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An ancient stretch of DNA that behaves like a parasite within the genome can cause health problems for an individual organism. However, the genetic mobility it bestows on the genome could give rise to genetic variation in offspring and so may be a prime mover in speciation and evolution. Now, researchers at the Max Planck Institute for Developmental Biology in Tübingen, Germany, have determined the crystal structure of the protein L1ORF1p, encoded by this gene. Testament to just how parasitic is the mobile gene LINE-1 is the fact that almost a fifth (17%) of our DNA consists of LINE-1 sequences. This is a particularly disturbing figure given that the estimated 30,000 human proteins are encoded by less than 5% of our DNA. Elena Khazina and Oliver Weichenrieder explain that the LINE-1 retrotransposon is a mobile genetic element that can multiply and insert itself into chromosomal DNA at almost any location along the genome. This, they say, disturbs the genetic code at the site of integration. Having determined the structure of L1ORF1p they believe it should now be possible to get a clearer view of the mechanism that underlies LINE-1 mobilization. Such work could have implications for understanding the relationship between retrotransposons and retroviruses as well as certain evolutionary processes in animals and humans. The research may also have direct applications, one day, in the development of highly specific gene therapy using novel vectors instead of the current less location-specific methods based on retroviruses. The LINE-1 retrotransposon is not only parasitic itself but is also responsible for integrating one million Alu-sequences (another parasitic gene) into the genomes of higher primates, these sequences account for 10% of our genome. The researchers point out that such insertions can happen with each new generation. Every twentieth baby born is thought to have at least one new insertion due to this parasitic gene. As such, almost all human genes have been affected through our evolutionary history by a LINE-1 or Alu element. "It is difficult to believe that the massive integration of LINE-1 and Alu sequences remained without consequences on human evolution," says lead scientist Weichenrieder. "Thus it is surprising how little we know so far about the mechanism of retrotransposition and about the proteins and nucleic acids involved in this process." Khazina and Weichenrieder have characterized one of the two proteins encoded by human LINE-1, the aforementioned L1ORF1p. Apparently, this protein binds to LINE-1 RNA, which itself is transcribed from a LINE-1 element in the genomic DNA. The researchers explain that it can be assumed that L1ORF1p supports the subsequent reverse transcription of LINE-1 RNA into DNA, especially as this process happens directly at the genomic integration site of the new LINE-1 element. The team's structure shows that L1ORF1p, a 40 kDa protein in humans, has three components. The first component causes it to trimerise, while the other two parts allow it to bind to LINE-1 RNA. "Especially surprising was the identification of a so-called RNA recognition motif (RRM) domain in the middle part of the protein, since this part was believed so far to be rather unstructured", adds Khazina, "Our crystal structure clearly proves the existence of this domain. Meanwhile we also identified RRM domains in other retrotransposons, in a variety of animal and plant species", she adds. The team explains that the identification of an RRM domain in the L1ORF1p protein could now explain why L1ORF1p binds LINE-1 RNA. The details of the crystal structure clarify how this can occur. It also provides some insight into the mechanisms used by the cell to try and block the excessive propagation of these genetic parasites. Related links:
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