Recent advances in acquiring genome information quickly and inexpensively have transformed many aspects of biomedical and environmental research. Clinical sequencing applications have emerged, and are at the beginning of touching our daily life. While the previously thought unreachable goal of $1,000 genome has become a difficult-to-miss target within the next 2-3 years, major challenges still remain in terms of both accuracy and long-range continuity, both have direct implications in the clinical applicability of genome sequencing as well as many non- medical applications. In this project we will develop SISSOR (SIngle-Stranded Sequencing using micrOfluidic Reactors), with the goal of sequencing a mammalian-size genome at the consensus error rate of 10-9 or lower, with a haplotype contig N50 of at least 10 Mb for $1,000. In addition, SISSOR can start with one single cell, providing the capability of dissecting somatic mutations in heterogeneous tissues (such as cancers and brain), and extracting genome information de novo from difficult-to-culture organisms. Instead of proposing a completely new sequencing method, we chose to develop an integrative device focusing on the front-end preparation, which, in combination with the existing sequencing-by-synthesis chemistry, provides a highly realistic path to achieve the above goal within a 4-year development cycle.

Public Health Relevance

In this project we will design, optimize and validate a microfluidic processor that allow for ultra-accurate genome sequencing of single human cells with the error rate lower than one in 100 millions bases at the cost of $1,000.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project (R01)
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Special Emphasis Panel (ZHG1-HGR-N (M1))
Program Officer
Schloss, Jeffery
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University of California San Diego
Engineering (All Types)
Schools of Arts and Sciences
La Jolla
United States
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Hoople, Gordon D; Richards, Andrew; Wu, Yan et al. (2018) Gel-seq: A Method for Simultaneous Sequencing Library Preparation of DNA and RNA Using Hydrogel Matrices. J Vis Exp :
Chu, Wai Keung; Edge, Peter; Lee, Ho Suk et al. (2017) Ultraaccurate genome sequencing and haplotyping of single human cells. Proc Natl Acad Sci U S A 114:12512-12517
Hoople, Gordon D; Richards, Andrew; Wu, Yan et al. (2017) Gel-seq: whole-genome and transcriptome sequencing by simultaneous low-input DNA and RNA library preparation using semi-permeable hydrogel barriers. Lab Chip 17:2619-2630
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Patel, Anand; Edge, Peter; Selvaraj, Siddarth et al. (2016) InPhaDel: integrative shotgun and proximity-ligation sequencing to phase deletions with single nucleotide polymorphisms. Nucleic Acids Res 44:e111