Deep functional analysis of synII, a 770-kilobase synthetic yeast chromosome.
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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 byloxP-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-SceI–mediated strategy, which enables parallel integration of synthetic chromosome arms and reduced the overall integration time by 50% for synII. An I-SceI 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-SceI–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 theURA3marker on the wild-type chromosome, we observed a tenfold increase inURA3-deficient colonies upon I-SceI 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 inTSC10, which is involved in regulation of the yeast high-osmolarity glycerol (HOG) response pathway. After replacement with wild-typeTSC10, 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.
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Owe to fast developments in large-scale oligo synthesis, route A became more advanced in terms of cost and labor intensity and has been applied widely in recent studies.
“Owe to the fast developments in large-scale oligo synthesis, route A became more advanced in terms of cost and labor intensity and has been applied widely in recent studies”
From Large-Scale de Novo Oligonucleotide Synthesis for Whole-Genome Synthesis and Data Storage: Challenges and Opportunities (2021) · cites this paper as Shen et al., 2017
Due to the low efficiency of in vitro assembly of long DNA fragments, in vivo assembly is the general choice in most previous studies.
“Due to the low efficiency of in vitro assembly of long DNA fragments, in vivo assembly is the general choice in most previous studies”
From Large-Scale de Novo Oligonucleotide Synthesis for Whole-Genome Synthesis and Data Storage: Challenges and Opportunities (2021) · cites this paper as Shen et al., 2017
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- Authors
- 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., & Yang, H.
- Affiliations
- BGI Group (China) (CN)
- University of Edinburgh (GB)
- University of Oxford (GB)
- University of Essex (GB)
- NYU Langone Health (US)
- Tsinghua University (CN)
- BGI-Shenzhen, Shenzhen 518083, China.
- 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.
- Johns Hopkins University (US)
- Centre National de la Recherche Scientifique (FR)
- School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK.
- Corresponding author
- Shen, Yue
- Wang, Yun
- Chen, Tai
- Cai, Yizhi
- Yang, Huanming
- ORCID
- Shen, Yue
- Wang, Yun
- Chen, Tai
- Gao, Feng
- Gong, Jianhui
- Abramczyk, Dariusz
- Walker, Roy
- Chen, Shihong
- Liu, Wei
- Luo, Yisha
- Müller, Carolin A.
- Stracquadanio, Giovanni
- Mitchell, Leslie A.
- Luo, Zhouqing
- Fan, Yanqun
- Zhou, Baojin
- Wen, Bo
- Wang, Yujia
- Xie, Zexiong
- Li, Bingzhi
- Yang, Kun
- Richardson, Sarah M.
- French, Christopher E.
- Nieduszynski, Conrad A.
- Koszul, Romain
- Marston, Adele L.
- Yuan, Yingjin
- Bader, Joel S.
- Dai, Junbiao
- Boeke, Jef D.
- Xu, Xun
- Cai, Yizhi
- Yang, Huanming
- Venue
- Science
- Published
- 2017-03-10
- Volume
- 355
- Issue
- 6329
- Pages
- eaaf4791
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5390853
- OpenAlex
- W2596950554
- Cited by
- 202
- References
- 55
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 17 · 2023: 27 · 2022: 22 · 2021: 23 · 2020: 15 · 2019: 21 · 2018: 33 · 2017: 23
- FWCI
- 10.27
- Type
- journal article
- Language
- en
- Open access
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Open Access at Essex (University of Essex) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- HAL (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/M005690/1, BB/M025640/1, BB/M00029X/1)
- Wellcome Trust (90903, 92076)
- NSF (MCB-1026068, MCB-1158201, MCB-1445545)
- U.S. Department of Energy (DE-FG02097ER25308)
- National Science Foundation of China (31471254)
- Chinese Ministry of Science and Technology (2012CB725201)
- Agence Nationale pour la Recherche (IESY ANR-14-SYNB-0001-03)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- chromosome II, homologous recombination, tRNA gene copy number, SCRaMbLE, chromosome segregation, chromosome replication, meiotic recombination, phenomics, transcriptomics, proteomics, metabolomics
- MeSH terms
- Culture Media, DNA Replication, Glycerol, Saccharomyces cerevisiae, Genome, Fungal, Sequence Analysis, DNA, Chromosomes, Artificial, Yeast, Chromosome Segregation, Proteomics, Synthetic Biology, Transcriptome
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