Opinion
The role of regulatory RNA in cognitive evolution

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The evolution of the human brain has resulted in the emergence of higher-order cognitive abilities, such as reasoning, planning and social awareness. Although there has been a concomitant increase in brain size and complexity, and component diversification, we argue that RNA regulation of epigenetic processes, RNA editing, and the controlled mobilization of transposable elements have provided the major substrates for cognitive advance. We also suggest that these expanded capacities and flexibilities have led to the collateral emergence of psychiatric fragilities and conditions.

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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