Evolution and Complexity of Micro RNA in the Human Brain

MicroRNA (miRNA): Sequence and stability, viroid-like properties, and disease association in the CNS

“…Moreover secondary structures also appear to be conserved between multiple miRNAs and internal stems, loops and mis-paired RNA ‘bulges’ are evident in identical positions in many pre-miRNA sequences (Fig. 1; Saetrom et al, 2006; Arteaga-Vazquez et al, 2006; Lukiw, 2012b, 2013; Hill et al, 2014). …”

“…The fact that there are probably less than 10 2 abundant miRNAs in any single cell type suggests an extremely high evolutionary selection pressure to utilize only specific ribonucleotide sequences in miRNAs that will yield biologically useful miRNA–mRNA interactions (Ambros et al, 2003, 2004; Arteaga-Vazquez et al, 2006; Neilson and Sharp, 2008; Guo et al, 2010; Lukiw, 2012a, 2013). Further to this idea, direct RNA-sequencing-, RT-PCR-, Northern dot blot and miRNA array-based analyses suggest that abundant miRNAs in the human neocortex number probably less than 40 or 50, and only a smaller fraction of these are misregulated in Alzheimer's disease (AD) and other inflammatory neurodegenerative disorders of the human CNS (Burmistrova et al, 2007; Lukiw and Pogue, 2007; Yuva-Aydemir et al, 2011; Lukiw, 2012b; Alexandrov et al, 2012). The abundance, speciation and complexity of these highly selected miRNAs may vary amongst human populations in health and disease (Lukiw, 2013).…”

MicroRNA-dependent genetic networks during neural development

“…While the authors note the methods used to collect and determine the mouse data could have caused this difference, others have hypothesized that miRNAs are strong contributors to brain evolution and cognition (Bentwich et al, 2005; Hu et al, 2011; Lukiw, 2012) suggesting that the difference between mouse, primate and human miRNA expression may have biological meanings.…”

Variability in micro RNA (miRNA) abundance, speciation and complexity amongst different human populations and potential relevance to Alzheimer's disease (AD)

“…The “normalcy” range was defined as that in which 95% of those “normal values” lie, while the remaining 5% are described as “abnormal.” Defining “normalcy” on a larger scale becomes a bit trickier however, and Pauling proposed that if we assume that 500 characters are independently inherited, then we can calculate that there is only a small chance, 10%, that one person in the entire global population would be normal (with respect to each of these 500 characters). If we assume that there are about 26,600 human genes available to be expressed in each cell and that each gene is responsible for at least one inherited trait or genetic function (a number that is probably vastly underestimated), in a global human population exceeding 7 billion it then becomes exceedingly difficult to define “ human genetic normalcy .” These ideas form the basis for the evolving concept of “human genetic individuality” and our ongoing efforts to better understand the genotypic basis of human phenotypic diversity in both health and disease (Li et al, 2010; Raj et al, 2010; Lukiw, 2012a,b; Olson, 2012; this paper). More recently, large population studies have analyzed the contribution of variability in gene expression, including the impact of genetic mutations, to “ human genetic normalcy ,” “human genetic individuality ,” phenotype, susceptibility to disease and related parameters that include the general redundancy in human gene expression that may directly impact the genetic evolution of the human species (Colangelo et al, 2002; Li et al, 2010; Zheng et al, 2011; Lukiw, 2012a,b; Ginsberg et al, 2012; Raj et al, 2012; Hulse and Cai, 2013).…”

“…A pathogenic quintet of up-regulated miRNAs have been described and partially characterized, and these include miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155, which have been shown to be involved in chronic inflammatory degeneration by many independent groups in multiple human diseases with a progressive inflammatory and degenerative component (Lukiw, 2007; Williams et al, 2007; Wang et al, 2009; Culpan et al, 2011; Lukiw et al, 2011; Hu et al, 2012; Iyer et al, 2012; Saba et al, 2012; Lukiw, 2013; Nussbaum, 2013; Zhao et al, 2013). In AD these five up-regulated miRNAs appear to play important roles in the down-regulation of brain gene expression normally involved in the brain's neurotrophic support, synaptogenesis, the innate-immune response, NF-kB-mediated inflammatory signaling and amyloidogenesis (Cui et al, 2005; Sethi and Lukiw, 2009; Lukiw, 2012a,b; Zhao et al, 2013). Preliminary data indicates that greater general abundance in the expression of these five miRNAs may in part explain differences in the incidence, course and/or severity of AD amongst elderly Caucasian American, African American, Hispanics and other minority populations.…”