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Mobile DNA elements in the generation of diversity and complexity in the brain

Key Points

  • Retrotransposons are endogenous mobile elements that are capable of generating genomic diversity between cells (including neurons) within the same individual.

  • Somatic retrotransposition occurs during neural development in mice, humans and flies.

  • The increase in somatic retrotransposition that occurs during mammalian neural development involves the activation of transcription of long interspersed nuclear element 1 (LINE1) elements. In Drosophila melanogaster, increased somatic retrotransposition in the brain may be caused by a de-repression of mobile elements in mushroom body neurons.

  • By generating cells with unique genomes, somatic retrotransposition has the potential to alter the transcriptomes and cellular phenotypes of individual cells. Brain-specific mobile element insertions have been found in many genes, including those encoding dopamine receptors and neurotransmitters.

  • Misregulation of retrotransposition correlates with many neurological disorders, including neurodegeneration, ageing, Rett syndrome and schizophrenia.

Abstract

Mobile elements are DNA sequences that can change their position (retrotranspose) within the genome. Although its biological function is largely unappreciated, DNA derived from mobile elements comprises nearly half of the human genome. It has long been thought that neuronal genomes are invariable; however, recent studies have demonstrated that mobile elements actively retrotranspose during neurogenesis, thereby creating genomic diversity between neurons. In addition, mounting data demonstrate that mobile elements are misregulated in certain neurological disorders, including Rett syndrome and schizophrenia.

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Figure 1: Retrotransposons in humans.
Figure 2: Consequences of germline and somatic retrotransposition events.
Figure 3: Regulation of retrotransposition in neural progenitors.
Figure 4: Impact of mobile element insertions on the transcriptome.
Figure 5: Effects of somatic mosaicism in neurons.

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Acknowledgements

The authors thank M. L. Gage for editorial comments. This work was supported by the G. Harold and Leila Y. Mathers Charitable Foundation, The Leona M. and Harry B. Helmsley Charitable Trust grant #2012-PG-MED002, and NIH TR01 MH095741.

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Correspondence to Fred H. Gage.

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PowerPoint slides

Glossary

Epigenetic regulation

A process that alters the state of gene expression through changes in chromatin structure (that is, DNA or histone modifications).

Alternative splicing

A process whereby different mRNAs can be produced from a single gene through the differential incorporation of exons into the mature transcript during splicing. Frequently, various mature proteins are generated from a single gene.

Stochastic mechanism

A mechanism that is governed by random effects.

Autonomous elements

Elements that mobilize by themselves and do not require any other transposable elements for mobilization.

Endonuclease

An enzyme that cleaves a polynucleotide chain.

Reverse transcriptase

An enzyme that generates complementary DNA from an RNA template.

Speciation

The evolutionary process by which new biological species arise.

Polymorphic insertions

Mobile element insertions into specific locations of the genome that are present in some individuals and absent in others.

Next-generation genome sequencing

Sequencing carried out using high-throughput sequencing technologies that are based on massively parallel pyrosequencing technology and that enable the discovery of rare sequences (for example, small RNAs).

Aneuploidy

A condition in which extra or missing chromosomes are present within a cell or organism.

Copy number variants

(CNVs). Changes in the normal number of copies of a given gene or locus. Usually, there are two copies of each locus, but if, for example, duplications or triplications occur the number of copies will increase.

Induced pluripotent stem cell

A cell that is created from differentiated cell types — for example, fibroblasts — and is reprogrammed by a cocktail of transcription factors (or other approaches) back to a pluripotent state. This cell can now be differentiated into cells of distinct lineages: for example, neurons.

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Erwin, J., Marchetto, M. & Gage, F. Mobile DNA elements in the generation of diversity and complexity in the brain. Nat Rev Neurosci 15, 497–506 (2014). https://doi.org/10.1038/nrn3730

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