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Title: Deep functional analysis of synII, a 770-kilobase synthetic yeast chromosome

Abstract

INTRODUCTION Although much effort has been devoted to studying yeast in the past few decades, our understanding of this model organism is still limited. Rapidly developing DNA synthesis techniques have made a “build-to-understand” approach feasible to reengineer on the genome scale. Here, we report on the completion of a 770-kilobase synthetic yeast chromosome II (synII). SynII was characterized using extensive Trans-Omics tests. Despite considerable sequence alterations, synII is virtually indistinguishable from wild type. However, an up-regulation of translational machinery was observed and can be reversed by restoring the transfer RNA (tRNA) gene copy number. RATIONALE Following the “design-build-test-debug” working loop, synII was successfully designed and constructed in vivo. Extensive Trans-Omics tests were conducted, including phenomics, transcriptomics, proteomics, metabolomics, chromosome segregation, and replication analyses. By both complementation assays and SCRaMbLE (synthetic chromosome rearrangement and modification by loxP -mediated evolution), we targeted and debugged the origin of a growth defect at 37°C in glycerol medium. RESULTS To efficiently construct megabase-long chromosomes, we developed an I- Sce I–mediated strategy, which enables parallel integration of synthetic chromosome arms and reduced the overall integration time by 50% for synII. An I- Sce I site is introduced for generating a double-strand break to promote targeted homologousmore » recombination during mitotic growth. Despite hundreds of modifications introduced, there are still regions sharing substantial sequence similarity that might lead to undesirable meiotic recombinations when intercrossing the two semisynthetic chromosome arm strains. Induction of the I- Sce I–mediated double-strand break is otherwise lethal and thus introduced a strong selective pressure for targeted homologous recombination. Since our strategy is designed to generate a markerless synII and leave the URA3 marker on the wild-type chromosome, we observed a tenfold increase in URA3 -deficient colonies upon I- Sce I induction, meaning that our strategy can greatly bias the crossover events toward the designated regions. By incorporating comprehensive phenotyping approaches at multiple levels, we demonstrated that synII was capable of powering the growth of yeast indistinguishably from wild-type cells (see the figure), showing highly consistent biological processes comparable to the native strain. Meanwhile, we also noticed modest but potentially significant up-regulation of the translational machinery. The main alteration underlying this change in expression is the deletion of 13 tRNA genes. A growth defect was observed in one very specific condition—high temperature (37°C) in medium with glycerol as a carbon source—where colony size was reduced significantly. We targeted and debugged this defect by two distinct approaches. The first approach involved phenotype screening of all intermediate strains followed by a complementation assay with wild-type sequences in the synthetic strain. By doing so, we identified a modification resulting from PCRTag recoding in TSC10 , which is involved in regulation of the yeast high-osmolarity glycerol (HOG) response pathway. After replacement with wild-type TSC10 , the defect was greatly mitigated. The other approach, debugging by SCRaMbLE, showed rearrangements in regions containing HOG regulation genes. Both approaches indicated that the defect is related to HOG response dysregulation. Thus, the phenotypic defect can be pinpointed and debugged through multiple alternative routes in the complex cellular interactome network. CONCLUSION We have demonstrated that synII segregates, replicates, and functions in a highly similar fashion compared with its wild-type counterpart. Furthermore, we believe that the iterative “design-build-test-debug” cycle methodology, established here, will facilitate progression of the Sc2.0 project in the face of the increasing synthetic genome complexity. SynII characterization. ( A ) Cell cycle comparison between synII and BY4741 revealed by the percentage of cells with separated CEN2-GFP dots, metaphase spindles, and anaphase spindles. ( B ) Replication profiling of synII (red) and BY4741 (black) expressed as relative copy number by deep sequencing. ( C ) RNA sequencing analysis revealed that the significant up-regulation of translational machinery in synII is induced by the deletion of tRNA genes in synII.« less

