Houston-based scientists develop faster, cheaper way to solve genetic mysteries
A team of Houston-based scientists have sequenced the complete genome of the mosquito that carries the Zika virus using a new technique that significantly lessens the cost and the time it takes to solve genetic mysteries.
The team’s research, published Thursday in the journal Science, demonstrates how they were able to stitch together thousands of DNA fragments from the Aedes aegypti mosquito using a technique known as 3D assembly.
With this method, scientists can assemble a complete genome sequence from scratch for about $10,000 in a matter of weeks.
To put that in context, it took the Human Genome Project about 10 years and $4 billion to sequence a genome from scratch, or de novo, as it’s called.
“Sequencing a patient’s genome from scratch using 3D assembly is so inexpensive that it’s comparable in cost to an MRI,” said Olga Dudchenko, a post-doctoral fellow who led the research at Baylor College of Medicine’s Center for Genome Architecture. “Generating a de novo genome for a sick patient has become realistic.”
The process could ultimately aid scientists trying to identify ge-
netic mutations that might make a person more susceptible to cancer and other diseases.
To test the power of 3D assembly, the research team decided to tackle the genome of Aedes aegypti. For years, scientists had struggled to assemble it from thousands of DNA fragments.
The Houston team’s efforts may yield new ways to combat Zika.
“We had been discussing these ideas for years — writing a chunk of code here, doing a proof-of-principle assembly there,” said Erez Lieberman Aiden, director of Baylor’s Center for Genome Architecture and one of the paper’s authors. “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.”
‘Short reads’ and costs
To understand the relative scale of the new 3D assembly method, you have to first understand how difficult it is to sequence a genome from scratch.
The human genome includes 6 billion chemical letters, called base-pairs, divided up among 23 pairs of chromosomes. Chromosomes can be hundreds of millions base-pairs long, which means determining the sequencing can be incredibly time-consuming and expensive.
In recent years, advances in technology have brought down the cost of DNA sequencing, but only when that work produces “short reads,” usually a hundred base-pair-long snippets. The only way to use those short reads is to compare them to an existing reference genome, which requires assembling those super long chromosomes.
Because human genomes differ from one another, the use of a reference genome doesn’t always tell a person’s complete genetic picture.
“As physicians, we sometimes encounter patients who we know must carry some sort of genetic change, but we can’t figure out what it is,” said Dr. Aviva Presser Aiden, a scientist in the Pediatric Global Health Program at Texas Children’s Hospital and a co-author of the new study. She is also married to the director. “We need technologies that can report a patient’s entire genome. But we also can’t afford to spend millions of dollars on every patient’s genome.”
How it works
The 3D assembly technique could change that.
Here’s how it works: A few years ago, Erez Aiden’s team at Baylor figured out how the 6.5-foot-long genome folds to fit inside the nucleus of a cell, which is less than a thousandth of an inch wide.
By carefully tracing the genome as it folds, the team found it could stitch together hundreds of millions of short DNA reads into the sequences of entire chromosomes. Because this technique doesn’t rely on more complex reference genomes, the cost is dramatically lowered.
The team, which also included researchers from Harvard University and the Broad Institute at MIT, also used 3D assembly to construct from scratch the genome of the Culex mosquito, which spreads the West Nile virus.
Having a better understanding of both mosquitos’ genetic makeups should help scientists trying to find new ways to stop the spread of that disease, too.