Dissecting aneuploidy phenotypes by constructing Sc2.0 chromosome VII and SCRaMbLEing synthetic disomic yeast

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  • Yue Shen
  • Feng Gao
  • Yun Wang
  • Yuerong Wang
  • Ju Zheng
  • Jianhui Gong
  • Jintao Zhang
  • Zhouqing Luo
  • Daniel Schindler
  • Yang Deng
  • Weichao Ding
  • Tao Lin
  • Reem Swidah
  • Hongcui Zhao
  • Shuangying Jiang
  • Cheng Zeng
  • Shihong Chen
  • Tai Chen
  • Yong Wang
  • Yisha Luo
  • Leslie Mitchell
  • Joel S. Bader
  • Xia Shen
  • Jian Wang
  • Xian Fu
  • Junbiao Dai
  • Jef D. Boeke
  • Huanming Yang
  • Xun Xu
  • Yizhi Cai
Aneuploidy compromises genomic stability, often leading to embryo inviability, and is frequently associated with tumorigenesis and aging. Different aneuploid chromosome stoichiometries lead to distinct transcriptomic and phenotypic changes, making it helpful to study aneuploidy in tightly controlled genetic backgrounds. By deploying the engineered SCRaMbLE (synthetic chromosome rearrangement and modification by loxP-mediated evolution) system to the newly synthesized megabase Sc2.0 chromosome VII (synVII), we constructed a synthetic disomic yeast and screened hundreds of SCRaMbLEd derivatives with diverse chromosomal rearrangements. Phenotypic characterization and multi-omics analysis revealed that fitness defects associated with aneuploidy could be restored by (1) removing most of the chromosome content or (2) modifying specific regions in the duplicated chromosome. These findings indicate that both chromosome copy number and specific chromosomal regions contribute to the aneuploidy-related phenotypes, and the synthetic chromosome resource opens new paradigms in studying aneuploidy.
OriginalsprogEngelsk
Artikelnummer100364
TidsskriftCell Genomics
Vol/bind3
Udgave nummer11
Antal sider19
ISSN2666-979x
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
This work is part of the international Synthetic Yeast Genome (Sc2.0) consortium. The project was supported by the National Key Research and Development Program of China (2018YFA0900100). This work was also supported by UK Biotechnology and Biological Sciences Research Council (BBSRC) grants BB/M005690/1, BB/P02114X/1 and BB/W014483/1; Engineering and Physical Sciences Research Council (EPSRC) EP/V05967X/1; and a Volkswagen Foundation “Life?” Initiative grant (ref. 94 771) (to Y.C.). J.D. was supported by a Royal Society Newton Advanced Fellowship (NAF\R2\180590) hosted by Y.C. This work was also supported by the National Natural Science Foundation of China (31800078 and 21901165); Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20180507183534578); Guangdong Provincial Key Laboratory of Genome Read and Write (2017B030301011); Guangdong Provincial Academician Workstation of BGI Synthetic Genomics (2017B090904014); Tip-top Scientific and Technical Innovative Youth Talents of Guangdong Special Support Program（2019TQ05Y876), China; and Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics (DRC-SZ[2016]884). We thank the DNA assembly automation platform of China National Genebank for the support on synthetic chunk assembly. L.M. J.S.B. and J.D.B. were supported by grants from the US National Science Foundation. Conceptualization, Y.S. and Y.C.; funding and resources, Y.S. and Y.C.; data production, F.G. Yuerong Wang, Y.S. J. Zheng, Z.L. D.S. Y.D. W.D. T.L. R.S. H.Z. S.J. C.Z. S.C. T.C. and Yong Wang; data analyses, investigation, and visualization, Yun Wang, J. Zhang, J.G. Y.L. L.M. J.S.B. G.Z. X.S. and X.F.; writing – original draft, Y.S. X.F. Yun Wang, Yuerong Wang, J. Zheng, F.G. Y.C. and J.D.B.; writing – review & editing, all co-authors. J.D.B. is a founder and director of CDI Labs, Inc.; a founder of and consultant to Neochromosome, Inc.; and a founder and scientific advisory board member of and consultant to ReOpen Diagnostics, LLC. J.D.B. serves or served on the scientific advisory board of the following: Logomix, Inc. Sangamo, Inc. Modern Meadow, Inc. Rome Therapeutics, Inc. Sample6, Inc. Tessera Therapeutics, Inc. and the Wyss Institute. J.S.B. is a founder of Neochromsome, Inc.; is a consultant to Opentrons Labworks, Inc.; and serves on the scientific advisory board of Reflexion Pharmaceuticals, Inc. We support inclusive, diverse, and equitable conduct of research.

Funding Information:
This work is part of the international Synthetic Yeast Genome (Sc2.0) consortium. The project was supported by the National Key Research and Development Program of China ( 2018YFA0900100 ). This work was also supported by UK Biotechnology and Biological Sciences Research Council (BBSRC) grants BB/M005690/1 , BB/P02114X/1 and BB/W014483/1 ; Engineering and Physical Sciences Research Council (EPSRC) EP/V05967X/1 ; and a Volkswagen Foundation “Life?” Initiative grant (ref. 94 771) (to Y.C.). J.D. was supported by a Royal Society Newton Advanced Fellowship ( NAF\R2\180590 ) hosted by Y.C. This work was also supported by the National Natural Science Foundation of China ( 31800078 and 21901165 ); Science, Technology and Innovation Commission of Shenzhen Municipality ( JCYJ20180507183534578 ); Guangdong Provincial Key Laboratory of Genome Read and Write ( 2017B030301011 ); Guangdong Provincial Academician Workstation of BGI Synthetic Genomics ( 2017B090904014 ); Tip-top Scientific and Technical Innovative Youth Talents of Guangdong Special Support Program（2019TQ05Y876), China; and Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics ( DRC-SZ[2016]884 ). We thank the DNA assembly automation platform of China National Genebank for the support on synthetic chunk assembly. L.M., J.S.B., and J.D.B. were supported by grants from the US National Science Foundation .

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