Genetics is the study of heredity and variations or change in DNA sequence. These changes or variations could be in the form of single nucleotide polymorphism (SNPs) or mutations.
Single Nucleotide Polymorphism (SNP)
Single Nucleotide Polymorphism (SNP) is defined as a single base change in a DNA sequence that occurs in a significant proportion i.e. more than 1 percent in a population. SNPs can be identified by Restriction Fragment Length Polymorphism (RFLP) through which genetic variation can be detected by cutting the DNA into fragments of different lengths with the help of restriction enzymes (molecular scissors).
single-nucleotide polymorphism can be considered as a germline substitution of a single nucleotide at a specific position in the genome and is present in a more than (1% or more) fraction of the population. For better understanding of the SNPs we can firstly the identify the specific base position in the human genome, the nucleotide T may appear in most individuals, but in a minority of individuals, the position is occupied by an C. This means that there is a SNP at this specific position, and the two possible nucleotide variations – T or C – are said to be the alleles for this specific position in an individual.
These simple changes can be of transition or transversion type and they occur throughout the genome at a frequency of about one in 1,000 bp. They may be responsible for the diversity among individuals, genome evolution, the most common familial traits such as curly hair, interindividual differences in drug response, and complex and common diseases such as diabetes, obesity, hypertension, and psychiatric disorders. SNPs may change the encoded amino acids (nonsynonymous) or can be silent (synonymous) or simply occur in the noncoding regions. They may influence promoter activity (gene expression), messenger RNA (mRNA) conformation (stability), and subcellular localization of mRNAs and/or proteins and hence may produce disease. Therefore, identification of numerous variations in genes and analysis of their effects may lead to a better understanding of their impact on gene function and health of an individual.
Effect of SNPs:
Mostly identified SNPs are not pathogenic but could be susceptible for wide range of diseases For example in age-related macular degeneration a common SNP in the (Complement Factor H) CFH gene is identified and found to be associated with increased risk of the disease. Another example is non-alcoholic fatty liver disease a SNP in the (Patatin-like phospholipase domain-containing protein 3) PNPLA3 gene is associated with increased risk of the disease. The severity of illness and the way the body responds to treatments are also manifestations of genetic variations caused by SNPs. For example, the Apolipoprotein (APOE E4) allele that is determined by two common SNPs, rs429358 and rs7412, in the APOE gene is not only associated with increased risk for Alzheimer’s disease but also younger age at onset of the disease.
Single nucleotide substitutions with an allele frequency of less than 1% are called “single-nucleotide variants” or mutations or SNVs.
Mutation:
These can be considered as the changes in DNA which in turn leads to changes in amino-acid sequence of protein structure and its function. For e.g.
Haploid human genome consists of 3 billion nucleotides and changes in even a single base pair can result in dramatic physiological malfunctions. For example, occurrence of sickle-cell anemia. It is a disease caused by the smallest genetic variation or mutation. Here, the alteration of a single nucleotide occurs in the gene for the beta chain of the hemoglobin protein (which is an oxygen-carrying protein that makes blood red) is all it takes to turn a normal hemoglobin gene into a sickle-cell hemoglobin gene. This single nucleotide change alters only one amino acid in the protein chain, resulting in devastating conditions by changing the shape of Red blood cells due to which they are not able to carry oxygen like the normal shaped Red blood cells.
This change occurs in the Beta hemoglobin (beta globin) which is a single chain of 147 amino acids. The resulting protein still consists of 147 amino acids, but because of the single-base mutation, the sixth amino acid in the chain is valine, rather than glutamic acid.
Effect of mutations:
Due to presence of this mutation in the RBCs molecules of sickle-cell hemoglobin stick to one another, forms rigid rods. These rods cause a person’s red blood cells to take on a deformed, sickle-like shape, thus giving the disease its name. The rigid, misshapen blood cells do not carry oxygen well, and they also tend to clog capillaries, causing an affected person’s blood supply to be cut off to various tissues, including the brain and the heart. Therefore, when an afflicted individual exerts himself or herself even slightly, he or she often experiences terrible pain, and he or she might even undergo heart attack or stroke—all because of a single nucleotide mutation.
Relationship Between Mutations and Polymorphisms
Mutation is defined as any alteration in the DNA sequence, biologists use the term “single nucleotide polymorphism” (SNP) to refer to a single base pair alteration that is common in the population. Specifically, a polymorphism is any genetic location at which at least two different sequences are found, with each sequence present in at least 1% of the population. Note that the term “polymorphism” is generally used to refer to a normal variation, or one that does not directly cause disease. Moreover, the cutoff of at least 1% prevalence for a variation to be classified as a polymorphism is somewhat arbitrary; if the frequency is lower than this, the allele is typically regarded as a mutation (Twyman, 2003).
SNPs are important as markers, or signposts, for scientists to use when they look at populations of organisms in an attempt to find genetic changes that predispose individuals to certain traits, including disease. On average, SNPs are found every 1,000–2,000 nucleotides in the human genome, and scientists participating in the International HapMap Consortium have mapped millions of these alterations (International Human Genome Sequencing Consortium, 2001).
This improved knowledge may provide a starting point for the development of new, useful SNP markers for medical testing and a safer individualized medication to treat the most common devastating disorders. This will revolutionize the medical field in the future. To illustrate the effect of SNPs on gene function and phenotype, this minireview focuses on evidences revealing the impact of SNPs on the development and progression of three human eye disorders (Norrie disease, familial exudative vitreoretinopathy, and retinopathy of prematurity) that have overlapping clinical manifestations.