A mutation ( Latin: mutare "change / change, transform") is a spontaneously occurring, permanent change in the genetic make-up in biology . The change initially affects the genome of only one cell , but is passed on to its daughter cells. In multicellular animals, a distinction is made between germline mutations, which can be passed on to the offspring through inheritance , and mutations in somatic cells , which are not present in the germ cells ( gametes ) but only in the other tissues of the body. An organism with a new trait created by mutation is called a mutant or mutant .
A mutation may or may not affect the characteristics of an organism ( silent mutation ). Deviating characteristics can have negative, positive or even no consequences with regard to viability and / or reproductive capacity. If a mutation manifests itself as a clearly different phenotype , which remains stable to a certain extent (over 1%) in a population , it is also referred to as polymorphism in biology . Polymorphism is an essential prerequisite for the emergence of new species ( biodiversity ).
Sometimes the unexpected phenotypic occurrence of very rare recessive hereditary factors, which were inherited from inconspicuous mixed hereditary ( heterozygous ) ancestors (as conductors ) to the common offspring, is mistaken for a mutation.
Real mutations can occur spontaneously or can be caused by external influences, such as mutagenic radiation or chemicals that change genes ( mutagens ).
In classical cytogenetics , mutations are classified according to their extent: Genome mutations are changes in the number of chromosomes , chromosome mutations are changes in the chromosome structure that can be recognized by light microscopy in chromosome preparations . On the other hand, gene mutations cannot be detected microscopically in such preparations and can only be determined by DNA analysis . A gene mutation can mean that new nucleotide sequences are created or that previously existing genetic information is lost, or both.
The term mutation was coined by the botanist Hugo de Vries in 1901.
Types of mutation
Differentiation according to heredity
- Germline mutations
- are mutations to offspring via the germ line inherited are; they affect egg cells or sperm and their precursors before and during oogenesis or spermatogenesis . These mutations play an important role in evolution because they can be transmitted from one generation to the next. Germline mutations usually have no direct impact on the organism in which they occur.
- Somatic mutations
- are mutations that affect somatic cells . They have an impact on the organism in which they take place, but are not passed on to offspring. Among other things, normal body cells can transform themselves into unchecked, proliferating cancer cells . Somatic mutations also play a role in the aging of an organism. They are therefore important for medicine.
Differentiation by cause
- Spontaneous mutations
- are mutations without a particular external cause, such as the chemical breakdown of a nucleotide (e.g. uracil can arise from cytosine through spontaneous deamination ) or the tunnel effect ( proton tunneling in DNA ).
- Induced Mutations
- are mutations produced by mutagens (substances that cause mutations or rays).
Differentiation by mechanism
- Errors in the replication
- According to the template, DNA polymerases build a complementary DNA strand with different error rates.
- Insufficient proof-reading activity
- Some DNA polymerases have the ability to independently recognize and correct incorrect installations ( English proof-reading , proofreading). However, z. B. the DNA polymerase α of the eukaryotes no proof-reading activity.
- Errors in pre- and post-replicative repair mechanisms
- If an unusual nucleotide, such as uracil, is found in DNA, it is removed. If there is a mismatch between two DNA-typical nucleotides, the repair enzyme makes a decision with a 50 percent probability of error .
- Uneven crossing-over
- Mismatches in meiosis can occur due to neighboring similar or identical sequences on the strand, such as satellite DNA or transposons .
- The incorrect segregation or non-disjunction (English disjunction , separation ') of chromosomes leads to incorrect distribution to the daughter cells and thus to trisomies and monosomies .
- Integration or jumping out of transposons or retroviruses
- These elements can be integrated into genes or gene regulatory areas.
