Avinash M. Veerappa

Genome-wide copy number scan identifies disruption of PCDH11X in developmental dyslexia

Developmental dyslexia (DD) is a complex heritable disorder with unexpected difficulty in learning to read and spell despite adequate intelligence, education, environment, and normal senses. We performed a whole genome copy number variations (CNV) scan on 11 dyslexic families consisting of 14 dyslexic subjects and 24 non dyslexic members using 1.8 million combined SNP and CNV markers. We found CNVs affecting protocadherin genes in six dyslexics from three families, while none among the non‐dyslexic control members showed any CNV in protocadherins. We identified duplications in five cases and a deletion in one case in Xq21.3 region bearing PCDH11X. Unequal recombination between the X‐transposed region (XTR) of Yp11.2 and the X chromosome might be causing these structural changes. PCDH11X, expressed in brain is implicated in cell–cell communication, verbal ability, cerebral asymmetry, and dendritic synaptic plasticity, may be regarded as a new candidate gene for dyslexia.

Family-based genome-wide copy number scan identifies five new genes of dyslexia involved in dendritic spinal plasticity

Genome-wide screening for copy number variations (CNVs) in ten Indian dyslexic families revealed the presence of five de novo CNVs in regions harboring GABARAP, NEGR1, ACCN1, DCDC5, and one in already known candidate gene CNTNAP2. These genes are located on regions of chromosomes 17p13.1, 1p31.1, 17q11.21, 11p14.1 and 7q35, respectively, and are implicated in learning, cognition and memory processes through dendritic spinal plasticity, though not formally associated with dyslexia. Molecular network analysis of these and other dyslexia-related module genes suggests them to be associated with synaptic transmission, axon guidance and cell adhesion. Thus, we suggest that dyslexia may also be caused by neuronal disconnection in addition to the earlier view that it is due to neuronal migrational disorder.

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

MicroRNAs are involved in post-transcriptional down-regulation of gene expression. Variations in miRNA genes can severely affect downstream-regulated genes and their pathways. However, population-specific burden of CNVs on miRNA genes and the complexities created towards the phenotype is not known. From a total of 44109 CNVs investigated from 1715 individuals across 12 populations using high-throughput arrays, 4007 miRNA-CNVs (∼9%) consisting 6542 (∼5%) miRNA genes with a total of 333 (∼5%) singleton miRNA genes were identified. We found miRNA-CNVs across the genomes of individuals showing multiple hits in many targets, co-regulated under the same pathway. This study proposes four mechanisms unraveling the many complexities in miRNA genes, targets and co-regulated miRNA genes towards establishment of phenotypic diversity.

Unravelling the Complexity of Human Olfactory Receptor Repertoire by Copy Number Analysis across Population Using High Resolution Arrays

Olfactory receptors (OR), responsible for detection of odor molecules, belong to the largest family of genes and are highly polymorphic in nature having distinct polymorphisms associated with specific regions around the globe. Since there are no reports on the presence of copy number variations in OR repertoire of Indian population, the present investigation in 43 Indians along with 270 HapMap and 31 Tibetan samples was undertaken to study genome variability and evolution. Analysis was performed using Affymetrix Genome-Wide Human SNP Array 6.0 chip, Affymterix CytoScan® High-Density array, HD-CNV, and MAFFT program. We observed a total of 1527 OR genes in 503 CNV events from 81.3% of the study group, which includes 67.6% duplications and 32.4% deletions encompassing more of genes than pseudogenes. We report human genotypic variation in functional OR repertoire size across populations and it was found that the combinatorial effect of both “orthologous obtained from closely related species” and “paralogous derived sequences” provide the complexity to the continuously occurring OR CNVs.

Molecular interaction network and pathway studies of ADAM33 potentially relevant to asthma

BACKGROUND Asthma is a complex disease caused by gene-gene, gene-protein, and protein-protein interactions and the influence of environment, which plays a significant role in causing asthma pathogenesis. ADAM33 is known to be an important gene involved in asthma pathogenesis. No one single gene is a causal factor of asthma; rather, asthma is caused by a complex interaction of multiple genes having pathogenetic and protective effects. OBJECTIVE To identify and understand the interacting genes and proteins of ADAM33. METHODS The Ingenuity Pathway Analysis and GeneMANIA tools and a literature survey were used to identify the interacting candidates of ADAM33 and the WEB-based GEne SeT AnaLysis Toolkit was used to perform enrichment analysis of the proteins identified. RESULTS Keeping ADAM33 as a major hub, the authors identified some proteins whose interaction with ADAM33 had been associated with asthma and they recognized some proteins, such as amyloid β (A4) precursor protein, ataxin-7, α4-integrin, α5-integrin, α9-integrin, tissue inhibitor of metalloproteinase-4, and ubiquilin-4, that had not been previously associated with asthma. CONCLUSION The proteins identified in this study were enriched for various mechanisms that are involved in airway hyperresponsiveness, and through the interaction with ADAM33, they may have potential relevance in asthma.

