What is a genetic marker? Why is it?

The discoveries of new genetic markers to identify are more and more frequent and, therefore, to better prevent multiple diseases.

These markers make it possible to link certain genetic mutations to the risk of developing and developing many hereditary disorders. The use of new genome sequencing techniques will be essential to advance knowledge about this type of disease and many others.

In this article, we explain what a genetic marker is, what types of markers exist, how different genetic variants are detected and what are the main techniques used in genomic sequencing.

    What is a genetic marker?

    Genetic markers are segments of DNA located at a known position (a locus) on a given chromosome. Typically, these markers are associated with disease-specific phenotypes and are very useful in identifying different genetic variations in specific individuals and populations.

    The technology of DNA-based genetic markers has revolutionized the world of genetics, because thanks to them it is possible to detect polymorphisms (responsible for the great variability between individuals of the same species) between different genotypes or alleles of a gene for a given DNA sequenced in a group of genes.

    Markers that confer a high probability of disease onset are more useful as diagnostic tools.. A marker can have functional consequences, such as altering the expression or function of a gene that directly contributes to the development of a disease; and conversely, they may have no functional consequences, but may be located near a functional variant so that the marker and the variant tend to be inherited together in the general population.

    DNA variations are classified as “neutral” when they produce no change in metabolic or phenotypic traits (observable traits), and when they are not subjected to any evolutionary pressure (whether positive, negative or balanced). ; otherwise, the variations are said to be functional.

    Mutations in key nucleotides in a DNA sequence can alter the amino acid composition of a protein and lead to new functional variants. These variants can have a greater or lesser metabolic efficiency compared to the original sequence; they can completely lose their functionality or even incorporate a new one.

    Polymorphism detection methods

    Polymorphisms are defined as genetic variants in the DNA sequence between individuals of the same species.. These can affect the phenotype if they are found in coding regions of DNA.

    To detect these polymorphisms, there are two main methods: the Southern method, a nucleic acid hybridization technique; and the polymerase chain reaction PCR technique, which amplifies specific small regions of DNA material.

    Using these two methods, genetic variations of DNA samples and polymorphisms in a specific region of the DNA sequence can be identified. However, studies show that in the case of more complex diseases, it is more difficult to identify these genetic markers because they are generally polygenic, that is, caused by defects in several genes.

    Types of genetic markers

    There are two main types of molecular markerss: those of posttranscription-translation, which are carried out by indirect DNA analysis; and those of the pre-transcription-translation type, which make it possible to detect polymorphisms directly at the level of DNA and which we will discuss next.

    1. RFLP markers

    Restriction Fragment Length Polymorphism (RFLP) genetic markers are obtained after extraction and fragmentation of DNA, by cleavage of an endonuclease by restriction enzymes.

    The restriction fragments obtained are then analyzed by gel electrophoresis. They are a fundamental tool for genomic mapping and analysis of polygenic diseases.

    2. AFLP markers

    These markers are bialelic and dominant. Variations in many loci (naming multiple loci) can be ordered simultaneously to detect variations in a single nucleotide of unknown genomic regions, in which a given mutation may be frequently present in indeterminate functional genes.

    3. Microsatellites

    Microsatellites are the most popular genetic markers in genetic characterization studies. Their high mutation rate and codominant nature make it possible to estimate genetic diversity within and between different breeds, and genetic mixing between breeds, even if they are closely related.

    4. Mitochondrial DNA markers

    these markers they provide a rapid means of detecting hybridization between species or subspecies.

    Polymorphisms in certain sequences or in the control region of mitochondrial DNA have greatly contributed to the identification of progenitors of domestic species, the establishment of geographic models of genetic diversity, and the understanding of domestication behaviors.

    5. RAPD markers

    These markers are based on the polymerase chain reaction or PCR technique. The fragments obtained by RAPD are amplified in different random regions.

    Its usefulness is that it is an easy-to-use technique that allows you to quickly and simultaneously distinguish many polymorphisms. It has been used in the analysis of genetic diversity and the improvement and differentiation of clonal lines.

    Genome sequencing techniques

    Many of the diseases that exist have a genetic basis. The cause is usually determined by the appearance of one or more mutations that cause the disease or at least increase the risk of developing it.

    One of the most common techniques for detecting these mutations and has been used until recently is the study of genetic association, Which involve the sequencing of the DNA of one or a group of genes suspected of being involved in a particular disease.

    Genetic association studies study DNA sequences in the genes of carriers and healthy people in order to find the responsible gene (s). These studies sought to include members of the same family to increase the likelihood of detecting mutations. However, these types of studies can only identify mutations linked to a single gene, with the limitations that this implies.

    In recent years, new sequencing techniques have been discovered that have overcome these limitations, known as Next Generation Sequencing Techniques (NGS). These allow the genome to be sequenced by investing less time (and less money). Thanks to this, the so-called genome-wide association studies (GWAS) are being carried out.

    Genomic sequencing using GWAS allows exploration of all mutations present in the genome, Exponential increase in the probability of finding the genes responsible for a given disease. This has led to the creation of international consortia with researchers around the world sharing chromosome maps with risk variants of a multitude of diseases.

    However, GWAS are not without limitations, such as their inability to fully explain the genetic and familial risk of common diseases, the difficulties in assessing rare genetic variants, or the small magnitude of the effect obtained in most studies. Definitely problematic aspects which will have to be improved in the years to come.

    Bibliographical references:

    • Korte, A. and Farlow, A. (2013). The Benefits and Limitations of Feature Analysis with GWAS: A Review. Plant methods, 9 (1), 29.

    • Pritchard, JK and Rosenberg, NA (1999). Use of unrelated genetic markers to detect population stratification in association studies. The American Journal of Human Genetics, 65 (1), 220-228.

    • Williams, JG, Kubelik, AR, Livak, KJ, Rafalski, JA and Tingey, SV (1990). DNA polymorphisms amplified by arbitrary prime numbers are useful as genetic markers. Nucleic Acid Research, 18 (22), 6531-6535.

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