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

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; Guojie Zhang; Xia Shen; Jian Wang; Xian Fu; Junbiao Dai; Jef D Boeke; Huanming Yang; Xun Xu; Yizhi Cai

doi:10.1016/j.xgen.2023.100364

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

Cell Genom. 2023 Nov 9;3(11):100364. doi: 10.1016/j.xgen.2023.100364. eCollection 2023 Nov 8.

Authors

Yue Shen^{1

2

3

4}, Feng Gao^{1

3}, Yun Wang^{1

2

3

5}, Yuerong Wang^{1

3

4}, Ju Zheng^{1

3}, Jianhui Gong¹, Jintao Zhang¹, Zhouqing Luo^{6

7

8}, Daniel Schindler^{9

10}, Yang Deng¹, Weichao Ding^{1

3

4}, Tao Lin^{1

3}, Reem Swidah⁹, Hongcui Zhao^{1

2

3}, Shuangying Jiang^{6

7}, Cheng Zeng^{6

7}, Shihong Chen¹, Tai Chen^{1

2

3}, Yong Wang¹, Yisha Luo⁹, Leslie Mitchell¹¹, Joel S Bader¹², Guojie Zhang⁵, Xia Shen^{13

14}, Jian Wang¹, Xian Fu^{1

2

3}, Junbiao Dai^{6

7}, Jef D Boeke^{11

15}, Huanming Yang¹, Xun Xu^{1

2

3}, Yizhi Cai⁹

Affiliations

¹ BGI Research, Shenzhen 518083, China.
² BGI Research, Changzhou 213299, China.
³ Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518120, China.
⁴ College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ University of Copenhagen, Universitetsparken 15, 2100 Copenhagen, Denmark.
⁶ Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Key Laboratory of Synthetic Genomics, Center for Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
⁷ College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China.
⁸ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
⁹ Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
¹⁰ Max Planck Institute for Terrestrial Microbiology, Karl-von-Frisch-Strasse 10, 35043 Marburg, Germany.
¹¹ Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY 10016, USA.
¹² Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
¹³ Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China.
¹⁴ Center for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
¹⁵ Department of Biomedical Engineering, NYU Tandon School of Engineering, Brooklyn, NY 11201, USA.

Abstract

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.

Keywords: SCRaMbLE; aneuploidy phenotypes; aneuploidy recovery approaches; growth rate; synVII; synthetic disomic yeast; synthetic genomics.