Effect of Single Nucleotide Polymorphisms on Genes and Disease

1. Effect of Single Nucleotide Polymorphisms on Genes and Disease Richard Kim YGTLC 01/06/07

2. Background Information: DNA and Human Diversity • The DNA of most people is 99.9 percent the same. • Only about 3 million base pairs are responsible for the differences among us — which is only 0.1% of our DNA. • Sequence variations occur in our genes, and the resulting different forms of the same gene are called alleles. • These DNA base sequence variations influence most of our physical differences and many of our other characteristics.

3. Mutations • A mutation or polymorphism is a change in the DNA "letters" of a gene or an alteration in the chromosomes. • Polymorphisms are common differences in the sequence of DNA, occurring in at least 1% of the population. Mutations are less common differences, occurring in less than 1% of the population. • Most DNA variation is neutral (not beneficial or harmful), but harmful sequence changes sometimes do occur. Changes within genes can result in proteins that don't work normally or don't work at all. Some of these changes can contribute to disease or affect how someone responds to a medicine.

4. Mutations (continued) • Mutations may be passed down from parent to child around the time of conception or may be acquired during a person's lifetime. • Mutations can arise spontaneously during normal cell functions, such as when a cell divides, or in response to environmental factors such as toxins, radiation, hormones, and even diet. • Nature provides us with a system of finely tuned repair enzymes that find and fix most DNA errors. But as our bodies change in response to age, illness and other factors, our repair systems may become less efficient. Uncorrected mutations can accumulate, resulting in diseases such as cancer.

5. What are SNPs? • A Single Nucleotide Polymorphisms (SNP) is a DNA sequence variation occurring when a single nucleotide in the genome differs between members of a species or between paired chromosomes in an individual. [Nucleotides (A, T, C, or G) are the basic units that make up a DNA sequence.] • For example: AAGCCTA toAAGCTTA Sequenced DNA fragments from different individuals contain a difference in a single nucleotide. In this case we say that there are two alleles: C and T.

6. SNPs (continued) • Single Nucleotide Polymorphisms (SNPs) make up 90% of all human genetic variations and occur frequently along the human genome. • These DNA sequence variations can affect human development of diseases and their response to pathogens, chemicals, drugs, etc. • As a result, SNPs are of great value to biomedical research and in developing pharmacy products. • SNPs are already being used in forms of genealogical DNA testing.

7. Genes and Monogenic Disease • Scientists currently believe that single gene mutations cause approximately 6,000 inherited diseases. • These diseases are called single gene or monogenic diseases because a change in only one gene causes the disease. • These conditions include a number of lung and blood disorders, such as cystic fibrosis, sickle cell anemia, and hemophilia. Although rare, as a group, they still affect millions of people worldwide.

8. Genes and Complex Disease • The rules that underlie the inheritance of major common diseases are not as straightforward. These diseases include heart disease, diabetes, Alzheimer disease, psychiatric disorders, and osteoarthritis. • These diseases affect many millions of people, and their treatment and prevention consumes the majority of health care resources in developed countries. • These common diseases result not just from a change in one or a few genes, but from a combination of the effects of the environment and a number of susceptibility genes. • Susceptibility genes contribute to an individual's risk of developing a specific disease, but usually are not enough to cause the disease. Susceptibility genes may influence the age of onset of a disease, contribute to its rate of progression, or help to protect against it. Understanding the rules of their inheritance and their roles in disease is not a simple task. • Different alleles may be associated with different degrees of susceptibility or risk.

9. Locating Disease Genes Search for DNA changes in people who have a particular disease compared to those who do not. • 1. Start with a gene whose function is known and suspected of playing a role in the disease • - Compare the DNA of people who have the disease with those who do not to see if that gene is associated with the disease. 2. Look in areas of the genome that are thought to be associated with the disease, then see if there are similarities among people who have the disease. 3. Examine the DNA of large numbers of people with and without the disease and search the whole genome for areas that differ between the two groups.

10. Problems Locating Disease Genes • Searching randomly through three billion base pairs of DNA for tiny changes that may be linked to disease has been difficult, time-consuming and expensive. • Scientists believe that the major common diseases are caused by alternative forms of many genes that interact with each other and with the environment, with each gene making a contribution to the disease. • It has been difficult for scientists to trace the effects of these genes, even when they study many large families with affected individuals.

11. Using SNPs to Locate Disease Genes • A new kind of genetic map, called a high-density SNP map, has the potential to speed up this research. • The frequency, stability and relatively even distribution of SNPs in the genome make them particularly valuable as genetic markers. • The marker itself (a SNP, for example) may or not cause the disease, medicine response or other phenotype that is being examined. In some cases, it may be directly linked to the phenotype, but it is useful as a signpost in either case.

12. Future Effects of Knowing Genetic Data • How might a doctor's knowledge of your genetic data affect your everyday life in the future? • Using the information SNPs provide, it may be possible to predict your genetic risk of developing a certain disease, to diagnose a disease more accurately, or to predict how you most likely will respond to a medicine. • Just as you carry your medical insurance card with you, you may also one day carry a wallet-sized card that has your genetic data coded on it. Doctors would be able to use this data to predict your risk of developing a disease and your likely response to a medicine before they prescribe it for you.