The Human Genome Project represented a great step forward in the search for answers about the relationship between phenotypic traits and genetic variations. When comparing the DNA of different individuals, it was possible to observe variants of a single nucleotide, then called SNP ( Single nucleotide polymorphism ) or SNV ( Single nucleotide variant ).
Mutations in DNA: Genetic Variants
The genetic material is approximately 99.5% similar between any individual. Therefore, only 0.5% correspond to the variable fraction of DNA . Permanent alterations in the sequence of nucleotides are popularly known as mutations , random errors that cause a genetic variant , that is, another form of the DNA sequence.
Many people associate genetic variants with the development of diseases. However, variants can also have a neutral or benign effect and, in addition, they are the main sources of genetic variability responsible for the evolution of species.
Types of genetic variants
Variants can be caused by errors during the replication (cell division) of the genetic material or induced by a mutagenic agent, such as a virus and ultraviolet rays.
In addition, the change can occur in two main ways:
- Somatic mutation : Occurs only in some tissue or cell
- Germline mutation: Occurs during embryonic development in reproductive cells. In this case, as the variant can be present in germ cells (ovum or sperm), the trait can be transmitted to the next generations.
Mutations can also be classified into Chromosomal mutation and gene mutation:
• Chromosomal variants : It is associated with numerical or structural alterations of the chromosomes . In this case, mutations can alter several genes simultaneously and are responsible for the main known syndromes, such as Down Syndrome or Patau .
• Genetic variants : Occur punctually in DNA sequences and may involve the alteration of one or more base pairs
What is SNP (SNV)?
SNP ( Single nucleotide polymorphism ) or SNV ( Single nucleotide variant ) is defined as the replacement of a single nucleotide (adenine, guanine, cytokine or thymine) by another at a given location in the DNA sequence. SNP is the most common form of variant found in the genome.
SNP or SNV?
Although SNP is the most popular name for this type of variant, the ACMG recommends using the SNV nomenclature . Since many times, the terms “polymorphism” and “mutation” lead to confusion due to the assumption of the effects they cause in the organism. Therefore both terms should be replaced by “variant”.
It is estimated that a SNP occurs at a frequency of 1 in 1000 base pairs in the DNA sequence. However, since only 2.5% of all genetic code is a coding region (which carries the information for protein synthesis), most SNPs happen in non-coding regions. Therefore, most of these mutations may not cause significant changes in the organism.
How is SNP (SNV) classified?
SNPs can be classified according to the base switch:
• Transition: when a purine is exchanged for another purine ( Denine and Guanine ) or a pyrimidine ( Cytokine and Thymine ) for another. In an AATCGC sequence it would be one SNP per transition, for example, the replacement of A by G resulting in AGTCGC.
• Transversion: when a purine is replaced by a pyrimidine and vice versa, for example A by C.
SNP and mutation types
Coding regions are sequences of nucleotides that carry information for protein synthesis. Therefore, when the SNP occurs in one of these regions, 3 situations can occur:
- Silent or synonymous mutation : Changing a nucleotide does not modify the coding for the same amino acid. However, it is possible that a change in the protein’s conformation occurs, which may influence its functioning.
- Nonsense mutation : The alteration of a nucleotide codes for the termination of translation, prematurely ending the synthesis of a protein.
- Sense/missense mutation : Changing a nucleotide modifies the coding, synthesizing a different amino acid. May affect protein function.
In all cases, SNPs can influence the activity of transcriptional promoters and alter the stability or conformation of the pre-mRNA. These mutations may also be responsible for modifying a protein’s ability to bind to a substrate or inhibitor and interfere with important metabolic reactions .
SNP (SNV) markers associated with diseases
One of the main goals of scientists when sequencing genomes is to identify which genes are responsible for certain characteristics and how variations in these sequences can interfere with their function.
In this context, genome wide association studies (GWAS) compare the genome of individuals from a group that present a certain phenotype , such as a disease, with individuals that do not present the phenotype. Thus, it is possible to associate some variant to this phenotype and later use it as a genetic marker.
As SNPs are found throughout the genome, are often present in regions close to genes and are relatively stable, that is, they are not affected by the environment, they are widely used as genetic markers .
As previously mentioned, most SNPs are not responsible for the development of diseases; however, as they are identified close to disease-related genes, they are widely used in association studies.
Currently, there are several databases that gather different information about SNP variants, such as NCBI dbSNP database , GWAS Catalog, GWASdb, among others. Researchers identify the SNPs found in their research work through a code in the database, thus allowing other researchers to have access to the information.
How can SNPs be used?
In addition to their use as a genetic marker for disease-related genes, SNPs are also important in population studies. Some SNPs may be unique to certain ethnicities or groups in different regions. Thus, SNPs can also be used to understand evolutionary processes, family traits, diversity among individuals, among others.
SNPs are also associated with genes that encode proteins (enzymes) of medical importance, that is, proteins that metabolize and transport drugs. As a result of polymorphism in these regions, individuals react differently to the effect of drugs.
In other words, a drug can be effective for a group of individuals, but toxic for another group, depending on the variant of these genes. Thus, maps of SNPs associated with genes that encode proteins of medical importance are being developed.
Soon, pharmaceutical companies and doctors will be able to offer individuals specific and targeted treatments according to their genetic profile.