Scaling DNA synthesis with a microchip-based massively parallel synthesis system

scaling-dna-synthesis-with-a-microchip-based-massively-parallel-synthesis-system

Data availability

DNA sequencing data from gene assembly have been deposited in the CNGB Nucleotide Sequence Archive (CNSA) under accession number CNP0007102 (refs. 31,29) and sequencing data of variant libraries are available in the Gene Expression Omnibus (GEO) under accession GSE265942 (ref. 26) (Supplementary Table 6). All data supporting the findings of this study are included within the Brief Communication and its Supplementary Information files. Source data are provided with this paper.

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Acknowledgements

We thank Z. Zhang and L. Yang for their efforts on schematic illustration design in Fig. 1a. X.J. and X.Z. are supported by the National Key R&D Program of China (grant number 2023YFF1206100). Y.S. is supproted by National Natural Science Foundation of China (grant number 32322047) and the Shenzhen Science and Technology Program (grant number RCYX20210609103822039). X.Z. is supported by National Natural Science Foundation of China (grant number 32401214) and the Jiangsu Provincial Department of Science and Technology (grant number BM2023009).

Author information

Author notes

  1. These authors contributed equally: Xiandi Zhang, Xiang’er Jiang.

Authors and Affiliations

  1. BGI Research, Changzhou, China

    Xiandi Zhang, Xiang’er Jiang, Yun Wang, Qinzhen Chen, Hao Jiang, Hu Zhang, Weiya Yang, Chenglong Liang, Ning Cheng, Yun Huang, Chengwang Xie, Nanfeng Gao & Yue Shen

  2. Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen, China

    Xiandi Zhang, Xiang’er Jiang, Yun Wang, Qinzhen Chen, Hao Jiang, Hu Zhang, Weiya Yang, Chenglong Liang, Ning Cheng, Yun Huang, Chengwang Xie, Nanfeng Gao, Dong Cai, Lihao Zhu, Songjin Mo, Mengzhe Shen, Wenwei Zhang, Xun Xu & Yue Shen

  3. Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain

    Antoni Beltran & Ben Lehner

  4. GCATbio, Changzhou, China

    Tai Chen

  5. State Key Laboratory of Materials for Integrated Circuits, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, China

    Guqiao Ding

  6. MGI Tech, Qingdao, China

    Juntao Liu, Wei Xu, Jinlei Huang & Ming Ni

  7. University Pompeu Fabra, Barcelona, Spain

    Ben Lehner

  8. Institució Catalana de Recerca i estudis Avançats, Barcelona, Spain

    Ben Lehner

  9. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK

    Ben Lehner

  10. BGI, Shenzhen, China

    Jian Wang

  11. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China

    Yue Shen

Authors

  1. Xiandi Zhang
  2. Xiang’er Jiang
  3. Yun Wang
  4. Qinzhen Chen
  5. Hao Jiang
  6. Hu Zhang
  7. Antoni Beltran
  8. Weiya Yang
  9. Tai Chen
  10. Chenglong Liang
  11. Ning Cheng
  12. Yun Huang
  13. Guqiao Ding
  14. Chengwang Xie
  15. Nanfeng Gao
  16. Juntao Liu
  17. Wei Xu
  18. Jinlei Huang
  19. Dong Cai
  20. Lihao Zhu
  21. Songjin Mo
  22. Mengzhe Shen
  23. Wenwei Zhang
  24. Ben Lehner
  25. Ming Ni
  26. Jian Wang
  27. Xun Xu
  28. Yue Shen

Contributions

Conceptualization: Y.S., J.W. and X.X.; methodology: Y.S., X.Z., X.J. and Y.W.; validation: Q.C., A.B., H.J., W.Y., T.C., N.C., H.Z., Y.H., C.L., G.D., C.X., J.L., W.X., J.H., M.S., D.C., L.Z., S.M., N.G., M.N., B.L. and W.Z.; formal analysis: X.Z., X.J. and Y.W.; data curation: X.Z., X.J., Y.W. and H.J.; writing—original draft: X.Z., X.J. and Y.S.; draft revision: all authors.

Corresponding author

Correspondence to Yue Shen.

Ethics declarations

Competing interests

J.W., X.X., Y.S., M.N., W.Z. and X.J. are inventors on a patent application (WO2020119706A1) related to this work. The other authors declare no competing interests.

Peer review

Peer review information

Nature Biotechnology thanks Marcel Hollenstein and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

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Extended data

Extended Data Fig. 1 Evaluation of mMPS performance for high throughput gene assembly.

(a) Schematic comparison of the gene assembly workflow using traditional microarray chip–based synthesis versus the mMPS platform. (b) Benchmarking of mMPS against two conventional array chip synthesis methods (ink-jet printing and electrochemistry) for 185 genes (600–1,200 bp). (c) Assembly performance of mMPS for 204 genes ranging from 1,600 to 3,400 bp. (d) Assembly success rates for long DNA constructs (5,000 bp, 8,000 bp, and 10,000 bp) using the mMPS platform. (e) Error rate analysis of 361 assembled genes by variations, including substitutions, insertions, and deletions. The box plot shows the interquartile range with median lines, and whiskers extend to values within 1.5 times the interquartile range.

Source Data

Extended Data Fig. 2 Performance of mMPS-generated deep mutational scanning libraries.

(a) Summary statistics of the mutagenesis library design. (b) Schematic of deep mutational scanning library design. (c) Distribution of protein domain lengths and their corresponding NNK variant region lengths across 1,254 protein domains (Supplementary Table 5). (d) Analysis of sequence length deviation (ΔLength) from the expected length. (e) Coverage analysis of the library. (f) Amino acid usage frequency comparison between expected NNK codon distribution and that observed in the mMPS-derived library. The * symbol denotes stop codons. (g) Positional analysis of codon usage bias across the entire 61,615-position NNK region. The top box plot displays NNK codon frequency by position, while the heatmap below visualizes log2(observed/expected) codon frequency ratios. All box plots show the interquartile range with median lines, and whiskers extend to values within 1.5 times the interquartile range.

Source Data

Supplementary information

Source data

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Zhang, X., Jiang, X., Wang, Y. et al. Scaling DNA synthesis with a microchip-based massively parallel synthesis system. Nat Biotechnol (2025). https://doi.org/10.1038/s41587-025-02844-0

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  • DOI: https://doi.org/10.1038/s41587-025-02844-0