An integrated semiconductor device enabling non-optical genome sequencing

An integrated semiconductor device enabling non-optical genome sequencing

21 JULY 2011 | Jonathan M. Rothberg¹, Wolfgang Hinz¹, Todd M. Rearick¹, Jonathan Schultz¹, William Mileski¹, Mel Davey¹, John H. Leamon¹, Kim Johnson¹, Mark J. Milgrew¹, Matthew Edwards¹, Jeremy Hoon¹, Jan F. Simons¹, David Marran¹, Jason W. Myers¹, John F. Davidson¹, Annika Branting¹, John R. Nobile¹, Bernard P. Puc¹, David Light¹, Travis A. Clark¹, Martin Huber¹, Jeffrey T. Branciforte¹, Isaac B. Stoner¹, Simon E. Cawley¹, Michael Lyons¹, Yutao Fu¹, Nils Homer¹, Marina Sedova¹, Xin Miao¹, Brian Reed¹, Jeffrey Sabina¹, Erika Feierstein¹, Michelle Schorn¹, Mohammad Alanjary¹, Eileen Dimalanta¹, Devin Dressman¹, Rachel Kasinaskas¹, Tanya Sokolsky¹, Jacqueline A. Fidanza¹, Eugeni Namsaraev¹, Kevin J. McKernan¹, Alan Williams¹, G. Thomas Roth¹ & Tanya Bustillo¹
This paper presents a novel DNA sequencing technology that uses a semiconductor-based integrated circuit to perform non-optical genome sequencing. The system directly senses ions produced by DNA polymerase synthesis using all-natural nucleotides on a massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, allowing for parallel, simultaneous detection of independent sequencing reactions. The use of complementary metal-oxide semiconductor (CMOS) processes enables low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. The system was tested by sequencing three bacterial genomes and a human genome, demonstrating its robustness and scalability. The technology overcomes previous limitations in DNA sequencing by using electronic detection, enabling the production of chips with a large number of fast, uniform, working sensors. The system uses an ion-sensitive field-effect transistor (ISFET) sensor, which is compatible with CMOS processes and sensitive to hydrogen ions. The system is designed to detect the hydrogen ions released during nucleotide incorporation, providing a direct transduction from the incorporation event to an electronic signal. The ion chips are manufactured on wafers, cut into individual die, and robotically packaged with a disposable polycarbonate flow cell. The system uses a simple, scalable ISFET sensor architecture, with each sensor element having a single floating gate connected to an underlying ISFET. The system is capable of producing 25 million bases in a 2-hour run using an ion chip with 1.2 million sensors. The system was used to sequence the genomes of three bacterial species and a human genome, demonstrating its effectiveness and scalability. The system was also used to sequence the genome of Gordon Moore, demonstrating its ability to scale to large arrays. The system uses all-electronic detection, simplifying and reducing the cost of the sequencing instrument. The system is capable of producing 100-base read lengths and perfect read lengths exceeding 200 bases. The system has the potential to enable low-cost, high-throughput genome sequencing, making it a valuable tool for research and medicine. The system is based on CMOS technology, which is widely used in modern integrated circuit manufacturing, and is expected to enable the production of one-billion-sensor ion chips and low-cost routine human genome sequencing.This paper presents a novel DNA sequencing technology that uses a semiconductor-based integrated circuit to perform non-optical genome sequencing. The system directly senses ions produced by DNA polymerase synthesis using all-natural nucleotides on a massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, allowing for parallel, simultaneous detection of independent sequencing reactions. The use of complementary metal-oxide semiconductor (CMOS) processes enables low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. The system was tested by sequencing three bacterial genomes and a human genome, demonstrating its robustness and scalability. The technology overcomes previous limitations in DNA sequencing by using electronic detection, enabling the production of chips with a large number of fast, uniform, working sensors. The system uses an ion-sensitive field-effect transistor (ISFET) sensor, which is compatible with CMOS processes and sensitive to hydrogen ions. The system is designed to detect the hydrogen ions released during nucleotide incorporation, providing a direct transduction from the incorporation event to an electronic signal. The ion chips are manufactured on wafers, cut into individual die, and robotically packaged with a disposable polycarbonate flow cell. The system uses a simple, scalable ISFET sensor architecture, with each sensor element having a single floating gate connected to an underlying ISFET. The system is capable of producing 25 million bases in a 2-hour run using an ion chip with 1.2 million sensors. The system was used to sequence the genomes of three bacterial species and a human genome, demonstrating its effectiveness and scalability. The system was also used to sequence the genome of Gordon Moore, demonstrating its ability to scale to large arrays. The system uses all-electronic detection, simplifying and reducing the cost of the sequencing instrument. The system is capable of producing 100-base read lengths and perfect read lengths exceeding 200 bases. The system has the potential to enable low-cost, high-throughput genome sequencing, making it a valuable tool for research and medicine. The system is based on CMOS technology, which is widely used in modern integrated circuit manufacturing, and is expected to enable the production of one-billion-sensor ion chips and low-cost routine human genome sequencing.
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