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [2];  [3]; ORCiD logo [3]; ORCiD logo [4]; ORCiD logo [4];  [3];  [3]; ORCiD logo [4]; ORCiD logo [4]; ORCiD logo [5];  [4];  [4]; ORCiD logo [6]; ORCiD logo [7]; ORCiD logo [8]; ORCiD logo [3];  [3];  [3] more »;  [3];  [3];  [3]; ORCiD logo [9]; ORCiD logo [9]; ORCiD logo [10]; ORCiD logo [11];  [3];  [4]; ORCiD logo [5]; ORCiD logo [12]; ORCiD logo [4]; ORCiD logo [9];  [3]; ORCiD logo [13]; ORCiD logo [8]; ORCiD logo [7];  [2]; ORCiD logo [4]; ORCiD logo [14] « less
+ Show Author Affiliations
  1. BGI-Shenzhen, Shenzhen 518083, China., School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK., James D. Watson Institute of Genome Sciences, Hangzhou 310058, China., BGI-Qingdao, Qingdao 266555, China.
  2. BGI-Shenzhen, Shenzhen 518083, China., BGI-Qingdao, Qingdao 266555, China.
  3. BGI-Shenzhen, Shenzhen 518083, China.
  4. School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK.
  5. Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.
  6. High-Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA., Department of Biomedical Engineering, School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA., School of Computer Science and Electronic Engineering, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK.
  7. Institute for Systems Genetics, New York University Langone Medical Center, ACLSW Room 503, 430 East 29th Street, New York, NY 10016, USA.
  8. Key Laboratory of Industrial Biocatalysis (Ministry of Education), Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  9. Key Laboratory of Systems Bioengineering (Ministry of Education), SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, PR China.
  10. High-Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  11. High-Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA., Department of Biomedical Engineering, School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
  12. Department of Genomes and Genetics, Institut Pasteur/CNRS UMR3525, 25-28, Rue du Docteur Roux, 75724 Paris Cedex 15, France.
  13. Department of Biomedical Engineering, School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA., Institute for Systems Genetics, New York University Langone Medical Center, ACLSW Room 503, 430 East 29th Street, New York, NY 10016, USA.
  14. BGI-Shenzhen, Shenzhen 518083, China., James D. Watson Institute of Genome Sciences, Hangzhou 310058, China.
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1435471
Grant/Contract Number:  
FG02097ER25308
Resource Type:
Published Article
Journal Name:
Science
Additional Journal Information:
Journal Name: Science Journal Volume: 355 Journal Issue: 6329; Journal ID: ISSN 0036-8075
Publisher:
American Association for the Advancement of Science (AAAS)
Country of Publication:
United States
Language:
English

