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Medical Fix for 3-billion-year-old genetic error could dramatically improve genetic sequencing

  1. Jun 24, 2016 #1


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  3. Jun 24, 2016 #2


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    Here's a citation for the scientific article being discussed:

    Ellefson et al. 2016 Synthetic evolutionary origin of a proofreading reverse transcriptase. Science 352: 1590

    Most reverse transcriptase (RT) enzymes belong to a single protein family of ancient evolutionary origin. These polymerases are inherently error prone, owing to their lack of a proofreading (3′- 5′ exonuclease) domain. To determine if the lack of proofreading is a historical coincidence or a functional limitation of reverse transcription, we attempted to evolve a high-fidelity, thermostable DNA polymerase to use RNA templates efficiently. The evolutionarily distinct reverse transcription xenopolymerase (RTX) actively proofreads on DNA and RNA templates, which greatly improves RT fidelity. In addition, RTX enables applications such as single-enzyme reverse transcription–polymerase chain reaction and direct RNA sequencing without complementary DNA isolation. The creation of RTX confirms that proofreading is compatible with reverse transcription.

    Basically, they use laboratory evolution techniques to make an reverse transcriptase (RT) enzyme that is able to proofread during DNA synthesis (so if RT inserts the incorrect nucleotide, it can go back and correct that mistake).

    I would not characterize the work as correcting a 3-billion-year-old error. RT evolved to replicate the genomes of RNA viruses like HIV. These viral genomes are ~ 10 kb long, and RT makes an error approximately once every 104 bases synthesized. Thus, the error rate of RT is optimized to enable the virus to generate diversity during replication. If RT had an error rate of the evolved RTX crated by the Ellington lab, retroviruses like HIV would go extinct as they would lack the ability to generate mutations and evolve (for example, to combat antiretroviral drugs).

    Similar work has been published previously to use laboratory evolution to convert DNA polymerases into RT enzymes (for example, see this paper from 2012 by the Holliger group at the MRC in Cambridge), though this work did not use proofreading polymerases as the starting point.

    The RTX does seem like it will be useful for biotechnological applications both in research and in the clinic. It does seem like it could help RNA sequencing methods, and RNA sequencing will likely have clinical applications as a diagnostic method and could be a useful tool in the age of personalized medicine.
    Last edited: Jun 24, 2016
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