Your Own Personal Genome

Stephen R. Quake has an important question he hopes his genome can answer.

“In my family, a number of us respond poorly to anesthetics. I’d like to figure out why,” Quake, a professor of bioengineering at Stanford University, says. “We haven’t totally gotten to the bottom of that, but we have a few clues, and having my genome is going to make it that much easier to get there.”

Quake’s is one of just a handful of whole genomes that have been sequenced. But that won’t be true for long. Advances in DNA-sequencing technology (see page 16) that are driving down the cost and time needed for sequencing are bringing clinical applications of individual whole genomes into view. Researchers expect the floodgates to open, leading to a day in the not-so-distant future when we will all know details about our personal genome. Companies are already getting into the act by selling whole-genome-sequencing services. As we move forward, ethical and privacy minefields loom.

Digging clinically relevant information out of any genome remains challenging. The dearth of complete genomes means that we know very little about how variations in genome sequence actually translate to disease risk. The only way to gain that knowledge is to collect many genomes and associated trait information.

Some researchers are already tracking down the genetic basis of rare diseases with small cohorts of patients and whole-exome sequencing, which can be considered “whole genome lite.” The exome, which is the protein-coding portion, makes up only 1% of the genome.

“We can achieve sequence data on the coding portion of the genome with one-twentieth the sequencing needed for whole-genome sequencing,” says Jay Shendure of the University of Washington, Seattle. As long as the costs are dominated by the costs of sequencing rather than those of isolating that 1% of the genome, exome sequencing makes economic sense, he says.

Shendure and his collaborators have used exome sequencing to identify the causative mutations in two diseases. In one study, they identified the mutation responsible for a disorder called Freeman-Sheldon syndrome, for which they already knew the answer (Nature 2009, 461, 272). In the other study, they used exome sequencing of four unrelated affected individuals to identify the previously unknown mutation that causes the malformation disorder Miller syndrome (Nat. Genet., DOI: 10.1038/ng.499). The mutation is in the gene that encodes an enzyme in the pyrimidine biosynthesis pathway.

Richard P. Lifton of Yale University used whole-exome sequencing to assist in the diagnosis of a patient whose symptoms resembled those of kidney diseases that Lifton had previously characterized. In such cases, Lifton would normally genotype the patient by looking only at selected regions of the genome typically associated with inherited renal disease. By taking the whole-exome approach instead, he found that the patient actually had a gastrointestinal disease.

“In the past we had to make educated guesses” to diagnose such patients, Lifton says. “If we were wrong, we were just left scratching our heads and wondering what was going on, which was not very satisfying. This shows that we can make diagnoses that were not expected.”

Whole-exome sequencing is a transitional step on the way to doing whole-genome sequencing. Exome sequencing is cheaper, but whole-genome sequencing is more comprehensive because it can find changes both inside and outside of protein coding regions.

The disease on which whole-genome sequencing is best positioned to have an immediate impact is cancer. That’s because each cancer patient comes with a built-in control sample. By sequencing the genome in normal cells and tumor cells in the same patient, geneticists can identify the mutations that underpin different cancer types.

Richard K. Wilson and his coworkers at the Genome Sequencing Center at Washington University in St. Louis have already used whole-genome sequencing to look at a couple of cancer types. In acute myeloid leukemia (AML), they found about a dozen mutations between normal and cancer cells. In one ovarian cancer tumor, they found more than 100 mutations. They plan to analyze mutations in significant numbers of AML, breast cancer, and lung cancer cases, in addition to a handful of brain and ovarian tumors.

They found a mutation in a gene called isocitrate dehydrogenase both in glioblastoma (a type of brain cancer) and in AML. This mutation “wouldn’t have been on anybody’s cancer gene list before this year,” Wilson says. In glioblastoma, that mutation is an indicator of good prognosis, but in leukemia it signals poor prognosis.

Wilson’s sequencing center is participating in The Cancer Genome Atlas (TCGA), a joint program of the National Cancer Institute and the National Human Genome Research Institute. TCGA aims to improve the understanding of the molecular basis of cancer through whole-genome sequencing. The project is starting with brain and ovarian cancers and will ultimately include breast, kidney, and lung cancer as well.

Several projects in addition to TCGA have set out to gather the data needed to make genomic sequencing clinically relevant. The most ambitious of these is the Personal Genome Project (PGP) at Harvard University.

PGP got its start in 2003 as the result of a grant proposal that genetics professor George M. Church was writing to fund research into next-generation DNA sequencing technology. He realized that if the cost of DNA sequencing per base continued to follow a Moore’s law-like progression, scientists would need to start connecting genes and traits. That’s exactly what PGP aims to do through whole-genome sequencing of individuals from whom the project also obtains full medical histories.

