Sequencing Price Drops Even Lower

Complete Genomics, a start-up based in Mountain View, CA, has again lowered the stick in the financial limbo dance of human genome sequencing, announcing in the journal Science that it has sequenced three human genomes for an average cost of $4,400. The most recently sequenced genome–which happens to be that of genomics pioneer George Church–cost just $1,500 in chemicals, the cheapest published yet. A cost of about $1,000 is considered to be the price point at which average Americans might invest in having their genomes sequenced. The hope is that by making the process more affordable, genome analysis could become a routine part of medical care.

Complete Genomics first made waves in the sequencing scene in October 2008 when it announced plans to offer a $5,000 human genome sequencing service. The announcement generated both excitement and skepticism. Lowering the cost of sequencing would allow scientists to study large numbers of human genomes, which is now thought necessary to understand the genetic basis of complex disease. But the cheapest estimates at the time hovered around $50,000. Without details on specific costs, accuracy rates, and other metrics, many saw the Complete Genomics announcement as hype. (Others in the race to lower sequencing costs include San Diego-based Illumina, Cambridge, MA-based Helicos, and Applied Biosystems, based in Foster City, CA.)

Complete Genomics aimed to quell skepticism earlier this year by releasing proof-of-principle genome sequence data from a Caucasian male who is part of the International HapMap project, which has built a database of human genetic variation. Because some genetic information is already available for HapMap samples, sequencing the genomes of HapMap participants allows scientist to assess the accuracy of novel sequencing technologies. The new publication builds on that data, giving detailed cost estimates and describing the Complete Genomics technology. It’s also the first peer-reviewed article published by researchers at Complete Genomics.

In the paper, scientists describe the sequence of three human genomes: the previously released Caucasian male, a West African female who has also been sequenced through the HapMap project, and that of Church, a Harvard professor and head of the Personal Genome Project. Costs ranged from $8,005 for 87-fold coverage of one genome–because genomes are sequenced in fragments of DNA, they must be sequenced multiple times to correctly assemble those fragments–to $1,726 for 45-fold coverage of Church’s genome. The technology has an accuracy rate of about 99.999 percent, says Complete Genomics’ chief scientific officer, Radoje Drmanac, who adds that this is comparable to other methods.

“I think it compares nicely to the 1000 Genomes data sets we have been generating with Illumina data in terms of accuracy,” says Chad Nusbaum, co-director of the Genome Sequencing and Analysis program at the Broad Institute, in Cambridge, MA. (The 1000 Genomes project is an international effort to sequence human genomes from around the world.) Nusbaum’s team recently received data from five genomes sequenced by Complete Genomics, though it hasn’t had time to analyze the information. “If thedata resembles what they have in the paper, we will likely want to do more,” says Nusbaum.

Calculating the cost of sequencing a human genome is a tricky business–price estimates can vary depending on what’s included in the calculation. One common measure is the cost of the chemicals used, and this is what Complete Genomics used. However, this measure doesn’t incorporate the cost of the machines that do the sequencing, the human labor, or the computational effort required to assemble raw sequence information into a whole genome. “What’s important is not just the reagent costs, but also the cost of analyzing the sequence,” says Jeff Schloss, program director for technology development at the National Human Genome Research Center, in Bethesda, MD. “It’s unclear how computational costs for this method compare to some of the others.”

One of Complete Genomics’ cost advantages comes from its business model. While most sequencing companies sell machines to labs, which then do their own sequencing, Complete Genomics offers a sequencing service. Because everything is done in-house, the company hasn’t had to spend time or money making the machines consumer-friendly. And because it focuses only on human genomes, its scientists can optimize the pipeline around this single target.

Lower costs also come from the company’s novel method of packing DNA on a chip. Like other, newer sequencing technologies, such as those sold by Illumina and Applied Biosystems, Complete Genomics’ technology is based on massively parallel sequencing–it collects thousands of snippets of DNA on a microarray and sequences them at the same time. Strips of DNA are condensed into tight balls, which are then poured onto specially fabricated arrays with unprecedented density–about a billion balls fit on a chip the size of a microscope slide.

“They very efficiently use the real estate on the chip, which saves on camera time and reagent use,” says Church, who is on the company’s scientific advisory board. Complete Genomics’ sequencing chemistry is based on a method developed in Church’s lab. (For more on the technology, seeFive Thousand Bucks for Your Genome).

Despite the low reagent costs reported in the paper, Complete Genomics isn’t offering $5,000 genomes to the public just yet. “We are still doing genomes in small quantities, like eight, at $20,000 [each],” says Clifford Reid, the company’s chief executive officer. “Not all of the cost is materials; some of it is in labor and machines.” He says that while larger projects will cost less, “it will take a very large number to get down to $5,000.”

Reid anticipates reaching that point in 2010 and 2011. And $20,000 is still cheaper than other offerings–earlier this year, Illumina announced a $48,000 genome sequencing service that could be ordered with a doctor’s prescription.

This week Complete Genomics also announced a project with the Institute for Systems Biology, in Seattle, to sequence the genomes of 100 people with Huntington’s disease, a rare and debilitating inherited neurological condition, along with their family members. The aim of the project is to find genetic variations that affect the severity of the disease. The study will be the first to search for disease-linked variants across the entire genome–previous studies have used gene microarrays, which survey about a million different spots across the genome.