Genetic Alterations: Chromosomal Anomalies, Mutations and Polymorphisms

It is considered a genetic alteration to any mutation or permanent change in the phenotypic and genotypic structures of an organism.

The genetic alterations include chromosomal abnormalities and genetic mutations. Chromosomal abnormalities generally arise during cell division.

They can be numerical, involving the amount of chromosomes, or structural, that involve the atypical configuration of one or more chromosomes.

Many different chromosomal abnormalities have been identified, some of which are associated with genetic disorders and diseases such as cancer.

Genetic mutations are permanent changes in the sequence of the DNA gene. They may arise during normal DNA replication or in response to environmental factors. There are many kinds of genetic mutations. Certain mutations cause diseases.

Chromosomal abnormalities

Each human has 46 chromosomes (23 pairs). If a human does not have 46 chromosomes, a chromosomal abnormality has occurred. A general term for a chromosome gain or loss is aneuploidy.

Chromosomal abnormalities often occur during cell division (meiosis and mitosis). There are two main groups of chromosomal abnormalities: numerical and structural.

Numerical anomalies, as the name implies, involve the number of chromosomes. Monosomy occurs when one of the two chromosomes is missing. An example of a monosomy disorder is Turner syndrome, in which part or all of a woman’s second X chromosome is missing.

Trisomy occurs in individuals with an additional chromosome. For example, those with Down syndrome have three copies of chromosome 21 instead of two copies.

In addition to chromosomal losses or gains, chromosomes can simply be altered, which is known as a structural abnormality. Many structural abnormalities exist.

A translocation occurs when a piece of a chromosome breaks and joins another chromosome. Eliminations occur when a part of the chromosome breaks down and the genetic material is lost or eliminated.

A duplication occurs when a part of a chromosome is copied and there is additional genetic material present. When a chromosome has been broken, rotated and reassembled, an inversion has occurred.

A pericentric inversion occurs in the centromere, and a paracentric inversion occurs in the P or Q arms.

Isochromosomes are another type of structural abnormality in which the chromosome has two identical arms (for example, two P arms). A dicentric chromosome is a chromosome with two centromeres.


A genetic mutation is a permanent change in the DNA sequence of a gene. Mutations can occur in a single base pair or in a large segment of a chromosome and can even span multiple genes.

Mutations can be the result of endogenous factors (which occur during DNA replication) or exogenous (environmental) factors.

There are two main categories of mutations:

  • Germinal.
  • Somatic.

Germline mutations (hereditary) : Mutations in the germ line are inherited from a parent (ie, the mutation was present in the ovum or sperm cells of the parent).

A person with a germline mutation will have the mutation in every cell of the body. Mutations in the germ line are the cause of some diseases, such as cystic fibrosis and cancer (eg, breast and ovarian cancer, melanoma).

Cystic fibrosis is an inherited genetic disorder that produces a thick, sticky accumulation of mucus in the lungs, pancreas, and other organs.

Cystic fibrosis is the most common genetic disease and arises from a mutation in a single gene called the transmembrane regulatory gene of cystic fibrosis (CFTR). The location of this gene is in the long arm (Q) of chromosome 7.

Some forms of breast cancer can be inherited. Two genes are associated with hereditary breast cancer, BRCA1 and BRCA2. The BRCA1 gene is on chromosome 17 and the BRCA2 gene is located on chromosome 13.

Carriers of the mutated BRCA1 and BRCA1 genes have an increased risk of breast and ovarian cancer.

In approximately 10% of patients with melanoma, hereditary mutations may play a role. On chromosome 9, the CDK2N gene instructs the development of proteins.

The proteins made by CDK2N include p16 and p14. These proteins prevent cells from growing out of control and are called tumor suppressors.

Some studies have also indicated that genes on chromosomes 1 and 2 may play a role in hereditary melanoma.

Somatic mutations (acquired): Somatic mutations can occur at any time in a person’s life. These mutations are often caused by environmental or lifestyle factors and may also be the result of errors during cell division.

This type of mutation is not transmitted from parents to children and, therefore, is not present in all the cells of the body.

Although several types of hereditary cancers can be linked to germline mutations in genes that alter the gene’s original function (eg, tumor suppression), most cancers arise from somatic mutations.

Somatic mutations arise after conception and can affect any of the cells in the body, with the exception of germ cells. Approximately 10% of cancers show both germline and somatic mutations.

Alterations in genes, whether they occur in a germ line or somatic, change the function of the gene, which may contribute to the development or spread of cancer.

Types of mutations

  • Missense : Change in a codon that results in the substitution of an amino acid in the protein made by a gene. It may or may not have a detrimental effect.
  • Nonsense : Change in a pair of DNA bases in which the altered DNA sequence tells the cell to stop forming a protein. The protein generally lacks function or is impeded.
  • Insertion: The addition of DNA produces a change in the number of DNA bases in a gene. It can have a detrimental effect and cause diseases.
  • Suppression: Eliminate DNA that produces a change in the number of DNA bases; deletions can occur in one or more base pairs or can eliminate a complete gene. It can have a detrimental effect and cause diseases.
  • Duplication: DNA is abnormally copied at least once. The function of the protein may be altered.
  • Change: A deletion or insertion of DNA that alters the way in which the DNA sequence is read during translation. Resulting protein typically non-functional.
  • Repetition: Occurs when a short nucleotide sequence is repeated (three or four base pairs). The resulting protein function is altered.

Single nucleotide polymorphisms

A single nucleotide polymorphism (SNP) is a difference in a single base pair, or nucleotide, in a section of DNA. SNPs result in genetic variation in humans.

SNPs can occur with a gene or close to a gene, but are more commonly found in DNA between genes. To be designated as a SNP, the change in the base pair must be found in at least 1% of the population.

SNPs are common and normal variations in DNA and are responsible for many of the normal differences between people, such as eye color, hair color and blood type.

Many SNPs do not have negative effects on a person’s health, but some variations may influence the risk of developing certain health problems, such as diabetes, heart disease or cancer.

On average, SNPs occur once in every 300 base pairs of nucleotides, which means that the human genome has approximately 10 million SNPs.