Sunday, April 7, 2013

Why there is genome instability? – Discovery of sleeping beauty

Why there is genome instability? – Discovery of sleeping beauty

Transposable elements (TE) are a large family of DNA elements widely presented in the genome of organism. These elements may not share the exactly same sequence, but consist of elements that confer similar biological function, which is inserting into genome and causing target site duplications. There are two classes of TE in eukaryotic cells: retrotransposon elements and DNA transposons.

The first transposon, founded by Barbara McClintock in 1983, is a naughty gene jumping around in the genome of maize. She found that there were deletions and insertions in the genome that are related to the change in the color of corn kernels. This transposon belongs to class II TEs, being called as DNA copy & paste system (or ctrl+x & ctrl+v system, geeky joke). Class II transposons are composed of two inverted repeats (IR) at each end, and one transposase element in the middle, which determines the autonomy of the transposon. The structure enables class II transposons to insert in the genome, changing the size of the genome and leading to genome instability.

Class I transposon is a family of retroviral genome (I have talked about retrotransposon and viral oncology in a previous post). It is interesting to know that not only in retrovirus, in yeast cells there are transposons that resemble retrotransposon structure. Ty element includes TyA, a gag-like protein and TyB, homology to RTase. The structure of Ty element is shown as follows.

Indication of evolution

Comparing these transposons from different branches of species reveal the role of transposon in organism development and evolution. Because the unstable nature of TE leads to mutagenesis, changes in genome sizes and eventually deleterious mutations, most biologists regard these TEs as “selfish DNA parasites”. Therefore, selection force is “giving a harsh time” to the TEs. Many organisms have their special mechanism to inhibit the activity of TE. In human genome, most of the transposable elements have been inactivated by mutagenesis long time ago. Very few transposons still remain their function of being a troublemaker. For example, Alu element is a most common transposon in human and has been proved to have association with inherited diseases and cancer. The figure below shows the karyotype of human chromosome of a female (XX). Green color labels the hybridized Alu element widely distributed in the chromosomes.

The discovery of TE also shed light on the speciation of organism in a molecular level. Scientists claim that these TEs have a common ancestor, and that transposons help exchange genetic information in the horizontal gene transmission. However, some researchers believe that these TEs emerged independently in multiple times. But still, except for the understanding of retroviral genome integration into host genome, we are unable to tell how the transposon from one ancestral species has been introduced to another species.

The wake up of sleeping beauty

TEs are named as sleeping beauty by their inactivated nature. However, in 1997 Ivics et al successfully woke up the sleeping beauty in salmonid cells. The researchers used a powerful approach to construct an activated transposon in fish cells by mutagenesis. They mapped several inactivated mutation in the ORF of sleeping beauty, replaced these mutations with robust amino acid residues, and finally woke up the beauty. The following shows how they performed this elegant biological trial.

Ivics, Z., Hackett, P. B., Plasterk, R. H., & Izsvák, Z. (1997). Molecular Reconstruction of< i> Sleeping Beauty</i>, a< i> Tc1</i>-like Transposon from Fish, and Its Transposition in Human Cells. Cell, 91(4), 501-510.

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