The 46 human chromosomes come in pairs, one in each pair is inherited from each parent. Although each chromosome of a pair contains the same genes in the same order, the sequences are not identical. On average, one in every 500 to 1000 base pairs of our genome differs from the one found in the majority of people. These randomly occurring changes are passed from generation to generation and account for a high proportion of the DNA differences between us. It is estimated that up to ten million such variations lie hidden in our genome. When such a variation is present in at least one percent of a particular population, for example an ethnic group, it is referred to as a single nucleotide polymorphism, or SNP (pronounced “snip”). For example, one individual may have a cytosine (C) at a specific point in his DNA, whereas another individual may have a thymine (T). If the individuals possess two copies of T or of C at this location, one on each chromosome pair, they are referred to as “homozygous”. If they possess a T and a C, they are “heterozygous”. Each person's genetic material contains a unique SNP pattern that is made up of many different genetic variations.
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SNPs are the smallest and the most common type of difference in DNA: they make up about 90% of all human genetic variation and occur every 1000 or so bases along the 3-billion-base human genome. The majority of SNPs are thought to be biologically “silent” i.e. they do not affect gene function or inherited traits. However, some SNPs may affect gene expression in disease situations or be present in the gene itself and affect protein function. By so doing, they can have both negative and positive influences on your body, frequently modifying individual responsiveness to environmental influences that can cause disease. These factors can be things like cigarette smoke or air pollution, excessive alcohol consumption, poor diet, sun exposure, bacterial infection, chronic nutrient deficiencies, endocrine imbalances, or toxic exposure. In other words, the vast majority of genetic polymorphisms only have the potential to cause health problems if one is exposed to the wrong "mix" of harmful agents over time.
Preventive genetic diagnostics helps to explain why individuals are affected differently by the same environmental factors. Most importantly, it enables the physician to select suitable measures for his patient tailored to his individual genetic needs.
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The ability to distinguish between maternal and paternal alleles allows human disease genes to be mapped. In germ cells, which produce eggs or sperm, the maternal and paternal chromosomes pair up and exchange segments of DNA via recombination. Recombination will occur frequently between DNA sequences that are a long way apart but only rarely between sequences that are close together. One consequence of this is that blocks of sequences on the same chromosome tend to be inherited together. Such groups of alleles, which are rarely separated by recombination, are known as haplotypes. In the human genome, haplotypes tend to be approximately 60,000 base pairs in size and therefore contain up to 60 SNPs. Because these SNPs are inherited together as blocks, they can be used to distinguish individuals and populations and determine what specific diseases or other traits are associated with different haplotypes.
Most chromosome regions have only a few common haplotypes, which account for most of the variation from person to person in a population. This means that although a block may contain many SNP's, it takes only a few SNP's to identify or “tag” each haplotype in the block. Consequently, the use of only a few "tag" SNPs that represent each haplotype is sufficient to obtain most of the information on the pattern of genetic variation in a particular region. An example of the value of haplotype analysis comes from research on Crohn's disease. Crohn's disease is a chronic inflammatory disease of the digestive tract that tends to cluster in families. Researchers identified a haplotype on chromosome 5 that correlates with the disease. This region of the chromosome contains genes involved in immunity; these genes may then be important in other inflammatory diseases, such as lupus or asthma.
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Detection of SNPs
There are a number of techniques that make it possible to detect single nucleotide changes in the human genome. These use different methods to analyse and compare selected regions of a DNA sequence obtained from multiple individuals who share a common trait for SNP patterns. These are compared to patterns obtained by analysing the DNA from a group of individuals unaffected by the disease. This type of 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. This permits the establishment of SNP profiles that are characteristic of a variety of risks/diseases and can be used to screen individuals for risk or disease susceptibility by analysing their DNA samples for specific SNP patterns.
SNP analysis aims to answer some of the following questions:
- What is my individual risk of developing a particular disease?
- Am I more susceptible to environmental influences that can cause disease?
- How will my body react to any drugs I am being prescribed?
- How successful is the treatment regimen I am undergoing likely to be?
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How can SNPs be used as risk
factors in disease development?
SNPs are ideal genetic markers for many applications because they are stable, widespread, and can often be linked to particular characteristics (phenotypes) of interest. They are proving to be among the most useful human markers for studies of evolutionary genetics and medicine. In general, SNPs do not cause disease, but they can help determine the likelihood that someone will develop a particular disease. 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. For example, apolipoprotein E or ApoE is one of the genes associated with Alzheimer's disease. It contains two SNPs that result in three possible alternate forms (alleles) for that gene termed E2, E3, and E4. Each allele differs by one DNA base, and the protein product of each gene differs by one amino acid. Each individual inherits one maternal copy and one paternal copy of ApoE. An individual who inherits the E4 allele will have a greater chance of developing Alzheimer's disease, whereas an individual inheriting the E2 allele will have a reduced risk.
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Results generated by SNP analysis can be difficult to interpret in a meaningful way, as it requires expert knowledge and a considerable amount of training. In addition, SNPs are not absolute indicators of disease development or how severe a medical condition might be. Someone who has inherited two E4 alleles may never develop Alzheimer's, while another who has inherited two E2 alleles may. Genetic tests fail to give precise information about disease severity and time of onset because most common chronic disorders such as heart disease, diabetes, cancer or Alzheimer's in humans are not caused by genetic variation within a single gene. Instead, they are influenced by complex interactions among multiple genes as well as environmental and lifestyle factors and ApoE is just one gene that has been linked to this condition. It is still hard to measure and evaluate the overall effect of multi factorial events on a disease process and this contributes enormously to the uncertainty of any individual developing a disease.
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From the perspective of patients, SNPs are a major step towards a more personalised approach to treatment that takes genetic differences between people into account. It is essential that all tests meet consent, sample handling, database protection, clinical validity, quality, accuracy and reliability requirements and are supplied with appropriate information and interpretation which is based on the results of research into the consequences of positive and negative test results. It may be difficult to distinguish between health prediction and diagnosis. For example a test for a disease susceptibility gene may be useful in diagnosis when other signs and symptoms of disease are present. Where these signs and symptoms are not present the same test could be considered as predictive. For so-called life-style traits it is important that the individual is able to make a judgement as to the potential impact of a particular test on their particular circumstances. At GeneticHealth we understand the importance of clear and accurate information provision for individuals before and after tests are conducted.
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