Key concepts about genetics

Genetics is a fundamental pillar of medicine, its study provides valuable information for both the prevention and diagnosis of diseases. Medical genetics is an area that presents complexity, in this blog we will try to explain certain basic concepts that allow to improve the understanding of this science and to initiate in its study.

The first step to start talking about genetics is how this information is presented in the organism. The totality of the genetic information of an organism is called the genome and is in the form of DNA. DNA is the abbreviation for DeoxyriboNucleic Acid, a complex molecule found inside every cell of our body. The information contained in DNA is encoded with a system of 4 nucleotides: adenine (A), thymine (T), cytosine (C) and guanine (G). The basic unit in genetics are the genes and these contain the information to give rise to the proteins that make up our body.

We can differentiate between two types of DNA depending on their cellular location. The major type is found in the nucleus of the cell and is known as nuclear DNA, however, we can also find another type of DNA in the mitochondria called mitochondrial DNA. Nuclear DNA is inherited from both parents, however, mitochondrial DNA is inherited only from the mother.

DNA is packaged by proteins called histones, which together form chromatin. The assembly and disassembly of DNA by histones is key in the regulation and expression of many genes. When cell division occurs, the chromatin is highly compacted and forms chromosomes.

In humans, each human cell has 46 chromosomes, organized in 23 pairs, of which 22 pairs are autosomal and 1 pair of sex chromosomes. Of each pair, one of the chromosomes is inherited from the mother and the other from the father.

In the case of autosomal chromosomes, the fact that we have two chromosomes means that we also have two copies of the genes they contain. Each version of these genes is called an allele. If for a given position in the genome the two alleles are identical, the individual is homozygous for this variant, but if he has two different versions he is considered heterozygous.

We all have different genetic variants that make us unique. Among the variants that we can present, single nucleotide polymorphisms or SNPs (Single Nucleotide Polymorphisms) are common variants found in more than 1% of the population. In addition to SNPs we find mutations, these are rare variants, present in less than 1% of the population and can be associated with genetic diseases.

Depending on the tissue in which they occur, mutations are classified as somatic or germline, which will give us the difference between genetic and hereditary diseases. Germline DNA is the DNA found in gametes and in most cells of the body. Somatic DNA is the DNA of a specific tissue in which localized mutations can occur that are not found in the rest of the body. Mutations in germline DNA are inherited and passed on to offspring, whereas variants in somatic DNA are not inherited.

When we speak of the genome, we are talking about the total genetic information of an individual. At this point it is important to remember the central dogma of molecular biology: DNA is transcribed into RNA and RNA is translated into proteins. The regions of the genome that are transcribed into proteins are called coding regions. The genome contains both coding and non-coding regions. The most important part of the genome is the exome, coding regions that account for about 1-2% of the entire genome. The choice between a genome and exome test depends largely on the indication for testing.

When a failure or change occurs in the DNA sequence, the genetic code is altered and therefore, the synthesis of the protein. These changes, also known as variants, can occur in different forms, such as substitutions, deletions, duplications, inversions, among others. Similarly, there are alterations at the chromosome level called chromosomal abnormalities, which are the loss or gain of one or more chromosomes (numerical abnormalities) or when there is partial loss or gain of a chromosome or when a fragment of a chromosome is in an abnormal location (structural abnormalities).

The genotype is the set of all the genetic information that makes up an individual. When an alteration in the genotype is detected, it is important to establish whether it will manifest itself in the phenotype, that is, in the observable characteristics of the individual, which may have an impact on his or her health. There are different types of pathologies with different impact on people’s health, in general terms we can distinguish:

• Monogenic disorders: A single gene is responsible for a disorder or pathology also known as Mendelian diseases.
• Multifactorial diseases: The variants related to this type of disease increase the predisposition to present it, but by themselves are not expected to cause disease, but arise due to the combined effect of genes and the environment.

When the variants are produced during the reproductive process, so they have not been inherited from the parents, we speak of de novo variants. When the variants are inherited from the parents, we speak of inherited variants and they can follow different inheritance patterns depending on the chromosome in which they are located and their mechanism of disease generation:

• Autosomal dominant: The gene is located on an autosomal chromosome and the inheritance of a mutation in one of the alleles is sufficient to develop the disease.
• Autosomal recessive: The gene is on an autosomal chromosome and for an individual to develop the disease a mutation in both copies of the gene must be present. Both parents of an affected person are carriers. They do not usually occur in all generations.
• X-linked: The gene is located on the X sex chromosome. Females can be carriers and the disease mostly develops in males, since they have only one X chromosome.
• Mitochondrial inheritance: The alteration is in the mitochondrial DNA. It can affect both males and females, but is only transmitted maternally. It can appear in each generation

On the other hand, variants in the same gene do not always have the same impact on different individuals, i.e. they do not affect their phenotype in the same way. On many occasions the environment or variants in other genes can affect the development of disease in the presence of mutations. Penetrance is the percentage of individuals who have a given allele and who develop the associated phenotype, which can vary from person to person. Expressivity, on the other hand, is the degree to which the gene is expressed in an individual, which may be influenced by the environment or other genes. Different genetic conditions and diseases may have different expressivity and penetrance.

The study of the genome or exome for preventive or diagnostic purposes is becoming increasingly relevant in most medical areas. A key step in this type of study is the interpretation of variants. This work requires specialized personnel and access to public and private databases that allow the interpretation of variants to be as up-to-date and accurate as possible.