Abstract
Atherosclerosis (ATH) and coronary artery disease (CAD) are chronic inflammatory diseases with an important genetic background; they derive from the cumulative effect of multiple common risk alleles, most of which are located in genomic noncoding regions. These complex diseases behave as nonlinear dynamical systems that show a high dependence on their initial conditions; thus, long-term predictions of disease progression are unreliable. One likely possibility is that the nonlinear nature of ATH could be dependent on nonlinear correlations in the structure of the human genome. In this review, we show how chaos theory analysis has highlighted genomic regions that have shared specific structural constraints, which could have a role in ATH progression. These regions were shown to be enriched with repetitive sequences of the Alu family, genomic parasites that have colonized the human genome, which show a particular secondary structure and are involved in the regulation of gene expression. Here, we show the impact of Alu elements on the mechanisms that regulate gene expression, especially highlighting the molecular mechanisms via which the Alu elements alter the inflammatory response. We devote special attention to their relationship with the long noncoding RNA (lncRNA); antisense noncoding RNA in the INK4 locus (ANRIL), a risk factor for ATH; their role as microRNA (miRNA) sponges; and their ability to interfere with the regulatory circuitry of the (nuclear factor kappa B) NF-κB response. We aim to characterize ATH as a nonlinear dynamic system, in which small initial alterations in the expression of a number of repetitive elements are somehow amplified to reach phenotypic significance.
Highlights
Atherosclerosis (ATH) is a chronic inflammatory vascular disease that is characterized by the interactions and feedback mechanisms involving lipids, cells, and various molecules and genetic factors [1]
Some mathematical models describing the early stage of ATH were developed in an effort to study the recruitment of immune cells from the blood flow via inflammatory cytokines, demonstrating that the chronic inflammatory reaction was developed akin to the propagation of a traveling wave [7]
Focusing on ATH, we discuss the relationships between the Alu elements and two other families of ncRNAs, with a known involvement in ATH progression, namely, a group of small microRNAs, and the long noncoding RNA (lncRNA) antisense noncoding RNA in the INK4 locus (ANRIL), with specific alleles that have been acknowledged as risk factors for coronary artery disease (CAD)
Summary
The human genome is one of the most intricate molecular machines known to man, and a wide range of approaches are used to study and analyze its complexity. The first report of nonlinear correlations in the human genome was put forward by Xiao et al, who used a chaos theory-derived nonlinear prediction method to differentiate between “random” and “non-random” (deterministic) DNA sequences [16] In their analysis, the authors studied the β-globin locus, which encodes six globin genes (along with their exons and introns), and is enriched with a family of repeated nuclear sequences, named Alu repeats (see Section 3). The authors demonstrated that the exonic and intronic sequences in the β-globin locus did not show any significant deviation from a random nature, while the sequences harboring these Alu repeated nuclear elements presented nonlinear (deterministic) structures, likely because of a dimeric structure [16] This intriguing result was eventually confirmed through further work by Moreno et al, who reported that the human genome displayed multifractal behavior, rich in highly polymorphic sequences that were organized into a wide range of combinations [43]. ((iiiiii)) SShhoortrtncnRcNRANA(sm(asmllearlltehranth2a0n0–320000–n3t)0,0inncltu),diinngclmudicirnogRNmAic(rmoRiRNNAA)(m[5i7R],NPAiw) i-[i5n7te],raPctiiwnigRinNteAra(cptiinRgNAR)N[A58](,painRdNrAet)ro[5tr8a]n, sapnodsorne-tdroertrivaendspnocsRoNn-Ad,esruivcehdasnschRoNrtAi,ntseurcshpearssedshnourct leinatreerlsepmeresnetds (nSuINcleEasr) e[l5e9m].enRtset(rSoItNraEnss)p[5o9s]o.nR-edterroitvreadnsrpeopseotnit-idveerisveeqdureenpceetsitiavcecosueqnut efnocreosvaecrco5u0n%t foofr othveerh5u0m%aonf gtheenohmume a[6n0g].enome [60]
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