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.
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
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
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.”
Baker is a freelance writer in metro Atlanta. Illustration by Don Morris.