Citation Formats

Shen, Yue, Wang, Yun, Chen, Tai, Gao, Feng, Gong, Jianhui, Abramczyk, Dariusz, Walker, Roy, Zhao, Hongcui, Chen, Shihong, Liu, Wei, Luo, Yisha, Müller, Carolin A., Paul-Dubois-Taine, Adrien, Alver, Bonnie, Stracquadanio, Giovanni, Mitchell, Leslie A., Luo, Zhouqing, Fan, Yanqun, Zhou, Baojin, Wen, Bo, Tan, Fengji, Wang, Yujia, Zi, Jin, Xie, Zexiong, Li, Bingzhi, Yang, Kun, Richardson, Sarah M., Jiang, Hui, French, Christopher E., Nieduszynski, Conrad A., Koszul, Romain, Marston, Adele L., Yuan, Yingjin, Wang, Jian, Bader, Joel S., Dai, Junbiao, Boeke, Jef D., Xu, Xun, Cai, Yizhi, and Yang, Huanming. Deep functional analysis of synII, a 770-kilobase synthetic yeast chromosome. United States: N. p., 2017. Web. doi:10.1126/science.aaf4791.
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Shen, Yue, Wang, Yun, Chen, Tai, Gao, Feng, Gong, Jianhui, Abramczyk, Dariusz, Walker, Roy, Zhao, Hongcui, Chen, Shihong, Liu, Wei, Luo, Yisha, Müller, Carolin A., Paul-Dubois-Taine, Adrien, Alver, Bonnie, Stracquadanio, Giovanni, Mitchell, Leslie A., Luo, Zhouqing, Fan, Yanqun, Zhou, Baojin, Wen, Bo, Tan, Fengji, Wang, Yujia, Zi, Jin, Xie, Zexiong, Li, Bingzhi, Yang, Kun, Richardson, Sarah M., Jiang, Hui, French, Christopher E., Nieduszynski, Conrad A., Koszul, Romain, Marston, Adele L., Yuan, Yingjin, Wang, Jian, Bader, Joel S., Dai, Junbiao, Boeke, Jef D., Xu, Xun, Cai, Yizhi, & Yang, Huanming. Deep functional analysis of synII, a 770-kilobase synthetic yeast chromosome. United States. https://doi.org/10.1126/science.aaf4791
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Shen, Yue, Wang, Yun, Chen, Tai, Gao, Feng, Gong, Jianhui, Abramczyk, Dariusz, Walker, Roy, Zhao, Hongcui, Chen, Shihong, Liu, Wei, Luo, Yisha, Müller, Carolin A., Paul-Dubois-Taine, Adrien, Alver, Bonnie, Stracquadanio, Giovanni, Mitchell, Leslie A., Luo, Zhouqing, Fan, Yanqun, Zhou, Baojin, Wen, Bo, Tan, Fengji, Wang, Yujia, Zi, Jin, Xie, Zexiong, Li, Bingzhi, Yang, Kun, Richardson, Sarah M., Jiang, Hui, French, Christopher E., Nieduszynski, Conrad A., Koszul, Romain, Marston, Adele L., Yuan, Yingjin, Wang, Jian, Bader, Joel S., Dai, Junbiao, Boeke, Jef D., Xu, Xun, Cai, Yizhi, and Yang, Huanming. Fri . "Deep functional analysis of synII, a 770-kilobase synthetic yeast chromosome". United States. https://doi.org/10.1126/science.aaf4791.
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@article{osti_1435471,
title = {Deep functional analysis of synII, a 770-kilobase synthetic yeast chromosome},
author = {Shen, Yue and Wang, Yun and Chen, Tai and Gao, Feng and Gong, Jianhui and Abramczyk, Dariusz and Walker, Roy and Zhao, Hongcui and Chen, Shihong and Liu, Wei and Luo, Yisha and Müller, Carolin A. and Paul-Dubois-Taine, Adrien and Alver, Bonnie and Stracquadanio, Giovanni and Mitchell, Leslie A. and Luo, Zhouqing and Fan, Yanqun and Zhou, Baojin and Wen, Bo and Tan, Fengji and Wang, Yujia and Zi, Jin and Xie, Zexiong and Li, Bingzhi and Yang, Kun and Richardson, Sarah M. and Jiang, Hui and French, Christopher E. and Nieduszynski, Conrad A. and Koszul, Romain and Marston, Adele L. and Yuan, Yingjin and Wang, Jian and Bader, Joel S. and Dai, Junbiao and Boeke, Jef D. and Xu, Xun and Cai, Yizhi and Yang, Huanming},
abstractNote = {INTRODUCTION Although much effort has been devoted to studying yeast in the past few decades, our understanding of this model organism is still limited. Rapidly developing DNA synthesis techniques have made a “build-to-understand” approach feasible to reengineer on the genome scale. Here, we report on the completion of a 770-kilobase synthetic yeast chromosome II (synII). SynII was characterized using extensive Trans-Omics tests. Despite considerable sequence alterations, synII is virtually indistinguishable from wild type. However, an up-regulation of translational machinery was observed and can be reversed by restoring the transfer RNA (tRNA) gene copy number. RATIONALE Following the “design-build-test-debug” working loop, synII was successfully designed and constructed in vivo. Extensive Trans-Omics tests were conducted, including phenomics, transcriptomics, proteomics, metabolomics, chromosome segregation, and replication analyses. By both complementation assays and SCRaMbLE (synthetic chromosome rearrangement and modification by loxP -mediated evolution), we targeted and debugged the origin of a growth defect at 37°C in glycerol medium. RESULTS To efficiently construct megabase-long chromosomes, we developed an I- Sce I–mediated strategy, which enables parallel integration of synthetic chromosome arms and reduced the overall integration time by 50% for synII. An I- Sce I site is introduced for generating a double-strand break to promote targeted homologous recombination during mitotic growth. Despite hundreds of modifications introduced, there are still regions sharing substantial sequence similarity that might lead to undesirable meiotic recombinations when intercrossing the two semisynthetic chromosome arm strains. Induction of the I- Sce I–mediated double-strand break is otherwise lethal and thus introduced a strong selective pressure for targeted homologous recombination. Since our strategy is designed to generate a markerless synII and leave the URA3 marker on the wild-type chromosome, we observed a tenfold increase in URA3 -deficient colonies upon I- Sce I induction, meaning that our strategy can greatly bias the crossover events toward the designated regions. By incorporating comprehensive phenotyping approaches at multiple levels, we demonstrated that synII was capable of powering the growth of yeast indistinguishably from wild-type cells (see the figure), showing highly consistent biological processes comparable to the native strain. Meanwhile, we also noticed modest but potentially significant up-regulation of the translational machinery. The main alteration underlying this change in expression is the deletion of 13 tRNA genes. A growth defect was observed in one very specific condition—high temperature (37°C) in medium with glycerol as a carbon source—where colony size was reduced significantly. We targeted and debugged this defect by two distinct approaches. The first approach involved phenotype screening of all intermediate strains followed by a complementation assay with wild-type sequences in the synthetic strain. By doing so, we identified a modification resulting from PCRTag recoding in TSC10 , which is involved in regulation of the yeast high-osmolarity glycerol (HOG) response pathway. After replacement with wild-type TSC10 , the defect was greatly mitigated. The other approach, debugging by SCRaMbLE, showed rearrangements in regions containing HOG regulation genes. Both approaches indicated that the defect is related to HOG response dysregulation. Thus, the phenotypic defect can be pinpointed and debugged through multiple alternative routes in the complex cellular interactome network. CONCLUSION We have demonstrated that synII segregates, replicates, and functions in a highly similar fashion compared with its wild-type counterpart. Furthermore, we believe that the iterative “design-build-test-debug” cycle methodology, established here, will facilitate progression of the Sc2.0 project in the face of the increasing synthetic genome complexity. SynII characterization. ( A ) Cell cycle comparison between synII and BY4741 revealed by the percentage of cells with separated CEN2-GFP dots, metaphase spindles, and anaphase spindles. ( B ) Replication profiling of synII (red) and BY4741 (black) expressed as relative copy number by deep sequencing. ( C ) RNA sequencing analysis revealed that the significant up-regulation of translational machinery in synII is induced by the deletion of tRNA genes in synII.},
doi = {10.1126/science.aaf4791},
journal = {Science},
number = 6329,
volume = 355,
place = {United States},
year = {Fri Mar 10 00:00:00 EST 2017},
month = {Fri Mar 10 00:00:00 EST 2017}
}
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