A research team from Baylor College of Medicine, Rice University, Texas Children’s Hospital, and the Broad Institute of MIT and Harvard recently made an exciting breakthrough in the fight against Zika. They have developed a new way to sequence genomes of organisms from scratch, and their method is much cheaper, faster, and extensive than existing technology.
While the original human genome project took 10 years and cost $4 billion, this new 3D genome assembly method can do the same thing for less than $10,000. To demonstrate how their process works, they assembled the genome of the Aedes aegypti mosquito, which carries Zika. This genome has the power to help scientists fight Zika by isolating vulnerabilities in the mosquito that allows the virus to spread.
A recent article from Baylor explains the method and illustrates why genome sequencing is so promising in efforts to combat Zika and other diseases.
The team developed a new approach, called 3D assembly, which determines the sequence of each chromosome by studying how the chromosomes fold inside the nucleus of a cell.
“Our method is quite different from traditional genome assembly,” said Olga Dudchenko, a postdoctoral fellow at the Center for Genome Architecture at Baylor College of Medicine, who led the research. “Several years ago, our team developed an experimental approach that allows us to determine how the 2-meter-long human genome folds up to fit inside the nucleus of a human cell. In this new study, we show that, just as these folding maps trace the contour of the genome as it folds inside the nucleus, they can also guide us through the sequence itself.”
By carefully tracing the genome as it folds, the team found that they could stitch together hundreds of millions of short DNA reads into the sequences of entire chromosomes. Since the method only uses short reads, it dramatically reduces the cost of de novo genome assembly, which is likely to accelerate the use of de novo genomes in the clinic. “Sequencing a patient’s genome from scratch using 3D assembly is so inexpensive that it’s comparable in cost to an MRI,” said Dudchenko, who also is a fellow at Rice University’s Center for Theoretical Biological Physics. “Generating a de novo genome for a sick patient has become realistic.”
Unlike the genetic tests used in the clinic today, de novo assembly of a patient genome does not rely on the reference genome produced by the Human Genome Project. “Our new method doesn’t depend on previous knowledge about the individual or the species that is being sequenced,” Dudchenko said. “It’s like being able to perform a human genome project on whoever you want, whenever you want.”
“Or whatever you want,” said Dr. Erez Lieberman Aiden, director of the Center for Genome Architecture at Baylor and corresponding author on the new work. “Because the genome is generated from scratch, 3D assembly can be applied to a wide array of species, from grizzly bears to tomato plants. And it is pretty easy. A motivated high school student with access to a nearby biology lab can assemble a reference-quality genome of an actual species, like a butterfly, for the cost of a science fair project.”
The effort took on added urgency with the outbreak of Zika virus, which is carried by the Aedes aegypti mosquito. Researchers hoped to use the mosquito’s genome to identify a strategy to combat the disease, but the Aedes genome had not been well characterized, and its chromosomes are much longer than those of humans.
“We had been discussing these ideas for years – writing a chunk of code here, doing a proof-of-principle assembly there,” said Lieberman Aiden, also assistant professor of molecular and human genetics at Baylor, computer science at Rice and a senior investigator at the Center for Theoretical Biological Physics. “So we had assembly data for Aedes aegypti just sitting on our computers. Suddenly, there’s an outbreak of Zika virus, and the genomics community was galvanized to get going on Aedes. That was a turning point.”
“With the Zika outbreak, we knew that we needed to do everything in our power to share the Aedes genome assembly, and our methods, as soon as possible,” Dudchenko said. “This de novo genome assembly is just a first step in the battle against Zika, but it’s one that can help inform the community’s broader effort.”
The team also assembled the genome of the Culex quinquefasciatus mosquito, the principal vector for West Nile virus. “Culex is another important genome to have, since it is responsible for transmitting so many diseases,” said Lieberman Aiden. “Still, trying to guess what genome is going to be critical ahead of time is not a good plan. Instead, we need to be able to respond quickly to unexpected events. Whether it is a patient with a medical emergency or the outbreak of an epidemic, these methods will allow us to assemble de novo genomes in days, instead of years.”
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