Trends in Cognitive Sciences
OpinionThe role of regulatory RNA in cognitive evolution
Section snippets
The path to cognition
Since the divergence of the human and chimpanzee lineages approximately 5 million years ago, the human brain has tripled in size, largely scaling with respect to numbers of neurons and a roughly equal number of glia [1]. Cortical expansion has involved a number of permitting mechanisms including increased cranial capacity (e.g., through genetic alterations [2]), human-specific metabolic changes [3], and an increased number of neuronal cells, possibly through an enhanced capability of progenitor
The proteome: evolving through adaptation
Analysis of the human genome sequence indicates that, contrary to expectations, the number and repertoire of encoded proteins are similar to a wide range of other animals 8, 9, although there are significant differences that undoubtedly account for some of the observed variation between species. New protein-coding genes can evolve through duplication, loss, and rearrangement processes [10] and, as studies investigating orphan genes indicate, de novo from non-coding sequences [11]. In the case
The programming of developmental complexity: non-coding RNA (r)evolution and regulation of epigenetic processes
In contrast to the relatively modest changes in the proteome through evolution, the amount of non-protein-coding DNA has increased dramatically and accounts for >98% of the human genome sequence [21]. The expansion of the non-coding genome in mammals, and particularly humans, may have been the consequence of the expansion of a regulatory RNA network required not simply for placental reproduction and development but also for brain function, processes that may themselves be closely linked.
Evolution of RNA plasticity in the brain
As discussed above, non-coding RNA-based regulatory networks may underpin epigenetic trajectories that control development and thereby ensure the cogent assembly of a functional multicellular organism. It also appears that evolution has superimposed plasticity on these processes to provide the epigenetic flexibility required for learning and memory, primarily by innovation and expansion of enzymes involved in nucleotide editing, which is emerging as the key basis of molecular plasticity in the
Evolution of genomic plasticity in the brain
A second editing mechanism deaminates cytosine to produce uracil, and is carried out by vertebrate-specific enzymes called APOBECs, which may act on RNA or DNA or both. There are 5 families of APOBECs, two of which (APOBEC 1 and 3) are mammal-specific 58, 59. The best characterized is AID, which is involved in somatic rearrangements and hypermutation of immunoglobulins in the immune system [58]. Interestingly, there are many parallels between the nervous and adaptive immune systems, including
New flexibility, new fragility
Although the increase in mammalian cognitive ability has provided unique mechanisms to evolve exceptional skills, such as reasoning and awareness, it would also seem likely that a relatively new and increasingly complex regulatory system would have weaknesses and be vulnerable to stressors. Drug abuse, for example, is an example of an environmental stressor that exposes cognitive vulnerability, especially as epigenetic mechanisms have been demonstrated to be dysregulated in the brain following
Future directions
RNA-mediated mechanisms are attractive candidates for underpinning the rapidly evolving plastic brain. However, the considerations above make several predictions and suggest several important directions for future research that only upon testing will ultimately reveal the true extent of the role of regulatory RNA in cognitive adaptation and function. In summary, it is known that cognitive processes are dependent on epigenetic mechanisms. Evidence is accumulating that the site-specificity of
Concluding remarks
We regard the observations and suggestions made here as the tip of a very large iceberg, as human-specific neural disorders will most likely include evolutionarily recent, or enhanced versions of more established, mechanisms (see also Box 2). Only by understanding the molecular basis of these newly developed systems will we be able to accurately diagnose and appropriately treat patients with disturbances in specifically affected neural pathways. We predict that a focus on RNA regulatory systems
Glossary
- Alternative splicing
- a regulatory mechanism by which multiple protein-coding RNA isoforms of the same gene are generated by variations in exon usage. This process can lead to increased genetic diversity by increasing the products derived from a single locus.
- Alu element
- Alu elements are repetitive ∼300 bp DNA elements that invaded the primate lineage early in its development. A subset of them are still active and capable of inserting into new genomic locations by relying on the LINE retrotransposon
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Mutual regulation of noncoding RNAs and RNA modifications in psychopathology: Potential therapeutic targets for psychiatric disorders?
2022, Pharmacology and TherapeuticsEpigenetic and Developmental Basis of Risk of Obesity and Metabolic Disease
2021, Cellular Endocrinology in Health and Disease, Second EditionPostmortem brain tissue as an underutilized resource to study the molecular pathology of neuropsychiatric disorders across different ethnic populations
2019, Neuroscience and Biobehavioral ReviewsNeuroepigenetics of Schizophrenia
2018, Progress in Molecular Biology and Translational ScienceCitation Excerpt :Non-coding RNAs are a group of RNA transcripts that do not necessarily code for protein products, as they make instead potentially functional RNAs. They include small RNA (sRNA) (for example, microRNA (miRNA), small interfering RNA (siRNA) and small nucleolar RNA (snoRNA)) and lncRNA [NB: for a classification of non-coding RNAs and their functions, we refer to extensive reviews that have been published on the topic73,75–79]. A great number of microRNAs has been associated with schizophrenia, based on GWAS and differential expression analyses performed in post-mortem brains or peripheral tissue.80,81
The RNA 3D Motif Atlas: Computational methods for extraction, organization and evaluation of RNA motifs
2016, MethodsCitation Excerpt :Evidence that many of these RNAs are likely to be functional is provided by the high temporal and spatial specificity of their transcription, especially in the brain [50,51] and by sequence and structural conservation within or across phylogenetic groups. Moreover, given that the numbers, types and even sequences of proteins are highly conserved among mammals, and even among animals of all kinds, evidence is accumulating that evolutionary processes producing new animal species, for example the emergence of humans from the great ape lineage, may be driven in part by rapid RNA evolution [52–54]. Understanding the functions of new RNAs can be aided by predictions of their 2D and 3D structures.