavlidis P, Rajcan-Separovic E - BMC Genomics (2013)

Bottom Line: Our results show that 1).The number of miRNAs is significantly higher in de novo or DECIPHER CNVs than in familial or common CNV subgroups (P < 0.01). 2). miRNAs with brain related functions are more prevalent in de novo CNV groups compared to common CNV groups. 3).Systematic analysis of expression/function of miRNAs in addition to coding genes integral to CNVs could uncover new causes of ID.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Lab Medicine, BC Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.

ABSTRACT

Background: MicroRNAs (miRNAs) are a family of short, non-coding RNAs modulating expression of human protein coding genes (miRNA target genes). Their dysfunction is associated with many human diseases, including neurodevelopmental disorders. It has been recently shown that genomic copy number variations (CNVs) can cause aberrant expression of integral miRNAs and their target genes, and contribute to intellectual disability (ID).

Results: To better understand the CNV-miRNA relationship in ID, we investigated the prevalence and function of miRNAs and miRNA target genes in five groups of CNVs. Three groups of CNVs were from 213 probands with ID (24 de novo CNVs, 46 familial and 216 common CNVs), one group of CNVs was from a cohort of 32 cognitively normal subjects (67 CNVs) and one group of CNVs represented 40 ID related syndromic regions listed in DECIPHER (30 CNVs) which served as positive controls for CNVs causing or predisposing to ID. Our results show that 1). The number of miRNAs is significantly higher in de novo or DECIPHER CNVs than in familial or common CNV subgroups (P < 0.01). 2). miRNAs with brain related functions are more prevalent in de novo CNV groups compared to common CNV groups. 3). More miRNA target genes are found in de novo, familial and DECIPHER CNVs than in the common CNV subgroup (P < 0.05). 4). The MAPK signaling cascade is found to be enriched among the miRNA target genes from de novo and DECIPHER CNV subgroups.

Conclusions: Our findings reveal an increase in miRNA and miRNA target gene content in de novo versus common CNVs in subjects with ID. Their expression profile and participation in pathways support a possible role of miRNA copy number change in cognition and/or CNV-mediated developmental delay. Systematic analysis of expression/function of miRNAs in addition to coding genes integral to CNVs could uncover new causes of ID.

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Genomic coverage of miRNA (A) and protein coding genes (B) in different CNV subgroups. The fraction was defined as observed number of miRNA (or protein coding genes) in each CNV group divided by the total miRNAs (or total number of protein coding genes) in human genome. The miRNA or gene fraction in CNVs was compared to the miRNA or gene fraction in the reference genome which was generated by extracting random DNA fragments with similar length to the respective CNVs 1000 times from human genome. * Indicates p < 0.05 (a Wilcoxon signed-rank test). 1: De novo CNVs; 2: DECIPHER CNVs; 3: Familial CNVs; 4: Common CNVs from controls; 5: Common CNVs from cases.
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Figure 2: Genomic coverage of miRNA (A) and protein coding genes (B) in different CNV subgroups. The fraction was defined as observed number of miRNA (or protein coding genes) in each CNV group divided by the total miRNAs (or total number of protein coding genes) in human genome. The miRNA or gene fraction in CNVs was compared to the miRNA or gene fraction in the reference genome which was generated by extracting random DNA fragments with similar length to the respective CNVs 1000 times from human genome. * Indicates p < 0.05 (a Wilcoxon signed-rank test). 1: De novo CNVs; 2: DECIPHER CNVs; 3: Familial CNVs; 4: Common CNVs from controls; 5: Common CNVs from cases.

Mentions: The genomic coverage of miRNA and protein coding genes (expressed as their number per CNV group per their total number in the whole genome) tended to be higher for de novo and DECIPHER CNVs, in comparison to the coverage of miRNAs and protein coding genes of randomly sampled sections from the reference genome of the same size as each of the CNV subgroups. This increase in comparison to the reference genome was the highest for miRNAs in de novo CNVs, but was not significant (p > 0.05, Wilcoxon signed-rank test) (Figure 2). The de novo and DECIPHER CNV coverage of protein coding genes was also slightly higher than expected by chance but not significant. In contrast, the protein coding genes covered a significantly smaller fraction of the common CNVs than expected by chance, i.e. when reference genome of the same size as CNVs was used (P < 0.01) (Figure 2B), in keeping with their suspected benign nature. For the familial CNVs, the observed-to-expected miRNA and protein coding gene coverage was comparable.


miRNA and miRNA target genes in copy number variations occurring in individuals with intellectual disability.

