Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Risk-associated coding synonymous SNPs in type 2 diabetes and neurodegenerative diseases: Genetic silence and the underrated association with splicing regulation and epigenetics
Introduction
The limited understanding of epigenetic inheritance is related to the fact that there is little experimental evidence with regard to the mechanisms influenced by epigenetics. One of the recent developments, which could shed light into the principle mechanisms involved in this process, is related to the finding that epigenetic parameters are involved in the process of alternative splicing. This discovery, which is expected to rebut several misconceptions involving the splicing process, might also be critical for evaluating the impact of genetic variations and their association to environmental parameters in disease.
The impact of environmental factors on the epigenetic profile and particularly on the DNA methylation process is presently documented through studies on identical twins [1], [2], [3] and the Agouti mice [4], [5]. This process is dynamic [6], [7], partially environmentally configured [8] and aging dependent [9], [10], [11]. On the other hand, splicing is also a process, which is affected by aging [12], [13], modified under degenerative conditions [14], [15], [16] and dependent on exposure to different environmental factors [17], [18], [19].
Although the role of epigenetic alterations in cancer is widely acknowledged, the relevance of epigenetics to common metabolic (e.g. type 2 diabetes – T2D) and neurodegenerative (e.g. Alzheimer's disease – AD) diseases (NDs), both conditions associated with aging [12], [20] and frequent global methylation modifications [21], [22], [23], [24], [25], [26], remains conspicuous to date. These processes share common pathogenic mechanisms in animal models [27]. However, more research is needed to clarify the exact role of epigenetic regulation in the proposed pathogenic mechanism shared by these two major disorders.
Coding single nucleotide polymorphisms (SNPs) are considered key to the individual's genetic predisposition. Based on the genetic code, coding SNPs which do not introduce modification of individual amino acids are classified as “synonymous” SNPs (sSNPs) and considered neutral with respect to their genetic impact. However, such a classification disregards two principle issues in functional genomics: the presence of sequence motifs which strongly affect splicing [28], [29], [30], [31], probably via nucleosomal binding [32], [33], [34], [35], [36] and the presence/absence of epigenetic modification sites which is also tentatively critical for splicing [37], [38], [39]. Recent studies have demonstrated that sSNPs can affect mRNA splicing, stability and structure as well as protein folding, indicating the role of synonymous mutations in the biosynthesis of proteins [40], [41], [42], [43], [44]. These changes can have a significant effect in the function of proteins and as a result sSNPs can be implicated in disease [45], [46], [47]. Bioinformatic analysis could provide useful tools for re-examining sSNPs with respect to these principle mechanisms of gene expression, and further our understanding on issues of epigenetic inheritance in critical pathological conditions.
In the present study we performed, using bioinformatic tools, an analysis of all sSNPs recorded in T2D and in ND disease-related genes. sSNPs introducing changes in splicing-affecting sequence elements and CpG sites were identified. Furthermore, we investigated via meta-analysis, data from clinical studies involving sSNPs from these genes. Our findings reveal high variability in epigenetic modification sites in genes related to both pathological conditions and disease-association in a large percentage of splicing-affecting sSNPs.
Section snippets
Materials and methods
The present study was performed on a set of 33 most promising genes associated with T2D [48], [49], [50], [51] and compared with 28 previous studied genes associated with NDs [52]. The exons contained in these genes were classified in two categories: (a) Exons that are expressed in all gene isoforms (constitutive) and (b) exons that are alternatively spliced i.e. are not part of all the resulting transcripts [53].
These genes were studied with respect to the recorded sSNPs that cause maximum
sSNPs in genes associated with T2D
Based on their functional characteristics reported in the literature [48], [49], [50], [51] and in Gene Ontology [59], we identified 33 genes associated with T2D (Table S1). These genes include a total of 371 exons, 305 constitutive and 66 alternatively spliced (116,954 nt and 21,119 nt), respectively and 670 total coding and 232 sSNPs (Table 1). The frequency of ESE-related sSNPs in constitutive exons is significantly higher than in alternatively spliced exons.
A detailed analysis of the
Discussion
We presently report that several synonymous SNPs, which are generally considered to be silent, introduce changes of the splicing regulatory elements of the coding sequence, modify its epigenetic profile and probably affect its functional characteristics. sSNPs which strongly affect the splicing potential, might introduce severe functional deregulation, far exceeding that of minor amino acid changes. It is evident however that, depending on the functional complexity of the gene product and the
Conflict of interest
None declared.
Acknowledgments
This research has been co-financed by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) – Research Funding Program: Heracleitus II. Investing in knowledge society through the European Social Fund.
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