Friday, September 30, 2011
Amplification, Mutation, and Sequencing of a Six-Letter Synthetic Genetic System
In this paper the Benner group is able to show that they successfully added two nucleotides to artificial DNA. Furthermore they present that they are able to perform PCR on the 6 nucleotide DNA incorporating the new bases. Beyond that they can mutate the artificial DNA making it viable for evolution. The expanded code could lead to several developments down the road including a way of incorporating unnatural amino acids into proteins. Though there is still a lot of work before these artificial DNAs could be functional in a cell, but these findings increase the the possible number of codons from 64 to 216.
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Wow, this is really cool. I can't wait to see what new technologies are enabled by this one.
ReplyDeleteIMO, a truly minimal but self sustaining synthetic organism will have 6 bases and 2 nucleotide codons. At the cost of genes for the biosynthesis of the 2 new bases, you'd reduce the genome size by 1/3 of all coding regions (~half a million bases, assuming minimal genome size of ~1400 genes and ~1000 bp per gene), and you would need less than 25 tRNA and aminoacyl tRNA synthetase genes. You would also want to reduce the number of amino acids. I'd bet that sequences composed of just ~10-15 amino acids could encode any functions essential to life.
ReplyDeleteJohn, I like where your going with that... They discuss in this paper the ability to expand coding potential, where as you see it as a way to decrease coding information for a minimal organism construct, which is a very interesting idea.
ReplyDeleteHowever, i think there are several limitations to the approach you are describing: Using a 6 base 2 codon system would produce 36 unique recognition sequences - but there would be a large increase in error rates, since the codons do not retain redundancy similar to that in nature. In a 3 codon system for 20 AA the 3rd base is often irrelevant, allowing for 1/3 of errors to be negligible. The organism would need an elaborate repair mechanisms and does not seem viable for a well defined predictable construct.
The idea of a minimal self sustaining organism is new to me - do you know of any good review for this topic?
Bah, I feel retarded. Of course it's 36. Before this paper, the best alternative base was one that paired with itself, making 5 total bases. Anyhow...
ReplyDeleteThere are a lot of reviews on minimal self sustaining organisms. All of the most recent ones cite Venter's synthetic organism paper, so that's a good place to start.
http://www.pnas.org/content/103/2/425.full
^^ pretty old, but another good one.
Actually the lack of redundancy is exciting if you want a more dynamic, evolvable system.
http://onlinelibrary.wiley.com/doi/10.1002/cbic.200800298/pdf
This paper looks at saturation mutant libraries where each codon position is randomized with 12 possible codons, each coding for a different amino acid. Active mutants were much more common than when a similar library was made using all 64 codons. This implies that in general when a selective pressure is presented, less redundancy increases survival rates.
Thanks for the cool article. Really interesting how they analyzed what genes are required - and that genes of unknown function made up 1/4th of the essential genes (should probably BLAST those for homology to other genes). Also, none of the DNA replication genes could be mutated, showing how important the mechanisms for DNA replication are to maintain. Even after they did their analysis they found enzyme redundancy, which i found surprising. Apparently multiple sets of enzymes are required for some gene cassettes.
ReplyDeleteI didnt think about how error rates would be beneficial for evolutionary development, very good point. I was only thinking of the problems with maintaining the genome; you again offer a great example of the flip side :)