Thermodynamics and kinetics guided probe design for uniformly sensitive and specific DNA hybridization without optimization

Xin Chen, Na Liu, Liquan Liu, Wei Chen, Na Chen, Meng Lin, Jiaju Xu, Xing Zhou, Hongbo Wang (), Meiping Zhao () and Xianjin Xiao ()
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Xin Chen: Huazhong University of Science and Technology
Na Liu: Huazhong University of Science and Technology
Liquan Liu: Huazhong University of Science and Technology
Wei Chen: Peking University
Na Chen: Huazhong University of Science and Technology
Meng Lin: Huazhong University of Science and Technology
Jiaju Xu: Huazhong University of Science and Technology
Xing Zhou: Huazhong University of Science and Technology
Hongbo Wang: Huazhong University of Science and Technology
Meiping Zhao: Peking University
Xianjin Xiao: Huazhong University of Science and Technology

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Sensitive and specific DNA hybridization is essential for nucleic acid chemistry. Competitive composition of probe and blocker has been the most adopted probe design for its relatively high sensitivity and specificity. However, the sensitivity and specificity were inversely correlated over the length and concentration of the blocker strand, making the optimization process cumbersome. Herein, we construct a theoretical model for competitive DNA hybridization, which disclose that both the thermodynamics and kinetics contribute to the inverse correlation. Guided by this, we invent the 4-way Strand Exchange LEd Competitive DNA Testing (SELECT) system, which breaks up the inverse correlation. Using SELECT, we identified 16 hot-pot mutations in human genome under uniform conditions, without optimization at all. The specificities were all above 140. As a demonstration of the clinical practicability, we develop probe systems that detect mutations in human genomic DNA extracted from ovarian cancer patients with a detection limit of 0.1%.

Date: 2019
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DOI: 10.1038/s41467-019-12593-9

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