PGP currently has 15,000 volunteers and is moving toward a goal of 100,000 participants. The bar for admission has been set high, Church says. Participants don’t merely sign a consent form. They must achieve a perfect score on an entrance exam that demonstrates their knowledge of human genetics and the implications for them and their families of the data being collected. Such familiarity and comfort with genetics is important because all data from PGP will be publicly available.

So far, whole-genome sequencing has remained predominantly a research activity, but as the price of genome sequencing continues to drop, that will change.

In fact, companies are already offering direct-to-consumer genome sequencing. Cambridge, Mass.-based Knome charges approximately $68,000 for whole-genome sequencing or $25,000 for exome sequencing, and Illumina, in San Diego, charges around $48,000 for whole-genome sequencing. At such prices, whole-genome sequencing remains a luxury item. Both companies expect the cost of sequencing to continue dropping precipitously in the months and years ahead.

“We believe that the consumer market ultimately is going to be one of the largest opportunities for sequencing,” says Jay T. Flatley, president and chief executive officer of Illumina. He notes that Illumina wanted to get into the market at this early stage so that it could wrestle with some of the nontechnical issues, such as privacy and regulatory concerns, that might otherwise constrain the sequencing market later on, when the cost of sequencing becomes low enough to create a large demand.

Currently, because clinical understanding of the genome is at a very early stage, whole-genome sequencing provides basically the same information as direct-to-consumer services (such as 23andMe and Navigenics) that test for already-known single-nucleotide polymorphisms.

The ultimate advantage of whole-genome sequencing is that “you don’t ever have to do it again,” Flatley says. Anytime a new disease-causing mutation is discovered, “you just look at your genome and you can tell immediately” if you have that mutation, he says.

But use of the technology also has important ethical aspects. Everybody who does whole-genome sequencing, whether in an academic or corporate setting, has to deal with how to report the findings in a sensitive manner and how best to protect patient privacy.

For example, do researchers have an obligation to tell people who donate genomic material for research purposes what’s in their genome? “Some people have argued that there might be a limited obligation to return research results when you have a genetic variant that has known clinical significance and there’s something you can do about it,” says Amy L. McGuire, a medical ethicist at Baylor College of Medicine. “Other people are cautious about creating an obligation even under those circumstances because there’s concern about blurring the line between research and clinical care.”

In PGP, “we want to educate participants in advance so that if we do have to report something back to them, we’re not faced with this bad decision of either not telling them something they should know or telling them something and having them say, ‘That’s terrible. I didn’t want to know that,’ ” Church says. “It’s better to specifically recruit people who want to know everything.”

PGP reports information to participants via open-source software called Trait-o-Matic, which analyzes each sequence in light of known variations. “We’re focusing on traits that are predictable and actionable, like the 1,500 gene tests that clinical geneticists order,” Church says.

Direct-to-consumer companies face similar issues, but they may be more willing to deal with customers who don’t want to know everything. “We have found that some people want to know absolutely everything, and they’re perfectly comfortable with that,” says Jorge Conde, CEO of Knome. “Some people are very specific about what they don’t want to know.”

Knome deals with such requests by removing modules from the company’s analytical software rather than removing sequence data. A downside to removing data is that “people change their minds over time,” Conde says. Redacting parts of the genome could deprive people of information if new associations are discovered.

Another ethical concern that Knome and Illumina have to address is privacy, for instance, ensuring that sequencing information remains private, even when the company doesn’t necessarily retain custody of those data. Illumina delivers the sequence on an encrypted hard drive to the physician who ordered the test. Knome delivers the sequence directly to the consumer on a USB drive. Knome, which markets itself as a data company and indeed contracts out the actual sequencing, does not keep a copy of the sequence. Illumina performs its own sequencing and, as a certified clinical lab, is required to keep a copy.

Further down the road, a potential roadblock to widespread acceptance of genome sequencing is worry about discrimination on the basis of genetic information in the areas of employment and insurance coverage.

Especially touchy is the idea of using whole-genome sequencing as a replacement for the newborn screening that is currently done to test for disorders such as phenylketonuria. “You wouldn’t just get the conditions that are malleable to treatment by diet. You would be getting the whole shebang,” says Robert Cook-Deegan, director of the Center for Genome Ethics, Law & Policy at Duke University. “We’d have to know that we were going to have some legitimate use for that information on every baby.”

Although challenges remain, everyone seems to agree that personal genomes are inevitable. Whole-genome sequencing “will become ubiquitous,” Flatley says. “In the future, sequencing will be so cheap and so easy to access that everybody could get sequenced if they want. It’ll be iPod pricing.”