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How do genome variations affect people?

In general, variations that are located outside of genes—that is, the majority of genome variations—don't affect the way your body works. And due to redundancy in the genetic code, some variations inside genes also have little or no effect. That is, two different DNA sequences may code for the same amino acid, so even if the DNA sequence changes the amino acid sequence of the corresponding protein stays the same. Thus, the protein's structure and function stay the same, too.

But a glance around at people on the bus, on the street, or at work reveals that some variations must affect human characteristics. The human species encompasses astonishing variety, in terms of appearance, personality, and physiology. Our genes affect (though they don't absolutely determine) our traits, so an equally dazzling genetic variety must exist. Since most genome variations are SNPs, scientists believe that these tiny differences in our DNA are actually the genetic underpinning for much of the human variety that we see around us.

Why study genome variation?

For one thing, knowing about genome variation has many practical applications, from genome mapping (discussed above) to screening for genetic diseases to forensic technologies such as DNA fingerprinting. Some of these applications, such as screening for genetic diseases, focus on the variations that affect a person's characteristics. Others, including genome mapping and DNA fingerprinting, make use of both variations that affect traits and those that do not. All of them involve, one way or another, analyzing a person's genome for the presence of specific variations. And such analysis isn't accurate or informative unless it's backed up by basic knowledge: how much variation exists in the genome, where it's located, and how common different alleles are in various population groups.

Image of a DNA fingerprint (banded electrophoresis gel)

In addition, the history of the human species is written in our genes—specifically, in the different patterns of genome variation in populations all over the world. In the past, when groups of humans split off from one another and migrated to different areas, their genomes accumulated differences, in part by chance and in part because genes that are an asset in one environment may be a liability in another. When populations grew or shrank, some variations that were once common became rare, and others that were once rare became common. And when groups that were previously isolated came in contact with one another and intermarried, the mixing of their genomes was reflected in the DNA of their offspring.

This story is told in the genomes of people alive today: We are all living fossils. By comparing the genomes of people from different populations all over the world, scientists called molecular anthropologists hope to gain insight into our collective history.

Finally, scientists are studying genome variations in order to learn about human traits, especially complex traits such as personality, weight, and susceptibility to heart disease. Such traits are thought to be affected by many different genes, so studying variation on a genome-wide scale is the only way to understand them.

SNPs are a major focus of this branch of research. Scientists believe that many of these ubiquitous and seemingly minor variations will help them understand people's widely differing susceptibilities to common diseases such as heart disease, diabetes, and various forms of cancer.

But unlike the more familiar mutations that are associated with inherited diseases (the sickle cell mutation, the Huntington's disease mutation), SNPs act in more subtle ways. SNPs don't cause disease—they are risk factors for disease. And many different SNPs in widely scattered genes may influence the risk of a single disease.

One of the best-known examples of how SNPs are thought to work involves Alzheimer's disease and a gene called apolipoprotein E, or ApoE. The ApoE gene contains two SNPs, and thus has three alleles, known as E2, E3, and E4.

The alleles differ from each other by one DNA base, and the corresponding proteins differ from each other by one amino acid. In the E2 protein, the 112th and 158th amino acids are both cysteine. In the E3 protein, the 112th is cysteine but the 158th is arginine. And in the E4 protein, both the 112th and 158th amino acids are arginine.

Each person has two copies of the ApoE gene, one inherited from each parent. Scientists have recently learned that people who carry at least one E4 allele have a greater risk of developing Alzheimer's than those who do not. By contrast, people who have at least one E2 allele actually seem to be protected from the disease.

Still, not all people with two "risky" E4 genes get Alzheimer's, and a very few people with two "protective" E2 genes nevertheless develop the disease. In other words, SNPs are informative, but not absolute.

Many scientists hope that research on the SNPs in ApoE and other genes will illuminate the biochemistry behind common human diseases, helping them develop new, more effective treatments. Some go even further, envisioning a day when a quick analysis of your genome will become a routine part of medical care. With a knowledge of which polymorphisms are associated with particular diseases, doctors could predict an individual patient's risk of various diseases just by analyzing the patient's DNA. If a medication were necessary, the same analysis might also help predict the patient's response to various drugs, enabling the doctor to prescribe the one most likely to work and least likely to cause unpleasant side effects.

None of this would make lifestyle and environmental factors any less important—finding out that you had "good" heart disease genes wouldn't give you a license to guzzle cholesterol. (Nor, in fact, would finding out that you had "bad" heart disease genes, since having a genetic susceptibility to a disease doesn't necessarily mean that you will get it.)

And in truth, genetically tailored medicine is still a long way off, for reasons well illustrated by the ApoE-Alzheimer's connection. We know the ApoE gene codes for a protein that helps carry cholesterol from place to place in the body, but we don't know what role that protein plays in the development of Alzheimer's or in causing confusion, memory lapses, and other symptoms of the disease. We don't know why it's good to have an ApoE protein in which the 158th amino acid is cysteine and bad to have one in which the 112th amino acid is arginine, or what to do to counteract the bad form of the protein. In short, finding a SNP linked to a certain disease is only a very small, first step. Nevertheless, it's a step that allows us to envision better, healthier lives for many people.

Sarah E. DeWeerdt is a freelance writer living in Seattle.
Barbara J. Culliton is executive editor of the Genome News Network.
Graphic Design by Mary S. Gibbs

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Updated on January 15, 2003