How sequencing has changed since the Human Genome Project


by Dr. Radoje Drmanac, CSO MGI and Complete Genomics

Today marks the 20th anniversary of the completion of the first human genome sequence, which was mapped on April 14, 2003.

Originally a targeted effort to understand radiation’s impact on humans, the Human Genome Project (HGP) set in motion countless advances that have revolutionized healthcare and given us the sub-$100 genomes available today. Having spent three decades in my career contributing to our collective understanding of the human genome, I look back on the achievements of myself and my colleagues with great pride.

Works at HGP

My involvement with HGP began in 1987, just as the initiative started, in the form of a $150,000 grant opportunity provided by the US Department of Energy, to advance genome analysis technology, including sequencing. As part of the HGP, I propose to develop DNA sequencing by hybridization, which at that time allows higher throughput and more efficient sequencing. This led me to move to the US Around this time, my idea of ​​massively parallel sequencing (MPS) using DNA microarrays prepared by emulsion PCR on microbeads was also born.

In essence, HGP is all about listing parts of the genome. At the time, we didn’t understand most of it, but there’s a list nonetheless. This is driving this important demand to sequence more genomes. It makes the shorter reads more useful because we now have a reference. It allows sequencing of exomes and panels using capture probes and genome sequence based primers. It proves that biology is getting into larger-scale projects, such as sending humans to the moon. It’s also what prompted me to start my own company, Complete Genomics, to maximize the potential of MPS.

Genomic revolution

MPS is critical in enabling routine, affordable, sequencing of individual genomes. I am motivated to make it happen. In 2005, with my team, I discovered patterned DNA nanospherical arrays (DNBs) that extended the capabilities of MPS to more efficient, larger-scale sequencing. Today, we call this core technology DNBSEQ.

The DNBSEQ sequencing array has no clonal errors or index jumps and produces a higher signal density than typical DNA sequences for significantly better detection accuracy. With advantages including increased accuracy, reduced duplicates, and reduced index assignment error, it is the technology currently used in all MGI sequencing instruments.

In 2010, another milestone was the first $5,000 genome to use DNBSEQ. This achievement demonstrates that routine, affordable, and accurate whole-genome sequencing (WGS) is achievable and beneficial.

I developed CoolMPS sequencing chemistry in 2016, which combines a base with a labeled antibody. A fundamentally unique chemistry, CoolMPS avoids DNA “scars” accumulated by traditional sequencing methods, which affect the accuracy of subsequent base readings. Instead, CoolMPS introduces an unlabeled nucleotide and four fluorescently labeled antibodies in its sequencing process to recognize the associated bases. In this new process, a natural non-scarred base is added at each sequencing cycle, enabling more accurate and longer readings, greatly expanding MPS applications.

Improve public health by lowering sequencing costs

Advances are being made in genomics at breakneck speed, which has allowed the price of genome sequencing to steadily fall over the last decade. On that front, recently the sub-$100 human genome was introduced – a huge step forward from the $3 billion and 13 years spent on a single human genome at HGP.

Indeed, from single-cell or spatial omics, sequencing applications will continue to evolve. This trend of declining prices demonstrates that routine genome sequencing for everyone is possible and that there is value in individual genome testing. With a projected four times today’s DNB array density to reduce reagent consumption, coupled with our single-tube long fragment reading (stLFR) technology, which enables data sequencing of long DNA molecules, we can provide affordable full-phase WGS and WGS. undertake deeper sequencing of the immune system and microbiome to holistically safeguard our health and aging.

Since the 80s, there has always been a common goal in the field of achieving limitless genome sequencing (because, at the end of the day, there is so much to measure and so many genomes to sequence). That said, we’re not going to stop even at the $10 genome. Once dubbed “big science,” HGP accomplished what few people imagined.

Genomics for all

In 2007, the first Asian private genome was published in Nature, inaugurating a new era of large-scale private genomics. Since then, more and more government-funded population-scale sequencing programs have been launched. From the 1,000 Genomes Project, which began in 2008, and the UK’s 100,000 Genomes Project, to the Icelandic Genome, these efforts have played a critical role in helping researchers identify genetic factors that contribute to the development and development of certain health conditions, as well as the treatment and prevention measures that can be used. in accordance.

At MGI, we participate in several national genome projects, in Thailand, Indonesia and Brazil, providing these countries with a better understanding of the unique genomic complexity of their local populations. Our analysis serves as the basis for developing personalized diagnostics, drug selection and treatment in the fields of cancer, infectious diseases, rare and undiagnosed diseases, non-communicable diseases and pharmacogenomic diseases, all of which are important research areas that can contribute to expanding life expectancy healthy human.

Looking back from HGP to now, the field of sequencing has grown tremendously thanks to MPS. Because of the efficient sequencing capabilities of laboratories around the world, almost every omic today is sequencing. We can measure protein levels in the blood by sequencing a barcode and even evaluate gene activity through sequencing.

With that said, the goal of sequencing also moves from understanding the genome to disease prevention and treatment using omics assays. Very soon, genetic sequencing will be part of our annual health checkup, where we will be able to monitor the molecular health of our tissues.

From seeing the application of the first genome sequence, to finding the first disease-causing mutation in the personal genome we sequenced, I have no doubt that genetic sequencing will work wonders as it touches every aspect of our lives.


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