Just the Facts: A Basic Introduction to the Science Underlying NCBI Resources

SNPs: VARIATIONS ON A THEME

Wouldn't it be wonderful if you knew exactly what measures you could take to stave off, or even prevent, the onset of disease? Wouldn't it be a relief to know that you are not allergic to the drugs your doctor just prescribed? Wouldn't it be a comfort to know that the treatment regimen you are undergoing has a good chance of success because it was designed just for you? With the availability of millions of SNPs, biomedical researchers now believe that such exciting medical advances are not that far away.

What Are SNPs and How Are They Found?

A Single Nucleotide Polymorphism, or SNP (pronounced "snip"), is a small genetic change, or variation, that can occur within a person's DNA sequence. The genetic code is specified by the four nucleotide "letters" A (adenine), C (cytosine), T (thymine), and G (guanine). SNP variation occurs when a single nucleotide, such as an A, replaces one of the other three nucleotide letters—C, G, or T.

An example of a SNP is the alteration of the DNA segment AAGGTTA to ATGGTTA, where the second "A" in the first snippet is replaced with a "T". On average, SNPs occur in the human population more than 1 percent of the time. Because only about 3 to 5 percent of a person's DNA sequence codes for the production of proteins, most SNPs are found outside of "coding sequences". SNPs found within a coding sequence are of particular interest to researchers because they are more likely to alter the biological function of a protein. Because of the recent advances in technology, coupled with the unique ability of these genetic variations to facilitate gene identification, there has been a recent flurry of SNP discovery and detection.

Needles in a Haystack

Finding single nucleotide changes in the human genome seems like a daunting prospect, but over the last 20 years, biomedical researchers have developed a number of techniques that make it possible to do just that. Each technique uses a different method to compare selected regions of a DNA sequence obtained from multiple individuals who share a common trait. In each test, the result shows a physical difference in the DNA samples only when a SNP is detected in one individual and not in the other.

Many common diseases in humans are not caused by a genetic variation within a single gene but are influenced by complex interactions among multiple genes as well as environmental and lifestyle factors. Although both environmental and lifestyle factors add tremendously to the uncertainty of developing a disease, it is currently difficult to measure and evaluate their overall effect on a disease process. Therefore, we refer here mainly to a person's genetic predisposition, or the potential of an individual to develop a disease based on genes and hereditary factors.

Genetic factors may also confer susceptibility or resistance to a disease and determine the severity or progression of disease. Because we do not yet know all of the factors involved in these intricate pathways, researchers have found it difficult to develop screening tests for most diseases and disorders. By studying stretches of DNA that have been found to harbor a SNP associated with a disease trait, researchers may begin to reveal relevant genes associated with a disease. Defining and understanding the role of genetic factors in disease will also allow researchers to better evaluate the role non-genetic factors—such as behavior, diet, lifestyle, and physical activity—have on disease.

Because genetic factors also affect a person's response to drug therapy, DNA polymorphisms such as SNPs will be useful in helping researchers determine and understand why individuals differ in their abilities to absorb or clear certain drugs, as well as to determine why an individual may experience an adverse side effect to a particular drug. Therefore, the recent discovery of SNPs promises to revolutionize not only the process of disease detection but the practice of preventative and curative medicine.

SNPs and Disease Diagnosis

Each person's genetic material contains a unique SNP pattern that is made up of many different genetic variations. Researchers have found that most SNPs are not responsible for a disease state. Instead, they serve as biological markers for pinpointing a disease on the human genome map, because they are usually located near a gene found to be associated with a certain disease. Occasionally, a SNP may actually cause a disease and, therefore, can be used to search for and isolate the disease-causing gene.

To create a genetic test that will screen for a disease in which the disease-causing gene has already been identified, scientists collect blood samples from a group of individuals affected by the disease and analyze their DNA for SNP patterns. Next, researchers compare these patterns to patterns obtained by analyzing the DNA from a group of individuals unaffected by the disease. This type of comparison, called an "association study", can detect differences between the SNP patterns of the two groups, thereby indicating which pattern is most likely associated with the disease-causing gene. Eventually, SNP profiles that are characteristic of a variety of diseases will be established. Then, it will only be a matter of time before physicians can screen individuals for susceptibility to a disease just by analyzing their DNA samples for specific SNP patterns.

SNPs and Drug Development

As mentioned earlier, SNPs may also be associated with the absorbance and clearance of therapeutic agents. Currently, there is no simple way to determine how a patient will respond to a particular medication. A treatment proven effective in one patient may be ineffective in others. Worse yet, some patients may experience an adverse immunologic reaction to a particular drug. Today, pharmaceutical companies are limited to developing agents to which the "average" patient will respond. As a result, many drugs that might benefit a small number of patients never make it to market.

In the future, the most appropriate drug for an individual could be determined in advance of treatment by analyzing a patient's SNP profile. The ability to target a drug to those individuals most likely to benefit, referred to as "personalized medicine", would allow pharmaceutical companies to bring many more drugs to market and allow doctors to prescribe individualized therapies specific to a patient's needs.

SNPs and NCBI

Because SNPs occur frequently throughout the genome and tend to be relatively stable genetically, they serve as excellent biological markers. Biological markers are segments of DNA with an identifiable physical location that can be easily tracked and used for constructing a chromosome map that shows the positions of known genes, or other markers, relative to each other. These maps allow researchers to study and pinpoint traits resulting from the interaction of more than one gene. NCBI plays a major role in facilitating the identification and cataloging of SNPs through its creation and maintenance of the public SNP database (dbSNP). This powerful genetic tool may be accessed by the biomedical community worldwide and is intended to stimulate many areas of biological research, including the identification of the genetic components of disease.

NCBI's "Discovery Space" Facilitating SNP Research

To facilitate research efforts, NCBI's dbSNP is included in the Entrez retrieval system which provides integrated access to a number of software tools and databases that can aid in SNP analysis. For example, each SNP record in the database links to additional resources within NCBI's "Discovery Space", as noted in Figure 1. Resources include: GenBank, NIH's sequence database; Entrez Gene, a focal point for genes and associated information; dbSTS, NCBI's resource containing sequence and mapping data on short genomic landmarks; human genome sequencing data; and PubMed, NCBI's literature search and retrieval system. SNP records also link to various external allied resources.

Providing public access to a site for "one-stop SNP shopping" facilitates scientific research in a variety of fields, ranging from population genetics and evolutionary biology to large-scale disease and drug association studies. The long-term investment in such novel and exciting research promises not only to advance human biology but to revolutionize the practice of modern medicine.