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Engineering tRNA neochromosomes in yeast


Project Description

Advances in DNA synthesis technology have led to rapid growth in the field of synthetic biology, heralding a nascent era of synthetic genomics. Sc2.0 (www.syntehticyeast.org) is an international consortium with the aim of designing and constructing a fully‐synthetic eukaryotic genome. Fundamental design changes to the synthetic genome include the removal of unstable tRNA genes and their intended collation onto a “tRNA neochromosome”, with the aim of producing a more robust and stable synthetic genome structure.

tRNA genes have been shown to be hotspots for DNA instability for several reasons. Firstly, tRNA genes are often the target of 5’ upstream retrotransposon incorporation. Secondly, tRNA genes are transcribed heavily, which can lead to single strand breaks during DNA synthesis, when RNA polymerase III and DNA polymerase collide and stall. Furthermore, homologous regions upstream of tRNA genes and tRNA genes themselves can aid homologous recombination of chromosomal regions. Thus in Sc2.0, all tRNA genes are moved to their own chromosome, so that the effect of their absence throughout the rest of the genome can be observed. We have now completed the first version of the tRNA neochromosome, the Cai lab is now aiming to recruit a highly motivated PhD student to undertake the next version of the tRNA neochromosome design, assembly and characterization.

Please see our recent publications in Science for further information (refs. 1-5). The student will have great opportunities to work with our international collaborators such as New York University (USA), Imperial College London (UK), EMBL (Germany) and Chinese Academy of Sciences and Beijing Genomics Institute (China).

Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in life sciences or related subjects. A Masters degree in a relevant subject and/or experience in life sciences subject area/discipline synthetic biology is desirable.

A successful candidate should have a good understanding of molecular biology, biotechnology and microbiology and ideally will be familiar with research in synthetic biology, biological materials and biosynthesis. A good track record in hands-on bioscience laboratory work, especially with bacterial/yeast systems, is highly desirable. Expertise in large DNA assemblies as well as their analysis and characterization with high throughput methodologies such as next generation sequencing would be an advantage. Most importantly, the applicant should be well-motivated and open-minded, able to thrive in s a multi-disciplinary research environment. The project can be tailored to the student within the research scope.

Contact for further Information:

Prof. Patrick Yizhi Cai
Email:
Website: http://www.cailab.org

Funding Notes

This is a 3.5 year funded studentship which covers fees and stipend (£15,009 in 2019-2020).

Open to UK/EU applicants only.

WE expect the studentship to start in September 2019.

References

(1) Richardson, S. M., Mitchell, L. A., Stracquadanio, G., Yang, K., Dymond, J. S., DiCarlo, J. E., Lee, D., Huang, C. L. V., Chandrasegaran, S., Cai, Y., Boeke, J. D., and Bader, J. S. (2017) Design of a synthetic yeast genome. Science 355, 1040–1044.

(2) Schindler, D., Dai, J., and Cai, Y. (2018) Synthetic genomics: a new venture to dissect genome fundamentals and engineer new functions. Current Opinion in Chemical Biology 46, 56–62.

(3) Shen, Y., Wang, Y., Chen, T., Gao, F., Gong, J., Abramczyk, D., Walker, R., Zhao, H., Chen, S., Liu, W., Luo, Y., Müller, C. A., Paul-Dubois-Taine, A., Alver, B., Stracquadanio, G., Mitchell, L. A., Luo, Z., Fan, Y., Zhou, B., Wen, B., Tan, F., Wang, Y., Zi, J., Xie, Z., Li, B., Yang, K., Richardson, S. M., Jiang, H., French, C. E., Nieduszynski, C. A., Koszul, R., Marston, A. L., Yuan, Y., Wang, J., Bader, J. S., Dai, J., Boeke, J. D., Xu, X., Cai, Y., and Yang, H. (2017) Deep functional analysis of synII, a 770-kilobase synthetic yeast chromosome. Science 355, eaaf4791.

(4) Mercy, G., Mozziconacci, J., Scolari, V. F., Yang, K., Zhao, G., Thierry, A., Luo, Y., Mitchell, L. A., Shen, M., Shen, Y., Walker, R., Zhang, W., Wu, Y., Xie, Z.-X., Luo, Z., Cai, Y., Dai, J., Yang, H., Yuan, Y.-J., Boeke, J. D., Bader, J. S., Muller, H., and Koszul, R. (2017) 3D organization of synthetic and scrambled chromosomes. Science 355, eaaf4597.

(5) Zhang, W., Zhao, G., Luo, Z., Lin, Y., Wang, L., Guo, Y., Wang, A., Jiang, S., Jiang, Q., Gong, J., Wang, Y., Hou, S., Huang, J., Li, T., Qin, Y., Dong, J., Qin, Q., Zhang, J., Zou, X., He, X., Zhao, L., Xiao, Y., Xu, M., Cheng, E., Huang, N., Zhou, T., Shen, Y., Walker, R., Luo, Y., Kuang, Z., Mitchell, L. A., Yang, K., Richardson, S. M., Wu, Y., Li, B.-Z., Yuan, Y.-J., Yang, H., Lin, J., Chen, G.-Q., Wu, Q., Bader, J. S., Cai, Y., Boeke, J. D., and Dai, J. (2017) Engineering the ribosomal DNA in a megabase synthetic chromosome. Science 355, eaaf3981.

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