Copy Number Variations Burden on miRNA Genes Reveals Layers of Complexities Involved in the Regulation of Pathways and Phenotypic Expression

Veerappa, Avinash M.; N, Megha Murthy; Vishweswaraiah, Sangeetha; Lingaiah, Kusuma; Suresh, Raviraj V.; Nachappa, Somanna Ajjamada; Prashali, Nelchi; Yadav, Sangeetha Nuggehalli; Srikanta, Manjula Arsikere; Manjegowda, Dinesh S.; Seshachalam, Keshava B.; Ramachandra, Nallur B.

doi:10.1371/journal.pone.0090391

Cited by 15 publications

(12 citation statements)

References 51 publications

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“… 12 However, copy number (CN) state of a CNV plays a significant role in determining the zygosity of alleles. 13 CNVs alter the genome by exon shuffling, disrupting coding sequences, modify the dosage of genes, and disturbing the regulation mechanism of gene expression. A previous study reveals the association of CNVs with asthma.…”

Section: Introductionmentioning

confidence: 99%

Copy Number Variation Burden on Asthma Subgenome in Normal Cohorts Identifies Susceptibility Markers

Vishweswaraiah

Veerappa

Mahesh

et al. 2015

Allergy Asthma Immunol Res

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PurposeAsthma is a complex disease caused by interplay of genes and environment on the genome of an individual. Copy number variations (CNVs) are more common compared to the other variations that disrupt genome organization. The effect of CNVs on asthma subgenome has been less studied compared to studies on the other variations. We report the assessments of CNV burden in asthma genes of normal cohorts carried out in different geographical areas of the world and discuss the relevance of the observation with respect to asthma pathogenesis.MethodsCNV analysis was performed using Affymerix high-resolution arrays, and various bioinformatics tools were used to understand the influence of genes on asthma pathogenesis.ResultsThis study identified 61 genes associated with asthma and provided various mechanisms and pathways underlying asthma pathogenesis. CCL3L1, ADAM8, and MUC5B were the most prevalent asthma genes. Among them, CCL3L1 was found across all 12 populations in varying copy number states. This study also identified the inheritance of asthma-CNVs from parents to offspring creating the latent period for manifestation of asthma.ConclusionsThis study revealed CNV burden with varying copy number states and identified susceptibility towards the disease manifestation. It can be hypothesized that primary CNVs may not be the initiating event in the pathogenesis of asthma and additional preceding mutations or CNVs may be required. The initiator or primary CNVs sensitize normal cohorts leading to an increased probability of accumulating mutations or exposure to allergic stimulating agents that can augment the development of asthma.

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Section: Introductionmentioning

confidence: 99%

Copy Number Variation Burden on Asthma Subgenome in Normal Cohorts Identifies Susceptibility Markers

Vishweswaraiah

Veerappa

Mahesh

et al. 2015

Allergy Asthma Immunol Res

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“…In a study on 1,715 subjects, about 5% of all miRNAs are harbored in the CNVs, ~9% of CNVs were shown to harbor miRNA genes and these CNV-miRNAs were identified in 83.8% individuals (Veerappa et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

Deletion Extents Are Not the Cause of Clinical Variability in 22q11.2 Deletion Syndrome: Does the Interaction between DGCR8 and miRNA-CNVs Play a Major Role?

