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Review
. 2018 Feb;55(2):1299-1322.
doi: 10.1007/s12035-017-0393-x. Epub 2017 Jan 24.

Copy Number Variations in Amyotrophic Lateral Sclerosis: Piecing the Mosaic Tiles Together through a Systems Biology Approach

Giovanna Morello  1 , Maria Guarnaccia  1 , Antonio Gianmaria Spampinato  1 , Valentina La Cognata  1   2 , Velia D'Agata  2 , Sebastiano Cavallaro  3
Affiliations
Review

Copy Number Variations in Amyotrophic Lateral Sclerosis: Piecing the Mosaic Tiles Together through a Systems Biology Approach

Giovanna Morello et al. Mol Neurobiol. 2018 Feb.

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating and still untreatable motor neuron disease. Despite the molecular mechanisms underlying ALS pathogenesis that are still far from being understood, several studies have suggested the importance of a genetic contribution in both familial and sporadic forms of the disease. In addition to single-nucleotide polymorphisms (SNPs), which account for only a limited number of ALS cases, a consistent number of common and rare copy number variations (CNVs) have been associated to ALS. Most of the CNV-based association studies use a traditional candidate-gene approach that is inadequate for uncovering the genetic architectures of complex traits like ALS. The emergent paradigm of "systems biology" may offer a new perspective to better interpret the wide spectrum of CNVs in ALS, enabling the characterization of the complex network of gene products underlying ALS pathogenesis. In this review, we will explore the landscape of CNVs in ALS, putting specific emphasis on the functional impact of common CNV regions and genes consistently associated with increased risk of developing disease. In addition, we will discuss the potential contribution of multiple rare CNVs in ALS pathogenesis, focusing our attention on the complex mechanisms by which these proteins might impact, individually or in combination, the genetic susceptibility of ALS. The comprehensive detection and functional characterization of common and rare candidate risk CNVs in ALS susceptibility may bring new pieces into the intricate mosaic of ALS pathogenesis, providing interesting and important implications for a more precise molecular biomarker-assisted diagnosis and more effective and personalized treatments.

Keywords: Amyotrophic lateral sclerosis (ALS); Copy number variations (CNVs); Genomics; Systems biology.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Schematic representation of the complex mosaic of ALS pathogenesis
Fig. 2
Fig. 2
The systems biology approach: from integration of large-scale “omics” data to personalized medicine practice
Fig. 3
Fig. 3
The most widely used methods for genome-wide and targeted CNVs detection and analysis
Fig. 4
Fig. 4
A representative illustration showing the functional correlation between ALS-associated CNV-affected genes and their biological processes. Interaction map represents the most promising candidate genes overlapping CNVs that have been consistently associated with ALS, grouped on the basis of the main biological processes associated with them. The map was created using the MetaCore Pathway Map Creator tool (GeneGo). Genes associated with CNV gain regions are labeled with red dots while genes associated with homozygous or heterozygous deleted CNVs are labeled with blue dots. The “checkerboard” color indicates genes displayed both CNV gains and losses. Detailed information about genes depicted in the figure and related biological processes are reported in Table 2. A detailed legend for the network objects is shown in Supplementary Fig. 1
Fig. 5
Fig. 5
The functional enrichment analysis of the most plausible candidate genes overlapping ALS-specific CNV loci reveals biological processes relevant to ALS pathogenesis. a Representation of the top 10 most significantly enriched (p value <0.05) canonical GO biological processes associated with genes significantly enriched in rare and novel ALS-specific copy number changes (not reported in controls of each of the individual studies and/or in >2500 controls present in DGV). The analysis was performed using the Gene Ontology and KEGG databases and the list is arranged in descending order with the most significant GO biological processes at the top. Detailed information about the entire list of genes affected by ALS-specific CNV loci are reported in Supplementary Table 1. b GO term pie chart of the top 10 enriched (p < 0.05) “Biological processes” for genes overlapping ALS-specific CNV loci. GO terms or biological features of candidate CNV-affected genes and the percentage of genes represented in each category are indicated
Fig. 6
Fig. 6
Functional network of known and predicted interactions between proteins encoded by genes affected by rare ALS-specific CNV loci and the most known causative ALS genes. The network was produced by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) v10 (http://string-db.org/) using default settings. Proteins are represented by spheres. Lines linking proteins indicate evidence for interactions: a red line indicates the presence of gene fusion (genes that are sometimes fused into single open reading frames); a green line gene neighborhood (genes that reside within 300 bp on the same strand in the genome); a blue line co-occurrence (gene families whose occurrence patterns across genomes show similarities); a purple line experimental evidence (interaction extracted from protein-protein interaction databases); a yellow line text mining (interaction extracted from scientific literature); a light blue line database (interaction extracted from curated databases); a black line co-expression (proteins whose genes are co-expressed in the same or in other species)
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