Richard Lifton helped make exome sequencing viable and has used it to make discoveries in blood pressure control and cancer.

Scientists had no way to quickly sequence many genes at once. They could painstakingly sequence the genes one by one, or they could sequence an entire human genome—far more expensive and just as time-consuming.

Finally, in 2009, a new automated method opened the floodgates. Called exome sequencing, it allows researchers to quickly piece together the sequence of the exome, the 1 percent of the genome that encodes proteins. Focusing on this small portion, where many disease-related genes had already been found, made sense.

“The goal of my lab used to be to identify one disease gene per year; now, we’re identifying one or two per week. It’s like a dam opening up.”

Joseph G. Gleeson

Researchers admit, however, that exome sequencing ignores mutations in the other 99 percent of the genome—the regulatory sequences that influence whether a protein is made or how much is produced plus the stretches of nucleotides with unknown functions. And there’s no shortcut for interpreting the data that come from exome sequencing. So, when the cost of whole genome sequencing drops, exome sequencing will likely become obsolete. But, for now, it’s giving scientists a head start on studying the human genome.

In October 2010, barely a year after the first reports of exome sequencing being used to locate disease genes, Walsh published the gene mutations responsible for one form of microcephaly. He used exome sequencing to burrow into the 148 genes on chromosome 19 and found that mutations in WDR62, a gene expressed in developing neurons, are involved. Within months, before and after Walsh’s discovery, two other labs used exome sequencing to do the same thing—and replicated Walsh’s results.

“It was a mountain that no one could climb and then as soon as the tools were developed to make it easier, everybody could do it,” says Walsh. Today, for many labs, exome sequencing is the go-to method to pin down genetic mutations responsible for rare diseases. And researchers who study more common afflictions—like heart disease and autism—are using it to make inroads as well.

For some researchers, exome sequencing is allowing findings that never would have been possible without the method. For others, it’s speeding the pace of discovery.

“The goal of my lab used to be to identify one disease gene per year,” says HHMI investigator Joseph G. Gleeson, who studies the genetics of pediatric brain disorders at the University of California, San Diego. “Now, we’re identifying one or two per week. It’s like a dam opening up.”

Saving Time

Before 2009, Gleeson, Walsh, and others who wanted to find the gene mutations responsible for an inherited disorder had to build extensive pedigrees of families with the disease. The more family members they could find, the better the odds of uncovering the relevant mutations. Then, they used genetic linkage studies—a classic technique based on observations made in the late 1800s—to narrow down the location of the mutation.

When egg and sperm cells form, genetic material is shuffled between matching chromosomes to form unique combinations. The idea behind genetic linkage is that genes closest to each other are likely to stick together and be inherited as a bundle after this shuffle. So by finding known genes shared by family members with a disorder—and lacking in those without the disorder—scientists can deduce that the disease-causing mutation is nearby. But linkage studies are tedious—researchers must test dozens of family members for genetic markers. Even once they crunch the numbers, they are often left with a large swath of chromosome that may or may not contain the mutation they’re looking for.

Each exome segment within this area must then be individually isolated and sequenced using a series of reactions. “In a typical project, there might be 200 genes in your candidate sequence and you were faced with running thousands of reactions to test for potential mutations,” Gleeson recalls.

Photo: Brian Park

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