title: DNA origami-based shape IDs for single-molecule nanomechanical genotyping.
abstract: Variations on DNA sequences profoundly affect how we develop diseases and respond to pathogens and drugs. Atomic force microscopy (AFM) provides a nanomechanical imaging approach for genetic analysis with nanometre resolution. However, unlike fluorescence imaging that has wavelength-specific fluorophores, the lack of shape-specific labels largely hampers widespread applications of AFM imaging. Here we report the development of a set of differentially shaped, highly hybridizable self-assembled DNA origami nanostructures serving as shape IDs for magnified nanomechanical imaging of single-nucleotide polymorphisms. Using these origami shape IDs, we directly genotype single molecules of human genomic DNA with an ultrahigh resolution of ∼10 nm and the multiplexing ability. Further, we determine three types of disease-associated, long-range haplotypes in samples from the Han Chinese population. Single-molecule analysis allows robust haplotyping even for samples with low labelling efficiency. We expect this generic shape ID-based nanomechanical approach to hold great potential in genetic analysis at the single-molecule level.
authors.affiliation: Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, PO Box 800-204, Shanghai 201800, China.|Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Honglu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Organic Electronics and Information Displays (KLOEID), Institute of Advanced Materials (IAM), School of Materials Science and Engineering, Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210046, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chao
authors.affiliation: Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, PO Box 800-204, Shanghai 201800, China.|Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Dun
authors.initials: D
authors.lastname: Pan
authors.affiliation: Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, PO Box 800-204, Shanghai 201800, China.
authors.forename: Huajie
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiang
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, PO Box 800-204, Shanghai 201800, China.
authors.forename: Chengjun
authors.initials: C
authors.lastname: Cui
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, PO Box 800-204, Shanghai 201800, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, PO Box 800-204, Shanghai 201800, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Key Laboratory for Organic Electronics and Information Displays (KLOEID), Institute of Advanced Materials (IAM), School of Materials Science and Engineering, Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210046, China.
authors.forename: Lianhui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory for Organic Electronics and Information Displays (KLOEID), Institute of Advanced Materials (IAM), School of Materials Science and Engineering, Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210046, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, PO Box 800-204, Shanghai 201800, China.
authors.forename: Chunhai
authors.initials: C
authors.lastname: Fan
mesh_terms: D044466:Asian People / Q000235:genetics*; D002681:China; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D018625:Microscopy, Atomic Force; D036103:Nanotechnology; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide
chemical_list: D004247:DNA