Family based genome‐wide copy number scan identifies complex rearrangements at 17q21.31 in dyslexics

Developmental dyslexia (DD) is a complex heritable disorder with unexpected difficulty in learning to read and spell despite adequate intelligence, education, environment, and normal senses. We performed genome‐wide screening for copy number variations (CNVs) in 10 large Indian dyslexic families using Affymetrix Genome‐Wide Human SNP Array 6.0. Results revealed the complex genomic rearrangements due to one non‐contiguous deletion and five contiguous micro duplications and micro deletions at 17q21.31 region in three dyslexic families. CNVs in this region harbor the genes KIAA1267, LRRC37A, ARL17A/B, NSFP1, and NSF. The CNVs in case 1 and case 2 at this locus were found to be in homozygous state and case 3 was a de novo CNV. These CNVs were found with at least one CNV having a common break and end points in the parents. This cluster of genes containing NSF is implicated in learning, cognition, and memory, though not formally associated with dyslexia. Molecular network analysis of these and other dyslexia related module genes suggests NSF and other genes to be associated with cellular/vesicular membrane fusion and synaptic transmission. Thus, we suggest that NSF in this cluster would be the nearest gene responsible for the learning disability phenotype.

Global Spectrum of Copy Number Variations Reveals Genome Organizational Plasticity and Proposes New Migration Routes

Global spectrum of CNVs is required to catalog variations to provide a high-resolution on the dynamics of genome-organization and human migration. In this study, we performed genome-wide genotyping using high-resolution arrays and identified 44,109 CNVs from 1,715 genomes across 12 populations. The study unraveled the force of independent evolutionary dynamics on genome-organizational plasticity across populations. We demonstrated the use of CNV tool to study human migration and identified a second major settlement establishing new migration routes in addition to existing ones.

Copy number variation burden on asthma subgenome in normal cohorts identifies susceptibility markers

Purpose Asthma 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. Methods CNV analysis was performed using Affymerix high-resolution arrays, and various bioinformatics tools were used to understand the influence of genes on asthma pathogenesis. Results This 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. Conclusions This 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.

Impact of copy number variations burden on coding genome in humans using integrated high resolution arrays

Copy number variations (CNVs) alter the transcriptional and translational levels of genes by disrupting the coding structure and this burden of CNVs seems to be a significant contributor to phenotypic variations. Therefore it was necessary to assess the complexities of CNV burden on the coding genome. A total of 1715 individuals from 12 populations were used for CNV analysis in the present investigation. Analysis was performed using Affymetrix Genome-Wide Human SNP Array 6·0 chip and CytoScan High-Density arrays. CNVs were more frequently observed in the coding region than in the non-coding region. CNVs were observed vastly more frequently in the coding region than the non-coding region. CNVs were found to be enriched in the regions containing functional genes (83-96%) compared with the regions containing pseudogenes (4-17%). CNVs across the genome of an individual showed multiple hits across many genes, whose proteins interact physically and function under the same pathway. We identified varying numbers of proteins and degrees of interactions within protein complexes of single individual genomes. This study represents the first draft of a population-specific CNV genes map as well as a cross-populational map. The complex relationship of CNVs on genes and their physically interacting partners unravels many complexities involved in phenotype expression. This study identifies four mechanisms contributing to the complexities caused by the presence of multiple CNVs across many genes in the coding part of the genome.

High-resolution arrays reveal burden of copy number variations on Parkinson disease genes associated with increased disease risk in random cohorts

Background: Parkinson disease (PD) is a neurological disease responsible for a considerable rate of mortality and morbidity in the society. Since the symptoms of the disease appear much later than the actual onset of neuron degeneration, a majority of cases remain undiagnosed until the manifestation of the symptoms. Objectives: In order to investigate the existence of such susceptibility in the population, we analyzed Copy Number Variation (CNV) influences on PD genes in 1715 individuals from 12 different populations. Results: Overall, 16 CNV-PD genes, 3 known to be causal and 13 associated, were found to be significantly enriched. PARK2, was under heavy burden with ~1% of the population containing CNV in the exonic region. The impact of these genes on the genome and disease pathway was analyzed using several genome analysis tools. Protein interaction network of CNV-PD genes revealed a complex interaction of molecules forming a major hub by the α-Synuclein, whose direct interactors, LRRK2, PARK2 and ATP13A2 are under CNV influence. Conclusions: We hypothesize that CNVs may not be the initiating event in the pathogenesis of PD and remain latent until additional secondary hits are acquired and also propose novel genes that may fall under the PD pathway which contribute in pathogenesis.