In the following topics we will briefly describe the different classifications of a variant. If you don’t know what mutations or genetic variants are, you should read the text Mutation: the origin of genetic variation first.
Types of genetic mutations
First, a variant can occur in only a few cells or tissues in an organism, and is thus called a variant or somatic mutation. However, it can also appear during embryonic development in cells of the reproductive lineage (in sperm or eggs) and is called a variant or germline mutation.
Germline mutations are transmitted to the offspring, giving rise to a new individual having all the cells with the mutation.
Somatic mutations can occur in any cell division from the first cleavage of the fertilized egg to the cell divisions that replace the cells of an adult individual. Somatic variants are not transmitted to the next generation (offspring), however, the cell with the mutation will transmit the change to all of its descendant cells.
Somatic variants are often caused by environmental factors, such as exposure to ultraviolet radiation or certain chemicals, and can lead to a lot of diseases, mainly found in cancer.
Mutations can be divided into two main categories
- Chromosomal alterations: affecting the number or structure of the cell’s chromosomes;
- Gene alterations: mutations that occur in the DNA sequence.
NOTE: The human genome consists of 46 chromosomes: 2 sets of 22 autosomal homologous chromosomes and 2 sex chromosomes, X and Y. Half of the chromosomes are inherited from the mother and the other half from the father. Chromosomes have two segments, called “arms”, separated by a compressed region known as a centromere. The shortest arm is called the “p” arm. The longest arm is called the “q” arm.
There are several types of chromosomal mutations, in general, we can organize them into two basic groups: numerical and structural alterations.
Numerical chromosomal mutations are alterations that affect the number of whole chromosomes (euploidies), increasing (polyploidy) or decreasing (haploidy or monoploidy) their total set, or they can change the number of specific isolated chromosomes (aneuploidies) (eg, trisomy of the chromosome 21, known as Down Syndrome).
Structural chromosomal mutations are changes that involve the structure (shape or size) of a chromosome.
- Inversion: a part of the chromosome broke, turned upside down and joined again.
- Translocation: a portion of a chromosome is transferred to another chromosome. There are two main types of translocation:
- Reciprocal translocation: segments of two different chromosomes were exchanged.
- Robertsonian translocation: two whole chromosomes are joined by the centromere.
- Deletion: a part of the chromosome has been lost.
- Duplication: a part of the chromosome was folded, resulting in extra material.
- Ring chromosome: the ends of a chromosome fuse to form a circular or ring-shaped chromosome. This can happen with or without loss of genetic material.
- Isochromosome: one arm of a chromosome is missing and the remaining arm is duplicated.
If the chromosome set is complete, even if reorganized in the wrong way, the change is called balanced. If there are additional or missing parts it is called unbalanced.
Gene mutations are changes in the DNA sequence that can involve from a single nucleotide to a few base pairs. The genetic alterations can be of the type:
Point mutations or single nucleotide substitutions: replacement of a base pair of DNA.
- Missense/meaning exchange mutations/not synonymous: alteration in a base pair of DNA that results in the substitution of one amino acid for another in the protein produced by a gene.
- Synonymous or silent: change in a base pair of DNA that changes the codon to another that encodes the same amino acid and does not cause changes in the protein produced.
- Nonsense/meaningless mutations: change in a base pair of DNA that prematurely signals the end of a protein. This type of mutation results in a reduced protein that may work improperly or not at all.
Nucleotide insertions or deletions (indels):
- Insertion: addition of one or more nucleotides to the DNA sequence.
- Deletion: removal of one or more nucleotides from the DNA sequence.
- Duplication: A duplication consists of a piece of DNA that is copied abnormally one or more times.
Reading frame change/frameshift mutation: This type of mutation occurs when the addition or removal of DNA bases alters the reading structure of a gene. A reading frame consists of groups of 3 bases (codon) that code for an amino acid.
A frame-changing mutation alters the grouping of these bases and changes the amino acid code. The resulting protein is generally non-functional. Insertions, deletions and duplications can be frameshift mutations.