Mutation

A mutation is a permanent change in the genetic material that is transferred to the daughter cell. A mutation can occur spontaneously or be caused by external influences (e.g. chemical products). Its consequences may be negative (e.g. tumor processing, see oncogene; protooncogenes), positive or have no effect (so-called silent or mute mutation) on the phenotype. Mutations can arise in the germline (germline mutations). They can then be transmitted to the offspring. Mutations in somatic cells are not inherited (somatic mutation). However, they play a role in the development of tumors. Mutations during embryogenesis lead to mosaic states.

A distinction is made between 3 types of mutation according to their extent:

• Genomic mutations: Genomic mutations (genomic mutations) result in changes in the number of chromosomes. One or more chromosomes may be missing or present in excess (aneuploidy). If 3 chromosomes are present instead of 2, this condition is called trisomy. They are only compatible with life if chromosomes with little genetic information are affected, such as chromosomes 21, 13, 18.
• Chromosomal mutations: Changes in the chromosome structure, such mutations can already be seen under the light microscope in chromosome preparations.
• Gene mutations: Mutation in the gene itself = point mutations. This change takes place in the early phase of embryogenesis or in the gametes themselves.
• Reverse mutations: these have been described in numerous diseases. The altered gene reverts to the wild type postzygotic or even in adulthood.

A further distinction is made between:

• Spontaneous mutations (here no external causes are known - e.g. the chemical decay of a nucleotide - cytosine spontaneously deaminates oxidatively to uracil).
• Induced mutations (mutagens are chemical substances or radiation).

A distinction is made according to their mechanism:

• Replication errors (DNA polymerases have different error rates).
• Insufficient proof-reading activity = possibility of proofreading (DNA polymerases have the ability to recognize and correct errors independently).
• Errors in pre- and post-replicative repair mechanisms
• Uneven crossing-over (mismatches in meiosis due to similar or identical sequences on a strand, such as satellite DNA or transposons.
• Non-disjunction (incorrect distribution of chromosomes and thus trisomies and monosomies).

Consequences of mutations

• No consequences:
  • Neutral mutations: lead to changes in DNA segments, but have no consequences for the organism. This is the case, for example, if the mutated site in the genome is not used for genetically relevant information (non-coding DNA). These mutations are therefore also called silent mutations. Neutral mutations contribute to the fact that functionally identical genes within a group of organisms have different genetic "letters" within their nucleotide sequence. These differences are known as polymorphisms.
• Negative consequences
  • Loss-of-function mutations (LOF): Here the gene product becomes non-functional due to a mutation in the gene.
  • Gain-of-function mutations (GOF): In this case, a gene or the gene product gains activity and is then also referred to as hypermorphic. Examples of GOF mutations can be found in autoinflammatory diseases.
  • Oncogenic mutation: If mutations lead to changes in gene sequences that play a role in normal cell growth, cell division and cell differentiation, this leads to the formation of oncogenes (see also MYC gene).

The causes of mutations are multifactorial and can be caused by chemical products as well as by high-energy radiation (e.g. UV rays, gamma rays, X-rays = mutagens). Such radiation is absorbed by the nucleotides and causes a structural change in the DNA. Increasing age also increases the probability of mutations.