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Bacterium with a Minimal Genome

  1. Mar 24, 2016 #1

    Ygggdrasil

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    How many genes does it take to make a living organism? Scientists at the J Craig Venter Institute published a paper today in the journal Science describing the design and synthesis of a bacteria containing the minimal set of genes required for that organism to live. Their work leverages their earlier work figuring out how to chemically synthesize genomes, allowing them to systematically remove genes and other sequences from the bacterial genome until they reach the point where they could not remove any more genes without dramatically affecting the growth and replication of the bacterium. In the end, identified a set of 473 genes that they term the minimal genome.

    Although many of these genes are well studied and what one might expect to be required, about 30% of the genes have unknown function. While there are organisms with smaller genomes, most of these are parasitic and rely on their hosts for many biological functions. The synthetic bacteria described in the paper has the smallest genome of any known autonomously replicating organism. The work could provide a nice model system for efforts to computationally model life, and provides a nice platform for designing synthetic genomes with new functions.

    Publication: Hutchison et al. (2016) Design and synthesis of a minimal bacterial genome. Science 351: aad6253. doi:10.1126/science.aad6253

    Popular press summary: http://www.theatlantic.com/science/...s-shows-how-little-we-know-about-life/475053/
     
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  3. Mar 24, 2016 #2

    berkeman

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    Very interesting. How did they figure out to include that 30% with the unknown function? Did they use some sort of a Monte Carlo variation on many tries?
     
  4. Mar 24, 2016 #3

    Ygggdrasil

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    They figured things out mostly by trial-and-error in a semi systematic way (though not via a Monte Carlo method). The key tool is a method that randomly inserts a small DNA sequence into the genome, which, if it inserts into a gene, is likely to disrupt the function of the gene. They can use this method to empirically identify genes, in an unbiased manner, that are nonessential for growth. Of course, one of the main difficulties in interpreting these results is that some genes encode essential functions but are redundant with one or more other genes in the genome. For example, gene A and gene B might redundantly encode the same essential function such that inactivation of gene A leads to a viable bacteria and inactivation of gene B leads to a viable bacteria (leading one to think that the genes are nonessential) but inactivating both gene A and B leads to a non-viable bacteria.

    Essentially what the authors did was iterative rounds of identifying nonessential genes to delete, testing different combinations of deletions to find viable combinations, then repeating the experiments to identify more nonessential genes in the smaller genome. This process pared the bacteria down from 901 genes in the starting strain, to 512 genes in an intermediate strain, to 473 genes in their final version.

    Initially, they tried to rationally design a minimal genome based the scientific literature (this was a theoretical question that others have investigated), but these efforts did not produce any viable bacteria, necessitating the empirical approach the authors employed.
     
  5. Mar 24, 2016 #4

    berkeman

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    Beautiful. Thanks :smile:
     
  6. Mar 28, 2016 #5

    Andy Resnick

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    Amazing breakthrough! Does anyone know if the designed genome permits alternative translation or post-translational modification?
     
  7. Mar 28, 2016 #6

    mfb

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    Well, "designed". They took an existing genome and removed as much as possible. A full bottom-up approach is still some major breakthroughs away. The bacterium needs more than 100 genes with unknown purpose.

    I guess that minimal genome will help to understand those genes - you can study what exactly goes wrong if you remove one of those genes, without too much interference.
     
  8. Mar 28, 2016 #7
    I expect that the procedure will be repeated with other microbes. Then a comparison can be made among those minimal genomes.
     
  9. Mar 28, 2016 #8
    I have been trying to find out what is in the artificial environment for these minimum gene bacteria. I understand all the amino acids are present, but what else? Can anyone here at the PF cite a reference with this information?
     
  10. Mar 28, 2016 #9
    I heard an interview on PBS (Science Friday) with J. Craig Venter, and if I understood him correctly, he said they did some other editing of the genome as well as just removing genes.
     
  11. Mar 28, 2016 #10

    Andy Resnick

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    An erroneous statement. 79 genes were not assigned a specific function, and of those, 24 are classified as 'generic', leaving 65 that have unknown functions. Of those, only 19 are essential- meaning they cannot be removed. 13 of the 19 are of completely unknown function, and as the authors state, these "must represent nearly universal functions and thus can provide biological insights.", possibly representing "fundamentally new processes".
     
