SNiPping Away at the Problem

Scientists tell us that identifying, cataloging and studying small genetic variations among humans will lead to more specialized and effective medical treatments. What do these variations look like, and what exactly makes them informative? Let's look at a hypothetical example of how a genetic variation might inform a medical decision.

Drug treatment today

It's springtime, and you have joined some friends in an effort to get in shape. Three times a week, you all head out the door for a short jog, with the goal of completing a 5-kilometer fun run later in the summer. Things go well, and you're feeling stronger every day. During your more strenuous workouts, though, you feel unusually short of breath. What's wrong?

You check in with your doctor, and she diagnoses you with exercise-induced asthma, a common problem among active young people. She prescribes an albuterol (pronounced "al-BYOO-teh-rol") inhaler for you, with instructions to use it before each workout.

In humans, however, there are known genetic variations that affect the protein that binds albuterol and relieves asthma attacks.

• One variation corresponds with greater albuterol effectiveness and relief of asthma attacks. It is found in 55 percent of the population.
• Another variation corresponds with reduced effectiveness and no relief. It is found in 40 percent of the population.

Which form of the protein do you have? Your doctor cannot tell. She can only base the treatment on how most people will respond to albuterol. So, you have a roughly one-in-three chance that the drug will not work for you.

What about the future?

Now let's travel 20 years ahead in time. You go to your doctor with the same symptoms, and she makes the same diagnosis.

This time, she collects a swab of your cheek cells (a painless procedure) and sends it to a laboratory for DNA testing.

In a few days, the results come back: you have the form of the protein that does not bind albuterol, and therefore, this treatment will not work for you. Instead, your doctor seeks an alternative treatment.

You have been spared the time, cost, and possible side effects of taking a medication that will not help you.

What would the DNA test look for?

The test would examine your DNA sequence in the area of the genome that contains the gene for the albuterol-binding protein. It would look for one or more single nucleotide polymorphisms (SNPs; pronounced "snips"). SNPs are single-nucleotide substitutions of one base for another that occur in more than one percent of the general population.

The challenge for scientists is to identify SNPs that correlate with a particular effect in patients: a response to albuterol, for example. Reliable SNPs could serve as predictive markers that inform our decisions about numerous aspects of medical care, including specific diseases, effectiveness of various drugs and adverse reactions to specific drugs.

This pharmacogenetic approach could save time, money, and discomfort for millions of patients through accurate diagnoses and matching patients with appropriate medicines.

The science behind the test: finding SNPs in the human genome

Scientists approach the problem of identifying, cataloging and characterizing SNPs in two main ways:

• Genomic approaches. This approach is used by scientists who want to see the big picture. Several large-scale projects have combined the efforts of many institutions to identify and catalog all of the SNPs in the 3-billion-base pair human genome. Each project involves hundreds of scientists, who compare the genomes of numerous individuals to identify the differences. These comparisons require a lot of computer-powered data analysis. As they work, scientists sort and catalog their results in databases that are available to anyone over the Internet, including other scientists and you. (See Additional Resources for links to these projects.)
• Functional approaches. This approach is used by scientists who are interested in a particular disease or drug response. The biological processes involved in diseases and drug responses are controlled by the activities of many genes. Scientists interested in a particular process select genes known to be involved in the process and examine them in people who have a response or disease, as well as those who don't. By comparing people's DNA sequences, scientists can identify SNPs that correspond with a particular function or response.

SNP Quick Reference

SNP (pronounced "snip") stands for Single Nucleotide Polymorphism. SNPs are single-nucleotide substitutions of one base for another. Each SNP location in the genome can have up to four versions: one for each nucleotide, A, C, G and T. A SNP and its distribution in a population might look like this:

Not all single-nucleotide changes are SNPs, though. To be classified as a SNP, two or more versions of a sequence must each be present in at least one percent of the general population.

SNPs occur throughout the human genome - about one in every 300 nucleotide base pairs. This translates to about 10 million SNPs within the 3-billion-nucleotide human genome.

SNPs and disease-causing mutations: Not the same!

If you know what a point mutation is, then the description of a SNP might sound similar. True, both are single-nucleotide differences in a DNA sequence, but SNPs should not be confused with disease-causing mutations. Here are some tell-tale differences:

First, to be classified as a SNP, the change must be present in at least one percent of the general population. No known disease-causing mutation is this common.

Second, most disease-causing mutations occur within a gene's coding or regulatory regions and affect the function of the protein encoded by the gene. Unlike mutations, SNPs are not necessarily located within genes, and they do not always affect the way a protein functions. SNPs are divided into two main categories:

Linked SNPs (also called indicative SNPs) do not reside within genes and do not affect protein function. Nevertheless, they do correspond to a particular drug response or to the risk for getting a certain disease.

Causative SNPs affect the way a protein functions, correlating with a disease or influencing a person's response to medication. Causative SNPs come in two forms:

Coding SNPs, located within the coding region of a gene, change the amino acid sequence of the gene's protein product.

Non-coding SNPs, located within the gene's regulatory sequences, change the level of gene expression and, therefore, how much RNA and protein is produced.

Supported by a Science Education Partnership Award (SEPA) [No. 1 R25 RR16291-01] from the National Center for Research Resources, a component of the National Institutes of Health, Department of Health and Human Services. The contents provided here are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.