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Scientists have, for the first time, determined the
order of virtually every letter of DNA code in an
individual, offering an unprecedented readout of the
separate genetic contributions made by that person’s
mother and father.
By
providing a detailed look at maternal and paternal DNA
strands, rather than the blended composite that was
yielded by the 2001 Human Genome Project, the work
offers the clearest snapshot yet of just how different
those two contributions can be. Assuming the newly
decoded sequence is typical, as scientists presume it
is, there are five times as many differences between
individuals’ DNA as was previously thought.
Of more
practical import, the ability to create such a detailed
genetic profile with relative ease suggests that it may
not be long before people of ordinary means will be able
to have their complete DNA codes spelled out, scientists
said.
That
could tell a lot about a person’s health risks, because
such a profile would include not only the few genes that
significantly increase the likelihood of getting certain
diseases, but also the many “lesser” genes that pose
modest risks individually but that together have the
lion’s share of impact on health.
For
better or worse, the advance also stands to bring
science to the pastime of guessing which parent deserves
blame or credit for passing along certain traits.
“This is
the ultimate form of genealogy. You’ll have incredible
information about yourself,” said Stephen Scherer of the
Hospital for Sick Children in Toronto, who was part of
the multimillion-dollar project described in the journal
PLoS Biology.
“I
wouldn’t be surprised if Internet-based browsers pop up
before long that allow you to compare your genome to
others.”
The
genetic sequence that was unveiled in all its naked
detail belongs to J. Craig Venter, the Maryland
scientist who led the project at the J. Craig Venter
Institute in Rockville, Maryland. It carries
significantly more information than the two previously
sequenced human genomes, released with great fanfare six
years ago.
Those
sequences—one assembled by Venter and co-workers at
Celera Genomics, and the other by federally funded
scientists—were composites of several people. And
although they were referred to as complete, they were in
fact half-genomes—or “haploid”—containing a parental
mosaic of the 3 billion DNA letters that can fit on one
set of the 23 chromosomes paired in every cell.
Not
emphasized in 2001 was the fact that people have in
their cells two versions of each of those 23
chromosomes, one from each parent—a “diploid” genome.
And increasingly scientists are finding that the
difference between being healthy and being sick has a
lot to do with how those genomes interact.
From
Dad, a person may inherit a version of a gene that
predisposes to a disease, but from Mom that person may
inherit a protective version—or an entirely different
gene elsewhere on the genome that counteracts Dad’s
contribution.
“I
might want to know: Do I have an additive risk from the
genomes from both my parents, or did I get some helpful
ones from her that counteract the ones from him?” Venter
said.
Sorting
out those details has been daunting.
“It’s
very easy to start mixing up the readouts from each
parent because they are so similar,” said Samuel Levy,
who led the research with Venter. But new sequencing
technologies and computational methods allow scientists
to chop a person’s DNA into pieces and reassemble the
maternal and paternal segments independently.
Challenges remain. Although Venter’s method produces a
six billion-letter diploid genome, it does not produce
complete paternal and maternal genomes of 3 billion
letters each. But it does produce chunks of DNA that are
hundreds of thousands of letters long, all from one
parent or the other, allowing the most meaningful
maternal-paternal comparisons yet. Previous such
snippets topped out at about 13,000 letters, too few to
be medically informative.
And
unlike the Human Genome Project, whose focus on
individual letters made it blind to many larger
mutations or variations involving hundreds or thousands
of letters, the newer methods that Venter used capture
all sizes.
The new
work showed, for example, that Venter lacks one parental
copy of the gstm1 gene, known to have a role in
neutralizing toxins and carcinogens—perhaps helping to
explain why he has had asthma and skin cancer, Levy
said.
All
told, 44 percent of the genes Venter received from one
parent were at least a little different from those he
inherited from his other parent, and a third of those
variations had never been seen in studies of those genes
in other people. Although most of the differences may
have no discernible health effect, the finding indicates
that humans are more genetically diverse than was
thought.
Specifically, older analyses suggested that humans’
genetic codes are, on average, 99.9 percent identical
(or 0.1 percent different), while the new estimate comes
in at 99.5 percent (or 0.5 percent different). The true
number may be as low as 99 percent, Venter said.
That
means each person is the product of more genetic
diversity—and more biological negotiation and compromise
during fetal development—than was believed.
Venter
is not alone in his effort to create personalized
sequences, and at least one competitor offered a more
tempered view of the work.
“I would
call this a small, quantitative milestone,” said George
Church, a Harvard University professor of genetics who
is also racing to produce cheap genomes.
He said
Venter’s sequence, like previous ones, still has many
gaps, was cumbersome to make and, at a cost of tens of
millions of dollars, was still way too expensive.
He also
noted that recent research by Scherer had already
suggested that human genetic variability is probably at
least 0.3 percent, not the 0.1 percent floated in 2001,
which Venter uses for comparison. So Venter’s new
finding of 0.5 percent amounts to something less than a
sea change, Church said.
But
Church sings with Venter’s choir on the vast benefits
that could come from inexpensive personalized genome
sequencing.
Cost
trends are encouraging. The first three billion-letter
genome sequences took more than a decade to complete and
cost billions of dollars. During Venter’s latest
project, costs dropped precipitously, and today, several
scientists said, an entire diploid genome could probably
be done for about $100,000. Some predict that a $1,000
genome will be available within five years.
Venter
and others hope that at that point many people will get
sequenced and, as Venter has already done with his own,
will post their genomes on public databases along with
their medical information and family history. That will
allow computers to start drawing connections between
gene patterns and diseases.
Given
the risks involved in such personal revelations,
including job discrimination and health insurance woes,
no one knows how many people will take that route.
“It’s
going to be a very interesting social experiment to see
the way people go,” said Scherer, who has predicted that
before long, parents of newborns will leave the hospital
with a six-gigabyte computer file of their screaming
bundle’s genome loaded on their BlackBerrys. He said
that people’s fascination with technology—and with
themselves—will prevail.
Among
the ethics questions raised by the prospect of people
posting their genomes is whether they have an obligation
to kin who may not want their familial patterns put on
display.
Asked if
he had consulted his living parent, his three siblings
or his 30-year-old son before posting his genome, Venter
said: “I’ve not asked any of their permission, but we’ve
discussed it all extensively. Their main response is not
‘Oh, my God.’ It’s ‘Can I get my genome done, too?’” |
