Now, here are some real brain mutations

This week's (June 16, 2005) Nature brings yet another example of the way brain function may be modulated (see earlier posts here and here). This time, the culprit is mobile genetic elements, or retrotransposons, called LINE-1 (L1) elements.

The study, from Fred H. Gage's lab at the Salk Institute focuses on the way that these retrotransposons can alter their expression in neuronal precursor cells, ultimately resulting in changes in neural function. From the Salk Institute press release:

Brains are marvels of diversity: no two look the same -- not even those of otherwise identical twins. Scientists at the Salk Institute for Biological Studies may have found one explanation for the puzzling variety in brain organization and function: mobile elements, pieces of DNA that can jump from one place in the genome to another, randomly changing the genetic information in single brain cells. If enough of these jumps occur, they could allow individual brains to develop in distinctly different ways.
"This mobility adds an element of variety and flexibility to neurons in a real Darwinian sense of randomness and selection," says Fred H. Gage, Professor and co-head of the Laboratory of Genetics at the Salk Institute and the lead author of the study published in this week's Nature. This process of creating diversity with the help of mobile elements and then selecting for the fittest is restricted to the brain and leaves other organs unaffected. "You wouldn't want that added element of individuality in your heart," he adds.

The study may help to explain why some of these L1 elements should be there at all:

Transposable L1 elements, or "jumping genes" as they are often called, make up 17 percent of our genomic DNA but very little is known about them. Almost all of them are marooned at a permanent spot by mutations rendering them dysfunctional, but in humans a hundred or so are free to move via a "copy and paste" mechanism. Long dismissed as useless gibberish or "junk" DNA, the transposable L1 elements were thought to be intracellular parasites or leftovers from our distant evolutionary past.

It also may help to explain why their expression should be limited to germ cells and early stem cells. Nature has an accompanying editorial with this to say:

In fact, previous studies of L1 expression and mobility demonstrate L1 activity in germ cells and in early developmental cells but not in other cell types. There has been only one previous example of L1 mobility in a human somatic cell: this insertion disrupts a gene that contributes to colon cancer. Muotri et al. provide the first evidence of L1 activity in normal cells cultured directly from an animal sample, and the first evidence of somatic L1 activity late in development of a transgenic mouse.
The expression of L1s in NPCs appears to be inversely correlated with the expression of SOX2, a gene that is poorly expressed in developing NPCs but that has several vital functions in adult neural cells. The authors further demonstrate that L1 activation is related to changes in histone proteins that are associated with gene expression in general. Histones interact directly with DNA, and their acetylation and methylation pattern can determine whether a region of DNA is 'open' and transcribed. That histone modification might be a host mechanism to control L1 activity is an intriguing possibility (Ostertag and Kazazian 2005:891).

The basic idea coming out of the research is that the L1 elements may increase the diversity of expression of neuronal types. Ultimately, an adult brain incorporates only a fraction of the neuronal cells and connections among those cells that are formed during embryonic and early childhood development. If the variation among these is increased by L1 alterations, then it provides another avenue for a sort of natural Darwinian process to cull out unused neurons and connections, leaving the brain tissue composed of maximally valuable structures and communication networks. Supporting this hypothesis is the fact that cells that undergo L1 retrotransposition events are more likely to differentiate into neurons. From the press release:

Apart from their activity in testis and ovaries, jumping L1 elements are not only unique to the adult brain but appear to happen also during early stages of the development of nerve cells. The Salk team found insertions only in neuronal precursor cells that had already made their initial commitment to becoming a neuron. Other cell types found in the brain, such as oligodendrocytes and astrocytes, were unaffected.

But there is much left to be demonstrated. The conclusion of the paper includes enough to intrigue, but makes clear how little has really been shown:

Thus, our findings indicate that an engineered human L1 can retrotranspose in rat NPCs and indicate that individual neurons might be mosaic with respect to L1 content. Future experiments will focus on whether endogenous L1s naturally retrotranspose in NPCs and whether this process has any developmental significance. However, with those caveats being clearly stated, it is tempting to speculate that some of the genomic changes necessary for the uniqueness of individuals within a population, as defined by their neural circuitry, might be driven, in part, by the activities of mobile elements (Muotri et al. 2005:909).

References:

Muotri AR, Chu VT, Marchetto MCN, Deng W, Moran JV, and Gage FT. 2005. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435:903-910. Nature online

Ostertag EM and Kazazian HH, Jr. 2005. Genetics: LINEs in mind. Nature 435:890-891. Nature online