The "jumping genes" of the brain

Have you ever wondered how a single cob of Indian corn can display so many beautiful colors? The answer came in 1948 thanks to scientist Barbara McClintock: she discovered that 50% of the maize genome is made of transposons, DNA sequences that can "jump" around in the DNA of a single cell. As they move around, these "jumping genes" can "stretch" the DNA by adding repeated copies, but they can also cause new mutations to appear. In the case of corn, the new mutations are responsible for the different colors displayed by the kernels.

Since McClintock's discovery (for which she was awarded the Nobel Prize in 1983), transposons have been found in many other organisms: fruit flies, bacteria, and, of course, humans. Transposons play an important role in evolution, as roughly 50% of our genome is derived from these movable bits of DNA [1]. They are responsible for many evolutionary processes, like new gene formation, the progressive increase in size of genomes, alternative splicing, and the introduction of new epigenetic regulations. Recombination between these DNA elements can cause deletions and mutations in the DNA, and some have been associated with diseases like Alzheimer's and breast and lung cancers.

There are two ways transposons can achieve mobility.

Retrotransposons are "cut and pasted" from the genome in two phases: first they are copied from DNA to RNA, and then the RNA is copied back to RNA through reverse transcription, and reinserted into the genome at a different position. This ability to switch back and forth from DNA to RNA reminds us of retroviruses, doesn't it? In fact, a portion of the endogenous retroviral sequences present in our DNA are retrotransposons. On the other hand, DNA transposons are able to "move" without the intermediate RNA step. Instead, they use an enzyme called "transposes" that binds to the transposon and also to the target site where it will deliver the bit of DNA.

Several studies have shown that in the human genome retrotransposition happens during embryonic development [2]. In particular, using mouse models with human genes, Kano et al. showed that "de novo retrotransposition events can occur even after the time of establishment of germ cells, or even in adult tissues, which cannot be transmitted to the next generation. These nonheritable retrotransposition events in somatic tissues may play a significant role in creating genomic diversity within an individual."

Indeed, this is what Baillie et al. [3] found when they looked at the brain tissue from three healthy donors and mapped retrotransposons from two regions in particular, the hippocampus and the caudate nucleus. They investigated three families of transposons found in the human genome: L1, Alu, and SVA, and found thousands of somatic insertions. Using deep sequencing, the researchers were able to link somatic retrotransposition to neurobiological genes. They found in particular high activity in the hippocampus, and hypothesized that this may be related to neural plasticity. In other words, even though highly mutagenic, this kind of somatic changes may also be linked to the normal functioning of the brain and confer its innate ability to constantly re-adapt to the environment.

These findings are extremely fascinating because they indicate, once again, that there's a lot more to a genome than genes. The high frequency of somatic retrotransposition activity found by Baillie et al. may explain why for example homozygote twins may have discordant behaviors and/or disease outcomes, and, to link to a previous post of mine, could also explain the "missing heritability" puzzle for some types of diseases.

[1] Cordaux R, & Batzer MA (2009). The impact of retrotransposons on human genome evolution. Nature reviews. Genetics, 10 (10), 691-703 PMID: 19763152

[2] Kano H, Godoy I, Courtney C, Vetter MR, Gerton GL, Ostertag EM, & Kazazian HH Jr (2009). L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes & development, 23 (11), 1303-12 PMID: 19487571

[3] Baillie, J., Barnett, M., Upton, K., Gerhardt, D., Richmond, T., De Sapio, F., Brennan, P., Rizzu, P., Smith, S., Fell, M., Talbot, R., Gustincich, S., Freeman, T., Mattick, J., Hume, D., Heutink, P., Carninci, P., Jeddeloh, J., & Faulkner, G. (2011). Somatic retrotransposition alters the genetic landscape of the human brain Nature DOI: 10.1038/nature10531

Photo: detail of sculpture by Warren Cullar, Santa Fe, NM. Canon 40D, shutter speed 1/50, focal length 85mm, f-stop 9, ISO speed 100.