Monday, November 19, 2018

BacterioFiles 362 - Combining Chromosomes

Saccharomyces cerevisiae yeast
This episode: Combining all 16 of yeast's chromosomes into one or two only impairs their growth slightly in the lab, but it prevents them from successful mating with wild yeasts!

Download Episode (12.4 MB, 13.6 minutes)

Show notes:
Microbe of the episode: Vibrio succinogenes

News item 1/News item 2

Journal Papers:
Luo J, Sun X, Cormack BP, Boeke JD. 2018. Karyotype engineering by chromosome fusion leads to reproductive isolation in yeast. Nature 560:392–396.
Shao Y, Lu N, Wu Z, Cai C, Wang S, Zhang L-L, Zhou F, Xiao S, Liu L, Zeng X, Zheng H, Yang C, Zhao Z, Zhao G, Zhou J-Q, Xue X, Qin Z. 2018. Creating a functional single-chromosome yeast. Nature 560:331–335.

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Episode outline:
  • Background: Yeast, Saccharomyces cerevisiae, very important
    • Makes important things by fermentation: bread, alcoholic beverages
  • Also very useful for studying eukaryote biology
    • And as biotech cell factories
  • In wild, have set of 16 kinds of chromosomes
    • Humans have 23 pairs, 46 in most cells (diploid)
    • Could be interesting/useful to change this number in yeast
      • Make genetic engineering/stability easier
      • But requires advanced genetic techniques
  • Have split into 33 kinds before, and combined into 12
    • No effects on health/reproduction of yeast
  • And used to have only 8 until doubled a long time ago (~100 million years)
    • Seem to be doing ok since then
  • Questions: what are limits of chromosome length? Why have more rather than less, or just one? How does changing affect reproduction?
  • What’s new: Now, two groups publishing in Nature have fused yeast's 16 chromosomes into much smaller numbers—as low as one or two!
  • Methods: 1st is group from US, from NYU and Johns Hopkins
  • Fused small ones together, leaving 12
    • Used CRISPR-Cas technique; cut off 1 end of 2
    • Put in molecule that matches some at each end, cell joins them together using added bridge
    • Combined 12 into 4, then 4 into 2
  • So 14 fewer chromosomes in final strain, without loss of genetic content
    • Couldn't get it down to 1
  • Tested in different conditions; strains with at least 4 chromosomes seemed healthy
    • 2-chromosome grew slightly slower, but otherwise seemed fine
    • No apparent changes in mutation rates
    • A little change in gene expression in 4+ but not much
    • 2 had some bigger changes, esp genes near ends and former ends
  • Also tested mating ability
  • Sex in yeast: 2 different mating types (sexes but not really), need one of each
    • Exude pheromones that attract each other, form growths along gradient called shmoo
    • Then meet and cells fuse, genetic material combines to make diploid
    • This can make spore or live as diploid or split again
  • Tried different combos: 16 x 16, 16 x 14, 16 x 2, etc
    • Each most successful with mating partner of same number
    • 16 x 16 had >90%, 16 x 14 only 34%, and down from there, but 8x8 was good, etc
    • But 8 and below can't mate with 16 strain at all: reproductive isolation from wild
  • 2nd is group from different institutions in China
    • Also fusing and testing whether result could go through sexual cycle
  • Group used CRISPR-Cas too, deleting telomeres and centromeres
    • Managed to fuse all 16 into 1
    • Had a few mutations and insertions/deletions though
    • Some genes near chromosome ends deleted
  • Gene expression: 28 genes different, not too many
    • Similar deal to 1st paper
    • Some extra gene expression related to stress
  • Slight growth reduction under some conditions, not all
    • Couldn't compete with normal yeast strain
  • Sexual cycle: could be tricky with extra-large chromosome
    • Succeeded in making diploid, and underwent meiosis and made spores
    • But some pairings had wrong number of copies, and fewer spores were viable
    • In-between chromosome number strains were intermediate in these qualities
  • Summary: Combining yeasts' genome from 16 even into 1 or 2 chromosomes impairs them only slightly, in growth and sexual viability in the lab, and combinations into larger numbers impairs them even less 
  • Applications and implications: Potential use for research and biotech
    • Create isolated yeast strains, can't mate with wild
    • Simplify engineering to some extent – only need targeting to fewer chromosomes
  • What do I think: Why have more when less is ok?
    • Could be not much selection either way; just go with what they happen to have
    • More potential for recombination between chromosomes, genetic diversity
    • Some helpful regulatory properties of ends, but more ends to maintain or lose
  • What happens in nature with genetics can be very different from what is possible with intention
  • Interesting question: are fused strains new species from wild? 
    • Much different genome structure, but genes and growth and everything otherwise similar
    • Could depend on what meaning of "species" is useful
    • If can't reproduce with 16 strain, meets one definition
  • Genes, chromosomes, or everything together? Not so simple

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