et al. 2017

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In humans, the most common genomic disorder is the hemizygous deletion of the chromosome 22q11.2 region, that results in the "22q11.2 deletion syndrome" (22q11.2DS). A peculiarity of 22q11.2DS is its great phenotypic variability that makes this pathology a classic example of a syndrome with variable expressivity and incomplete penetrance. The reasons for this variability have not been elucidated yet, and the molecular substrates underlying the different clinical features of 22q11.2DS are still debated. A cohort of 21 patients has been analyzed by array CGH in order to detect some of the genetic differences that may influence this variability. Two aspects have been investigated: (1) the precise localization of the deletion breakpoints within the low copy repeats (LCRs), (2) the additional Copy Number Variations (CNVs) elsewhere in the genome, by analyzing their gene content. Both protein-coding genes and miRNAs were considered, in order to discover possible epistatic interactions between genes of the 22q11.2 region and the rest of the genome. Eighteen out of twenty-one patients had a deletion of ∼3 Mb mediated by LCR22-A and D, whereas 3/21 had a smaller deletion. The breakpoints within the LCR22-A and D do not have a major role in the phenotypic variability since they are rather clustered and the small differences concern genes that are not directly related to clinical signs of 22q11.2DS. A detailed analysis of the gene content of 22q11.2 deleted region indicates that this syndrome could be a bioenergetic disorder or consequence of an altered post-transcriptional gene regulation, due to the presence of DGCR8, a major player of the microRNA (miRNA) biogenesis. Only four genes with mitochondrial function are harbored in the additional CNVs, whereas 11 miRNA, all related to biological pathways present in the 22q11.2DS, have been detected in 19/21 patients. CNVs and miRNAs are new entities that have changed the order of complexity at the level of gene expression and regulation, thus CNV-miRNAs (miRNA harbored in the CNVs) are potential functional variants that should be considered high priority candidate Bertini et al. miRNA-CNVs in 22q11.2 Deletion Syndrome variants in genotype-phenotype association studies. Deletion of DGCR8, the main actor in miRNA biogenesis, amplifies this variability. To our knowledge, this is the first report that focus on the miRNA-CNVs in 22q11.2DS, with the aim of trying to better understand their role in the variable expressivity and incomplete penetrance.

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“…CNVs can be used as a tool to understand various aspects of genome organization such as distribution of CNVs in the miRNA and coding regions (Veerappa et Veerappa et al, 2013 c;Veerappa et al, 2013 d;Veerappa et al, 2014). The CNV map we generated provides a rationale for prioritizing chromosomal regions, population specific genome organization and uncovered elements of the genome that had largely been unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…One such variation is the copy number variation (CNV), which forms an informative tool for assessing the alterations in the genome, since they leave CN signatures behind, which help to track and understand the effects of such variations on the genome (Kang et al, 2008;Simonson et al, 2010;Lou et al, 2011;Zhang et al, 2012;. The size and location of the variation determines the impact on the phenotype (Veerappa et al, 2014). CNVs, especially through gene duplication and exon shuffling, drive gene and genome evolution, which can be seen through the frequent recurrence of CNVs in regions of the genome that bear various multigene families (Niimura and Nei, 2003;Go and Niimura, 2008;Sudmant et al, 2010;Kim et al, 2012;Veerappa et al, 2013 c).…”

Section: Introductionmentioning

confidence: 99%

Global patterns of large copy number variations in the human genome reveal complexity in chromosome organization

et al. 2015

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Global patterns of copy number variations (CNVs) in chromosomes are required to understand the dynamics of genome organization and complexity. For this study, analysis was performed using the Affymetrix Genome-Wide Human SNP Array 6.0 chip and CytoScan High-Density arrays. We identified a total of 44 109 CNVs from 1715 genomes with a mean of 25 CNVs in an individual, which established the first drafts of population-specific CNV maps providing a rationale for prioritizing chromosomal regions. About 19 905 ancient CNVs were identified across all chromosomes and populations at varying frequencies. CNV count, and sometimes CNV size, contributed to the bulk CNV size of the chromosome. Population specific lengthening and shortening of chromosomal length was observed. Sex bias for CNV presence was largely dependent on ethnicity. Lower CNV inheritance rate was observed for India, compared to YRI and CEU. A total of 33 candidate CNV hotspots from 5382 copy number (CN) variable region (CNVR) clusters were identified. Population specific CNV distribution patterns in p and q arms disturbed the assumption that CNV counts in the p arm are less common compared to long arms, and the CNV occurrence and distribution in chromosomes is length independent. This study unraveled the force of independent evolutionary dynamics on genome organization and complexity across chromosomes and populations.

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Copy Number Variations Burden on miRNA Genes Reveals Layers of Complexities Involved in the Regulation of Pathways and Phenotypic Expression

Cited by 15 publications

References 51 publications

Copy Number Variation Burden on Asthma Subgenome in Normal Cohorts Identifies Susceptibility Markers

Copy Number Variation Burden on Asthma Subgenome in Normal Cohorts Identifies Susceptibility Markers

Deletion Extents Are Not the Cause of Clinical Variability in 22q11.2 Deletion Syndrome: Does the Interaction between DGCR8 and miRNA-CNVs Play a Major Role?

Global patterns of large copy number variations in the human genome reveal complexity in chromosome organization

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