With the help of two other people, the resources of one lab and a commercially available, refrigerator-sized machine, a US university professor has sequenced his entire genome at a cost of less than $50,000. In 2001 when scientists started mapping the DNA of humans, such a feat would have cost hundreds of million of dollars and involved enough people to fill half a jumbo jet, and even last year, the lowest reported cost for this was quarter of a million dollars and needed 200 people.
Dr Stephen Quake, a professor of bioengineering at Stanford University and Howard Hughes Medical Institute, Stanford, California, and his two colleagues, research manager Dr Norma F Neff and doctoral student Dmitry Pushkarev, have written a paper about it in the 10 August online issue of Nature Biotechnology.
The authors wrote that recent advances in high-throughput DNA sequencing technology have brought the cost and time it takes to map a genome tumbling down by orders of magnitude.
The result, said Quake in an article in Stanford University News, is that:
“It’s really democratizing the fruits of the genome revolution and saying that anybody can play in this game.”
“You don’t need a genome center to sequence a human genome,” said Quake.
The revolution Quake refers to is cause for great excitement, for as the cost and time it takes to expand our knowledge about the human genome comes down, the more quickly we discover how particular genes and mutations differ among us, contribute to disease and govern response to treatment.
The other exciting prospect is that it opens the door to “personalized medicine”, where a doctor sequences a patient’s genome and provides drugs and treatments tailored to his or her individual genetic profile.
Quake, who is Lee Otterson Professor in the School of Engineering and a member of Stanford’s Cancer Center said:
“This can now be done in one lab, with one machine, at a modest cost.”
“It’s going to unleash an enormous amount of creativity and really broaden the field,” he added.
To sequence Quake’s genome, the team used a used a commercially available, refrigerator-sized instrument called the Helicos Biosciences SMS Heliscope, or SMS for short. Quake pioneered the technology of the SMS in 2003 and is a co-founder of the company that makes it and he also chairs its scientific advisory board.
SMS stands for single molecule sequencing, a technology that does not require thousands of copies of a person’s DNA to be made. This is a key reason for the reduced cost and effort involved.
SMS relies on chopping the 3 million or so base units that make up human DNA into millions of strands about 30 bases long. The bases are like the alphabet of the DNA code and there are four of them: adenine (abbreviated A), cytosine (C), guanine (G), and thymine (T).
The SMS exploits an interesting feature of the DNA bases, each base matches with only one other, for instance T only matches with A.
The SMS captures the millions of chopped up strands of DNA on a specially treated glass plate, holds them there and bathes them in successive waves of fluorescently labeled “letters” which stick to the DNA letters (eg the fluorescent Ts will stick to the As of the DNA and vice versa).
Eventually each DNA strand has next to it a new fluorescent “twin” whose sequence comprises the complementary letters and this can be read and translated by the machine.
Using genomes that have already been decoded as a reference, powerful computers then reassemble the newly sequenced code of the millions of DNA strands into a cohesive genome. This is a bit like assembling a jigsaw of millions of pieces with the help of the picture on the box.
Quake and colleagues said this stage took about a month and presented many tricky challenges such as when Neff and Pushkarev had to write a sophisticated algorithm to check the accuracy of the process.
Overall, Quake’s genome is 95 per cent complete, which is on a par with the others. In the paper, the team points out that none of the currrent sequencing technologies, including the SMS one they used, produces a perfect sequencing, they are all incomplete approximations, but it is considered good enough to give reliable insights into the person’s traits and health.
Quake said that some of his colleagues at Stanford’s School of Medicine have been “poking and prodding” him and looking at his genome data, and looking for connections between what they observe about him, his DNA profile and his family history.
For example as a result of this work, Quake has discovered he carries a rare mutation that is linked to a heart disorder, which has helped to clear up a family mystery about the health of previous generations. On the upside, he also appears to be genetically predisposed to respond well to common cholesterol-lowering statins.
Quake said seeing the information was in his own genome was different to just knowing it was in the family, it made him take notice:
“If you know your uncle had something, you kind of discount that you can get it, but to see you’ve inherited the mutation for that is another matter altogether,” said Quake.
Another revelation is that Quake has a type of gene that has been linked to increased disagreeability, something people who know him well might find amusing because as Quake said:
“Of course, you don’t need my genome to tell you that.”
“My wife could have told you that and certainly the dean could have as well,” he joked.
Quake’s genome is now available to researchers worldwide. His is amongst less than a dozen that has been sequenced so far because of the costs involved.
The National Science Foundation and the National Institutes of Health funded the research.
— SNPedia shares information about effects of variations in DNA.
“Single-molecule sequencing of an individual human genome.”
Dmitry Pushkarev, Norma F Neff and Stephen R Quake.
DOI:10.1038/nbt.1561
Additional source: Stanford University News.
Written by: Catharine Paddock, PhD