Your Own Personal Genome

[Guest guest]

Your Own Personal Genome

http://pubs.acs.org/cen/coverstory/87/8750cover.html

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

syndrome (Nat. Genet., DOI: 10.1038/ng.499). The mutation is in the gene that

encodes an enzyme in the pyrimidine biosynthesis pathway.

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.

K. 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, " says. In

glioblastoma, that mutation is an indicator of good prognosis, but in leukemia

it signals poor prognosis.

'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.

" Sequencing will be so cheap and so easy to access that everybody could get

sequenced if they want. It'll be iPod pricing. " PGP got its start in 2003 as the

result of a grant proposal that genetics professor 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 '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 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

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. "