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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.
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
     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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