Qiao Y, Badduke C, Mercier E, Lewis SM, Pavlidis P, Rajcan-Separovic E - BMC Genomics (2013)

Genomic coverage of miRNA (A) and protein coding genes (B) in different CNV subgroups. The fraction was defined as observed number of miRNA (or protein coding genes) in each CNV group divided by the total miRNAs (or total number of protein coding genes) in human genome. The miRNA or gene fraction in CNVs was compared to the miRNA or gene fraction in the reference genome which was generated by extracting random DNA fragments with similar length to the respective CNVs 1000 times from human genome. * Indicates p < 0.05 (a Wilcoxon signed-rank test). 1: De novo CNVs; 2: DECIPHER CNVs; 3: Familial CNVs; 4: Common CNVs from controls; 5: Common CNVs from cases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750877&req=5

Figure 2: Genomic coverage of miRNA (A) and protein coding genes (B) in different CNV subgroups. The fraction was defined as observed number of miRNA (or protein coding genes) in each CNV group divided by the total miRNAs (or total number of protein coding genes) in human genome. The miRNA or gene fraction in CNVs was compared to the miRNA or gene fraction in the reference genome which was generated by extracting random DNA fragments with similar length to the respective CNVs 1000 times from human genome. * Indicates p < 0.05 (a Wilcoxon signed-rank test). 1: De novo CNVs; 2: DECIPHER CNVs; 3: Familial CNVs; 4: Common CNVs from controls; 5: Common CNVs from cases.
Mentions: The genomic coverage of miRNA and protein coding genes (expressed as their number per CNV group per their total number in the whole genome) tended to be higher for de novo and DECIPHER CNVs, in comparison to the coverage of miRNAs and protein coding genes of randomly sampled sections from the reference genome of the same size as each of the CNV subgroups. This increase in comparison to the reference genome was the highest for miRNAs in de novo CNVs, but was not significant (p > 0.05, Wilcoxon signed-rank test) (Figure 2). The de novo and DECIPHER CNV coverage of protein coding genes was also slightly higher than expected by chance but not significant. In contrast, the protein coding genes covered a significantly smaller fraction of the common CNVs than expected by chance, i.e. when reference genome of the same size as CNVs was used (P < 0.01) (Figure 2B), in keeping with their suspected benign nature. For the familial CNVs, the observed-to-expected miRNA and protein coding gene coverage was comparable.

Bottom Line: Our results show that 1).The number of miRNAs is significantly higher in de novo or DECIPHER CNVs than in familial or common CNV subgroups (P < 0.01). 2). miRNAs with brain related functions are more prevalent in de novo CNV groups compared to common CNV groups. 3).Systematic analysis of expression/function of miRNAs in addition to coding genes integral to CNVs could uncover new causes of ID.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Lab Medicine, BC Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.

ABSTRACT

Background: MicroRNAs (miRNAs) are a family of short, non-coding RNAs modulating expression of human protein coding genes (miRNA target genes). Their dysfunction is associated with many human diseases, including neurodevelopmental disorders. It has been recently shown that genomic copy number variations (CNVs) can cause aberrant expression of integral miRNAs and their target genes, and contribute to intellectual disability (ID).

Results: To better understand the CNV-miRNA relationship in ID, we investigated the prevalence and function of miRNAs and miRNA target genes in five groups of CNVs. Three groups of CNVs were from 213 probands with ID (24 de novo CNVs, 46 familial and 216 common CNVs), one group of CNVs was from a cohort of 32 cognitively normal subjects (67 CNVs) and one group of CNVs represented 40 ID related syndromic regions listed in DECIPHER (30 CNVs) which served as positive controls for CNVs causing or predisposing to ID. Our results show that 1). The number of miRNAs is significantly higher in de novo or DECIPHER CNVs than in familial or common CNV subgroups (P < 0.01). 2). miRNAs with brain related functions are more prevalent in de novo CNV groups compared to common CNV groups. 3). More miRNA target genes are found in de novo, familial and DECIPHER CNVs than in the common CNV subgroup (P < 0.05). 4). The MAPK signaling cascade is found to be enriched among the miRNA target genes from de novo and DECIPHER CNV subgroups.

Conclusions: Our findings reveal an increase in miRNA and miRNA target gene content in de novo versus common CNVs in subjects with ID. Their expression profile and participation in pathways support a possible role of miRNA copy number change in cognition and/or CNV-mediated developmental delay. Systematic analysis of expression/function of miRNAs in addition to coding genes integral to CNVs could uncover new causes of ID.

Show MeSH
Related in: MedlinePlus