Did "Selfish" DNA Change Your Mind?

L1 retrotransposition in human neural progenitor cells.

Coufal, et. al. Nature 460: 1127-1131 (2009).

Retrotransposons (a.k.a. mobile elements or "jumping genes") are short segments of DNA whose only function is to make copies of themselves. Our DNA is absolutely littered with retrotransposons. For example, the active human mobile element L1 (short for LINE-1, or "long interspersed nucleotide element 1") comprises approximately 20% of the human genome! Long considered "junk DNA," increasing evidence suggests that retrotransposons may play important roles in gene function and human development. A recent paper in the August 27 issue of Nature suggests that these mobile elements may be particularly active in the developing human brain, with potential implications for neuronal function and diversity.

These DNA segments have been referred to as "selfish" or parasitic genes because the proteins they encode only function to copy and insert the DNA segment elsewhere in the genome, co-opting cellular resources in the process (known as "retrotransposition"). Since mobilization and integration of these elements could potentially disrupt normal gene function, cells have evolved ways to inhibit retrotransposition. For example, the promoters of retrotransposons are often hypermethylated, which prevents the expression of the two retrotransposon open reading frames encoding the proteins required for replication and integration. Retrotransposons usually take advantage of decreased DNA methylation in germ cells in order to propagate, but until now they were believed to be silent in somatic cells since novel retrotransposition events would not be passed on to progeny.

This paper demonstrates that a human L1 reporter construct can, in fact, retrotranspose in a neuronal progenitor cell (NPC). Furthermore, NPCs in which retrotransposition occurs can differentiate into functional neurons or glia. Their data suggest that the brain may be particularly permissive for L1 retrotransposition due to decreased methylation of L1 promoters compared to the skin (this is a striking -if not surprising- example of two different tissues having completely different epigenetic landscapes). Indeed, the authors demonstrate that L1 retrotransposition may be a more frequent event in the brain than in other tissues, as quantitative PCR indicates that there are significantly more copies of L1 in the brain rather than in the heart or liver of the same individual. It is unclear if these retrotransposition events have any phenotypic consequences, although a previous paper by this group examining human L1 retrotransposition in rat hippocampal stem cells showed that retrotransposition events could occur inside or near neuronally expressed genes, with consequent effects on gene expression and neuronal differentiation.

While this study falls short of actually sequencing the genomic DNA of individual neurons and uncovering the location and frequency of novel retrotransposition events in a human brain, the implications of the findings are exciting. First, this paper challenges the idea that the genetic material you inherit from your parents is a static entity that cannot be changed. It seems the neuronal genome may actually be somewhat dynamic during human development. Second, some studies have shown that a single neuron can affect behavior. What if a retrotransposition event affects a neuron's ability to retain a memory? Or sense a particular smell? Or respond to a neurotransmitter that affects mood? In addition to generating cellular diversity, is this phenomenon a driving force in creating human diversity? Did "selfish DNA" make us who we are?

Other References:

Martin, S.L. Jumping-gene roulette. Nature 460, 1087-1088 (2009).

Muotri, A.R., et. al. The necessary junk: new functions for transposable elements. Human Molecular Genetics 16, R159-R167 (2007).

Muotri, A.R., et. al. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435, 903-910 (2005).