Developmental biology

Jumping-gene roulette

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Jumping genes, which make DNA copies of themselves through an RNA middleman, provide a stochastic process for generating brain diversity among humans. The effect of their random insertion, however, is a bit of a gamble.

The enormous complexity of the human nervous system is generated by the combined actions of incompletely understood genetic and environmental factors. Coufal et al.1 (page 1127 of this issue) now reveal one remarkable genetic contribution to individual variation in the nervous system. The authors show that normally quiescent 'jumping genes' can be activated in neural progenitor cells. Each hop generates genetic diversity in the nervous system that may or may not affect function or health.

LINE-1 (L1) retrotransposons are the most dynamic force operating in the human genome. These elements are regions of mobile DNA that make copies of themselves by converting their RNA transcript into DNA, which then reinserts into the genome — a process known as retrotransposition. Cleverly, the proteins that convert the L1 RNA transcript into a DNA copy are encoded by the L1 sequence itself. Depending on where the new L1 inserts, its effect on a neighbouring gene can range from nil to destruction2.

As selfish mobile elements whose goal it is to make copies of themselves, L1s must be able to retrotranspose in egg and sperm, or in the early embryo, ensuring that new L1 copies are passed on to future generations. That more than 600,000 copies of L1 retrotransposons pepper our genome is proof of the evolutionary success of this strategy. Meanwhile, the human genome has evolved elaborate mechanisms for repressing L1 retrotransposition3, particularly by blocking transcription, a compulsory first step in the process leading to insertion of a new L1 copy. Methylation of DNA in regulatory regions of genes is a widespread and effective method of transcriptional repression. However, during gamete formation, and in the early embryo, short waves of demethylation in a region of L1 that serves as a promoter of transcription allow the mobile element to temporarily escape transcriptional silencing.

In the body's non-gametes (somatic cells), where new copies of L1 would not be passed on to the next generation but transposition could be harmful, the L1 promoter is methylated and transcription is repressed. Thus, it was surprising to find4 that L1 transcription seemed to be increased during the differentiation of neuronal progenitor cells isolated from the hippocampus of adult rat brains. Human L1 also retrotransposed when introduced into these same cells and when expressed in the brain cells of transgenic mice4. These results raised the possibility that the genome of individual brain cells could harbour different insertion sites and numbers of L1s (so-called somatic mosaicism), and fuelled speculation that L1 retrotransposition might lead to unique neuronal properties among humans4.

Coufal et al.1 provide data to support this suggestion. They show that human neural progenitor cells, whether derived from fetal brains or from cultured embryonic stem cells, support the retrotransposition of an introduced human L1. Some cells in which L1 had retrotransposed continued to divide, which means that specific new L1 insertions are not necessarily restricted to a single daughter cell. Furthermore, progenitor cells with new L1 insertions generate different types of differentiated cells, including neurons that can conduct electrical impulses. Finally, the authors1 identified the genomic locations of 19 new L1 insertions by DNA sequencing; 16 of these were located within 100 kilobases of a gene, and many of these genes are expressed in neurons. These data1 convincingly show that L1s introduced into human neural progenitor cells can jump in the genome, and that these cells can give rise to functional neurons.

Whether native L1s jump in neural progenitor cells in vivo is a much more difficult question to answer, but several tantalizing results suggest that they do. Coufal and colleagues1 show that the native L1 promoter is relatively undermethylated, which allows for increased L1 transcription, and that L1 RNA transcripts are more abundant in fetal brain than in skin. Most provocative, however, are the results of an assay the authors developed to quantify the number of L1s in the brain. As L1 is a retrotransposon, each cycle of transposition adds a new copy of L1 DNA to the genome, and, if L1 is transposing in the brain, it should theoretically be possible to measure the increased numbers of L1 copies in that tissue. It is, however, a substantial challenge to document an increase from 600,000 copies of L1 in every cell to 600,000 plus 1 in one or a few cells of the human brain.

Remarkably, the authors did just that. Using a highly sensitive form of quantitative polymerase chain reaction (PCR), a technique that amplifies and quantifies specific DNA, they detected more L1s in the genome of adult human brain cells than in the genome of liver or heart cells from the same individuals. Cells from all brain regions tested contained more copies of L1 than cells from other tissues, with the highest number found in the dentate gyrus and frontal cortex1, perhaps reflecting a relatively greater contribution of the ongoing generation of neurons from precursor cells in these areas of the brain5. By adding a known amount of L1-containing DNA to the heart and liver samples before PCR, the authors1 provided evidence that not only is the apparently lower L1 content in heart and liver not an experimental artefact, but also that each brain cell contained approximately 80 additional copies of L1.

Conclusive evidence that L1 retrotransposons jump in human brain cells will require individual L1 insertions to be characterized by DNA sequencing. Although this is a difficult task, such data will probably soon become available. It is therefore important to ask whether it is reasonable to expect any aspect of brain function to be altered if L1s jump randomly in neuronal precursor cells. Given that changing the firing patterns of single neurons can have marked effects on behaviour6,7, and that single-gene alterations can cause profound effects in subpopulations of neurons8, it is likely that some L1 insertions, in some cells, in some humans9, will have significant, if not profound, effects on the final structure and function of the human brain (Fig. 1). These findings challenge the notion of the genome as a constant entity with limited impact on neuronal plasticity, and blur the distinction between genetic and environmental effects on the nervous system.

Figure 1: Human brain variation by retrotransposition.
figure1

These twins are genetically identical at conception, but at birth their brains differ because of new L1 insertions that take place during the development of the nervous system in the fetus. Ongoing retrotransposition in neural progenitor cells as shown to occur by Coufal et al.1 will further diversify the genetic make-up of their brains in adulthood. Depending on the target genes and the neurons affected by L1 insertions, the twins may differ in brain function or dysfunction. Each unique insertion is represented by a different colour. Darker-shaded areas highlight regions of the brain where L1 retrotransposition may be more likely to occur after birth.

References

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Martin, S. Jumping-gene roulette. Nature 460, 1087–1088 (2009) doi:10.1038/4601087a

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