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a $5,000 genome and a $500,000 analysis," says Francis Collins,
the former director of the National Human Genome Research
Institute and a leader of the Human Genome Project.
BEYOND COMMON VARIATIONS
Genomic medicine began in earnest in the 1980s, when scientists
identified genes linked to diseases such as Duchenne muscular
dystrophy and cystic fibrosis. Both are so-called Mendelian dis-
eases, meaning that they're caused by mutations in a single gene;
anyone who inherits either one or two copies of the mutated gene,
depending on the disease, will be a icted. Over the last 20 years,
researchers have identified genes for a number of Mendelian dis-
orders, and screening tests based on these discoveries have led to
earlier diagnoses. In the case of disorders that develop only when
a person inherits two copies of the mutation, the tests can identify
healthy carriers, helping them make better-informed decisions
about having children. Single-gene disorders, however, make up
a very small percentage of human diseases. For most diseases, it's
much harder to pinpoint the genetic culprits.
As scientists began assembling a rough draft of the genome
sequence in the late 1990s, they uncovered a useful phenomenon.
Large blocks of DNA, known as haplotype blocks, tended to be
passed down intact through generations. Di erent versions of
these blocks, which were linked to an individual's ancestral ori-
gins, had characteristic patterns of common genetic variations
known as single-nucleotide polymorphisms (SNPs), in which
the genetic sequence varies by just one DNA letter. Thus, a tell-
tale SNP could serve as a marker for its surrounding DNA. The
discovery was a boon to geneticists---if each block tended to occur
in a limited number of varieties within the human population, it
would be unnecessary to check every base in the genome for varia-
tions linked to common diseases such as asthma or schizophrenia.
The presence of a particular SNP would indicate which haplotype
block an individual carried.
Researchers developed genetic microarrays that could quickly
detect the presence of these common SNPs throughout the
genome; by scanning for the telltale variations, a relatively inex-
pensive process, the microarrays have enabled the largest genomic
studies to date. Scientists have used them to e ciently search
tens of thousands of human genomes for SNPs more common in
people with autism or Alzheimer's, for example, than in healthy
people. Over the last two years, a flood of studies have been pub-
lished, identifying more than 300 genetic variations linked to an
assortment of common traits and diseases.
But finding these variations has not led to the breakthrough that
some scientists had hoped for in understanding the genetic basis of
common diseases. That's because they turn out to account for only
a small fraction of the genetic risk for many illnesses. Research-
ers have identified 18 genes linked to type 2 diabetes, for example,
and tests to identify the variations have been introduced. Yet many
other heritable risk factors for the disease remain unidentified. That
means that the new tests give an incomplete picture of how likely
someone is to develop diabetes, making it di cult to use them to tai-
lor medical decisions. "There is very little reason to be encouraged
that prevention strategies can be revolutionized with what we've
discovered so far [on the genetic basis of common diseases]," says
David Goldstein, director of the Center for Population Genomics
and Pharmacogenetics at Duke University in Durham, NC.
The hunt for SNPs makes sense if the inherited risk for diseases
like type 2 diabetes results from a combination of many common
genetic variations, each exerting a small e ect. But what if that is
only part of the story? What if other, rarer types of genetic muta-
tions are also playing a role? Because microarrays were designed
to detect common SNPs, they miss variations that appear in less
than 1 percent of the population. These mutations are the focus of
an alternative hypothesis, in which---as in the Mendelian model---
high-impact individual variations contribute heavily to a disease.
Any one of the variations may occur infrequently, according to
this thinking, but if they a ect the same or related biochemical
pathways, they may produce similar outcomes. Collectively, they
could make a disorder relatively common.
Until recently, only limited e orts had been made to search
for rare variants linked to common diseases. This search may
involve sifting through every letter of DNA---something that can
only be done by sequencing. With the old technology, that was
too expensive to be practical. But in view of the disappointing
results from microarray studies, scientists are turning to the fast
new sequencing technologies to rigorously test the rare-variant
hypothesis. It's likely that "much of the rest of the heritability [of
disease] is hiding in rare variants with high impact," Collins says.
"If we really want to understand the genomics of disease, we need
complete genome sequences."
It's still unclear how much rare variations contribute to disease,
but evidence is starting to trickle in. In a study published this sum-
mer, biologists at the University of California, Berkeley, sequenced
the gene for an enzyme called MTHFR, which converts the B
vitamin folate (folic acid) from one form into another. Scientists
had previously identified a common genetic variant that produces
a weakened version of the enzyme, increasing the risk of birth
defects and possibly of heart disease. By sequencing the MTHFR
gene in 564 people of di erent ethnicities, Nick Marini and col-
leagues found four new variants that also impair the enzyme's func-
tion; present in fewer than 1 percent of the subjects, these variants
would have been undetectable in microarray studies.
Take a tour of Pacific Biosciences sequencing technology:
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