Medicina de precisão do Hospital Israelita Albert Einstein

Mutation: the origin of genetic variation

Find out what genetic mutations are and how to identify them
variação genética
variação genética

You may have heard about genetic mutations, but do you really know what it means? And what about genetic variants? Do you know if there is any difference between these terms?

Since the end of the Human Genome Project and the beginning of the genomic era, much has started to talk about genetic variants, but few people know or understand what it is.

After the discovery of the genetic code (which demonstrated the sequences of all genes that make up the human genome) one of the most significant discoveries in modern genetics  was the role of genetic variants or mutations in evolution, development, maintaining health and establishing diseases.

Hundreds of studies have been carried out around the world in order to discover which genetic alterations are associated with the most diverse types of diseases, and also, which are associated with health or resistance to certain diseases and even infections.

However, before studying the consequences of mutations, in the next topics we will explain what mutations (or variants) are and how they are identified.

What are mutations?

Both in storage and in the copying of genetic information, accidents and random errors occur, altering the nucleotide sequence – that is, creating mutations. Therefore, mutations are changes in the sequence of nucleotides or in the DNA arrangement of an organism.

Note: In many places, the term “mutation” is used in reference to a genetic change that causes disease, and therefore has a negative connotation. However, a mutation does not necessarily cause any disease or is pathogenic, and can be neutral or even benign. The current guidelines for interpreting changes in DNA sequences (see Richards 2015, Genet.Med. 17: 405-424) recommend using neutral terms like “alteration”, “change” or “variant” to avoid this confusion. Thus, in this text, we will use the terms “variant” and “mutation”to mean a change in the DNA sequence regardless of the consequence of that change.

About 99.5% of a person’s DNA is similar to that of anyone else even if they are not from the same family. And it is approximately 0.5% that makes all the difference, being responsible for genetic variability. These changes include changes in a single nucleotide, changes in one or more genes, and even changes in the number or structure of chromosomes. Mutations are extremely important sources of genetic variability in populations, as they provide new genetic information.

If the DNA of an organism remained always stable and was transmitted to the descendants always in an integral way, there wouldn’t be evolution, because there would never be the formation of something new. Therefore, genetic variation ensures that each individual has a unique genome.

Many variations in DNA sequences have little or no effect on the external appearance, while other differences are directly responsible for causing disease.

Still, there are variants responsible for genetically determined variability in anatomy, physiology, food intolerances, susceptibility to infection, predisposition to cancer, therapeutic responses or adverse reactions to medications, and perhaps even variability in various personality traits, athletic aptitude and artistic talent.

How do you identify a mutation?

To recognize a mutation, one must compare the observed variation with a standard considered normal. The reference genome, considered standard, is the most common arrangement or sequence in any position in the genome observed in the population.

A series of international collaborations studies, shares and updates data on the nature and frequency of DNA variations in different populations in the context of the human genome reference sequence, and makes the data available through public databases, which serve as essential resources for scientists, doctors and other health professionals.

There are several versions of the reference human genome. As more genomes of individuals around the world are sequenced, more variations are detected, and this reference genome is subject to constant changes and updates.

Several public databases are available that provide the genetic changes found in different populations, for example, genomAD and ExAC. In relation to the Brazilian population, which is highly miscegenated, the AbraOM (Brazilian Online Archive of Mutations) bank was recently made available.

Thus, through molecular biology techniques, such as Sanger sequencing or NGS, it is possible to compare the analyzed DNA with the reference genome and identify the changes.

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