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The
genetic blueprints of all people generally have the same information,
with approximately 99% of one human genome sequence being identical
to all others. That makes the 1% of places in the genetic
code that account for human variation very interesting to researchers
like Scott Devine. Along with others in the biochemistry department
at Emory School of Medicine, he has identified and created a map
of more than 400,000 insertions and deletions (INDELs) in the human
genome that mark genetic difference among individuals. |
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Devine
is part of a new discipline that studies variations and correlates
specific changes with them. The human genome sequence in DNA contains
three billion base pairs of four chemical building blocks—adenine,
thymine, cytosine, and guanine (A, T, C, G)—connected in various
combinations in long chains within 23 pairs of chromosomes. A single
block replacement called an SNP (single-nucleotide polymorphism)
accounts for some of the variation among humans. For example, part
of one person’s genetic sequence might read A-T-C, but G might
replace C in the next person, resulting in
A-T-G.
These naturally occurring differences,
polymorphisms, help explain differences in human appearance and
why some people are susceptible to diseases like lung cancer and
others aren’t, says Devine. They also provide an explanation
for why there can be individualized responses to environmental factors
and medications.
SNPs have been the subject of much
research. In fact, the International HapMap Project recently published
a catalog and map of more than 10 million SNPs derived from diverse
individuals throughout the globe. However, INDELs have
received far less attention. Devine and postdoctoral student Ryan
Mills are remedying that, using computer-based analyses to examine
DNA re-sequences that were originally generated for SNP discovery
projects.
So far, they have identified and mapped
415,436 unique INDELs, with their work being published in the September
issue of Genome Research. Currently, they are expanding the INDEL
map to reach between 1 and 2 million additional variations.
How do SNPs and INDELs differ specifically?
“While SNPS are differences in single chemical bases in the
genome sequence, INDELs result from the insertion and deletion of
small pieces of DNA of varying sizes and types,” Devine says.
“If the human genome is compared to a book, then SNPs are
analogous to single letter changes—typos here and there, letters
transposed that turn intended words into others. On the other hand,
INDELs are equivalent to inserting and deleting letters, words,
or entire paragraphs.”
INDELs are grouped into five major
categories, based on their effect on the genome: insertions or deletions
of single base pairs, expansions by only one base pair (monomeric
base pair expansions), multi-base pair expansions of two to 15 repeats,
transposon insertions (insertions of mobile elements), and random
DNA sequence insertions or deletions.
INDELs result in as much as 25% of
human genetic variations, says Devine. Insertions and deletions
can range from one to tens of thousands of bases, causing variations
that are often but not always benign. “For example, about
20% of the mutations that have been identified in patients with
cancers have been small INDELs,” Devine says. “And INDELs
have been shown to be the cause of several genetic diseases, including
one of the most common, cystic fibrosis (CF). The majority of CF
cases are caused by a three-base-pair deletion in the CF gene that
produces a single amino acid deletion n the encoded CF protein.”
Several dozen transposon INDELs (caused by mobile element insertions)
also have been identified that cause human diseases, including hemophilia,
muscular dystrophy, neurofibromatosis, and various cancers.
How do these findings fit into
the future of medicine? “The long-term goal of genetic research
in humans is to identify varying positions in our genomes and correlate
them with altered traits, including diseases and disease susceptibility,”
Devine says. “Ultimately, each person’s genome could
be re-sequenced in a doctor’s office and his or her genetic
code analyzed to make predictions about future health and to help
physicians provide guidance on health care decisions.
“Our maps of insertions and
deletions will be used together with SNP maps to create one big
unified guide to variations that can identify specific patterns
of genetic variation. These patterns will help us predict the future
health of an individual and develop personalized health treatments,
including specific drugs tailored to each individual, given their
specific genetic code.”
Some experts predict practical clinical
applications may be readily available in a decade, bringing with
them a host of ethical dilemmas. For example, Devine asks, “What
if you knew, when your genome was sequenced, that you have three
variant positions that indicate you’ll most likely have a
heart attack by age 50? What will your insurance company do if they
have that information? What will your employer do? What if your
fiancée wants access to your genetic info before agreeing
to marry you?”
While these ethical decisions must
be addressed, Devine believes the benefits of genetic research are
so profound that researchers have to go forward in the midst of
uncertainty. “If we know ahead of time that someone is headed
toward a problem, we can work to develop treatments before symptoms
appear and extend these people’s lives,” he says. “This
work also may help us restructure health care to identify the healthiest
people and conversely the the sickest who need the most help and
resources.”
Sherry
Baker is a freelance writer in metro Atlanta. Illustration by Don
Morris. |
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