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A Short History of Sequencing Part 3: personal NGS, disposable sequencers and what the future holds.

Content sponsored by Sigma-Aldrich® Advanced Genomics

Personalizing NGS

Due to the relative ease of whole human genome sequencing, clinical researchers became interested in how they might use this technology to help their patients. There were, and still are, obstacles to overcome- but the promise is so great! The Ion Torrent technology came in a small box which could easily sit in a doctors surgery, however, one of its significant limitations compared to HiSeq was its low yield. This actually turned out to be a positive feature for users who were interested in sequencing a few genes in multiple individuals.

The battle for supremacy

Around the same time, Illumina had seen this gap in the market and, in 2010/2011, launched the ‘MiSeq’ system. Based on the proven and robust ‘Sequencing-by-Synthesis’(SBS) chemistry, and with the simple sample-prep using bridge-amplification, the ‘MiSeq’ quickly went head-to-head to battle for personal genome sequencer supremacy. This battle is still on-going and it is not clear who will emerge triumphant! Ultimately, ease-of-use and cost-per-sample are going to be the deciding factors.

The future of NGS: the search for the Holy Grail

NGS systems are still developing and in the last five years, at least one has already faltered. Helicos developed the first single molecule DNA sequencer, unfortunately development was outpaced by companies like Illumina and the company is all but spent. The IP is likely to appear in products from other companies in the future. There are many ways to sequence DNA, and it seems that the success of 454, Illumina and Life Technologies (ABI) has opened the floodgates to genome sequencer development. The ‘holy grail’ of DNA sequencing is the ability to read very long DNA molecules with no amplification and to generate not just base-calls (identifying sequences from fluorescence data), but also base-modifications, such as methyl-cytosine.

DNA drops

Pacific Biosciences have developed the ‘Single Molecule Real-Time’ (SMRT) sequencing system. DNA molecules are circularized and a single strand is loaded with DNA polymerase and “dropped” into the bottom of a nanoscale well. As the polymerase incorporates fluorescently labeled nucleotides, a camera at the bottom of the well detects the base being added. Read lengths of 20 KB and higher have been recorded and it is possible to generate base-modification data as well.

A disposable USB sequencer

The latest NGS platform to be announced comes from Oxford Nanopore Technologies. They use a semiconductor chip with nanometer sized holes (‘nanopores’) to read DNA as it translocates through the pore under an electrophoretic current. The DNA is tethered to the pore by a polymerase which slows translocation down to around 1000 bases-per-second. Read lengths of 100,000 base pairs have been talked about. In 2012, they announced the ‘MinION’ sequencer, a disposable genome sequencer in a USB stick capable of generating over 1 GB of data.

Let’s see your teeth…and your genome!

There is little doubt that DNA sequencing technology has still got a long way to go before it is finished. Ultimately, we may be able to read entire chromosomes, genomes will be generated within the first few minutes of life and we are likely to be sequenced multiple times during our lifetimes. A DNA sequence might become as routine as a dental check-up, and could include our genome, methylation status, disease status and metagenome.

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