  12. Mar 28, 2016 #11

    Andy Resnick

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    It's located here:
    http://science.sciencemag.org/content/351/6280/aad6253/suppl/DC1

    They cultured the mycoplasma in SP4 media:

    https://catalog.hardydiagnostics.com/cp_prod/Content/hugo/SP4Media.htm

    SP4 media is not 'defined' media- supplements like fetal bovine serum and yeast extract are 'magic juice' that have essential and unknown growth factor(s).
     
  13. Mar 28, 2016 #12
    Hi Andy:

    Thank you very much for your prompt and useful citations.

    Regards,
    Buzz
     
  14. Mar 28, 2016 #13

    Ygggdrasil

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    What do you mean by alternative translation? Are you talking about alternative translation initiation (e.g. in the case of uORFs)? Alternative translation initiation is definitely an important regulatory process in eukaryotes, but I'm not sure whether it occurs in bacteria. Bacteria certainly have many post-translational modifications, but I'm not sure the extent to which these are lost in the minimum genome.

    Yes. For part of the genome, they performed an additional experiment where they reordered the genes to group them by function. Venter describes this as analogous to the process of defragmenting one's hard drive. After re-arranging the order of these genes, the bacteria grow just as well as the bacterium before re-ordering, showing that gene order and the position of genes in the bacterial genome is not really important for their function.

    They performed some other experiments to demonstrate that they could swap in homologous genes from other organisms and change other elements of the genome (e.g. changing all non-AUG start codons to AUGs).
     
  15. Mar 28, 2016 #14

    mfb

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    I got the number from the first post.
    Anyway, the number is not relevant - there are essential genes with unknown function.
     
  16. Mar 29, 2016 #15
    24+65=89, not 79.
    Meaning that 46 more could have been removed.
    Meaning 6 of the 19 do have a known function.
    So what were the symptoms of illness when essential genes were removed or damaged?
     
  17. Mar 29, 2016 #16
    Not being able to identify 30% of the genes sounds like a problem. Can't they check the protein synthesized by these unknown genes as to figure out what they do? But it seems like they're making progress. If they can eventually identify and self build a viable virus it would be huge progress, but again you can't just build something that took so many years to evolve, sort of like getting a balance between two points, I'd say it'll be easier to run it in a computer simulation program.

    P.S. Like the game of life program
     
    Last edited: Mar 29, 2016
  18. Mar 29, 2016 #17
    Nevermind, you can't predict the phase in which the compound would be in if any mutation is to occur
     
  19. Mar 29, 2016 #18

    Ygggdrasil

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    Yes, it's not entirely clear from the publication whether other non-essential genes could have been removed. Removal of many of these genes (which they term quasi-essential) still permits the bacteria to replicate, but at a much slower rate, making it harder to work with the bacteria. From a practical standpoint, the syn3.0 bacteria with a 3 hr doubling time is a much better starting point for future applications stemming from the work than a bacteria with a smaller genome but an 16-hour doubling time (the doubling time of M. genitalium, the naturally occurring bacterium with the smallest genome).

    Some of the unknown genes have similarity to other enzymes (e.g. kinases or hydrolases) but because their substrate its not known, it's unclear what the biological functions of these proteins are.

    This paper is a great step toward being able to build a computer simulation of a cell. Unfortunately, as this work points out, there's still more work to be done as it would be difficult to simulate a system when you don't know the function of 30% of the parts.
     
  20. Mar 29, 2016 #19
    To do a computer simulation of the bacteria is to eventually check for the mutations and how it adapts to the environment. Thing is there's more than 500 types of known amino acids and if a mutation does occur it would be hard to predict its functionality. And you need to simulate everything to a molecular scale along with its molecular structure depends on how detailed it needs to be, there's also different type of bonds so you need to account for the atomic structure. Depends on how detailed it needs to be it might not be an easy task. It's probably easier to examine a known organism for now
     
  21. Mar 29, 2016 #20

    Andy Resnick

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    Yeah, I was thinking about spliceosome activity (I know extremely little about eukaryotic gene expression, and even less about bacteria).
     
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