Differentiation according to size and place of change
- Gene mutation
- a hereditary change that affects only one gene. Examples are dot and grid mutations . With the point mutation, only one organic base is changed (mutated) in the genetic code. A frameshift mutation, i.e. an insertion (insertion) or deletion (removal) of a number of bases that is not a multiple of three, changes the entire structure of a gene due to the triplet coding in the genetic code and therefore usually has far greater effects. Another possible consequence is alternative splicing . The gene mutations also include deletions of longer sequences as well as gene duplications in which a certain section of a chromosome doubles or multiplies.
- Chromosomal mutation or structural chromosomal aberrations
- heritable change in the structure of individual chromosomes. The structure of a chromosome that is visible in the light microscope has changed. Chromosome pieces can be lost or parts of another chromosome can be incorporated. An example is cat cry syndrome , in which a section of chromosome 5 has been lost. As a result, numerous genes are missing that lead to a strong change and damage in the phenotype.
- Genome mutation or numerical chromosomal aberration
- a change in which entire chromosomes or even sets of chromosomes are increased ( aneuploidy , polyploidy ) or are lost. A well-known example in humans is Down's syndrome . Here is the chromosome 21 present in triplicate.
Differentiation according to consequences for the protein
- Drinking mutations
- Mutations of a genome segment coding for a protein , resulting in a shortened gene product (protein).
- Gain-of-function mutations (GOF)
- Here the gene product (protein) gains activity and is then also referred to as hypermorphic . If the mutation creates a completely new phenotype , the allele is also called neomorphic. A gain-of-function mutation that produces a visible phenotype is called 'dominant'. If a gain-of-function allele shows a phenotype exclusively in the homozygous state, however, one speaks of a recessive gain-of-function mutation.
- Loss-of-function mutations (LOF)
- The gene product (protein) is rendered inoperable by a mutation in the gene. If the loss of function is complete, one speaks of a null allele or an amorphous allele . If part of the wild-type function is retained, it is referred to as a hypomorphic allele.
Loss-of-function mutations are codominant or (mostly) recessive when another allele can compensate for the loss of function of a gene.
- Haploinsufficient mutations
- Loss-of-function mutations in a gene that does not tolerate haploinsufficiency, i.e. H. in which a halving of the expressed gene dose ( mRNA ) is already sufficient to cause an altered phenotype. (This only applies to diploid organisms with a heterozygous (monoallelic) genotype of the mutation).
- Dominant negative mutations
- As with loss-of-function mutations, the mutation causes the gene product to lose its function. However, the mutated protein is also able to suppress the function of the remaining second (wild-type) allele, which a mere loss-of-function allele usually does not or cannot. Many truncating mutations are dominant negative. (This only applies to diploid organisms with a heterozygous (monoallelic) genotype of the mutation).
Differentiation according to consequences for the organism
- Neutral mutations
- can change the phenotype, but have no fitness consequences .
- Silent mutations
- are mutations in which the protein produced remains unchanged. Nevertheless, changes in the organism can occur because the mRNA folds when it leaves the cell nucleus. Different folding can influence the amount of protein produced.
- Conditional lethal mutations
- Mutations, the modification of which in the gene product only kills an organism under certain growth conditions.
- Lethal mutations
- Mutations that after their occurrence kill an organism in any case, regardless of its respective phase of life.
Frequency of mutations
In humans, the number of new mutations ( de novo mutations) has been determined by sequencing the DNA of the father, mother and the corresponding child. An average of 45 new mutations were found, with around 80% of the mutations originating from the father's sperm. Since sperm formation ( spermatogenesis ) is continuous in men and thus the number of replications of DNA increases with age, it is not surprising that the number of new mutations increases with the age of the father. A young father of 20 contributes 20 mutations while an older father of 40 contributes 40 mutations. Although the woman's egg cells are all formed in the embryonic development before birth, and therefore no further replication of the DNA takes place, an increase in new mutations from 7 to 12 could be observed in women aged 40 compared to women aged 20. Obviously, the new mutations do not only occur during the replication of the DNA.
The high frequency of mutations is shown in a sequence analysis of the protein-coding DNA of humans in 60,706 people. The study reveals 7.4 million variants, which on average corresponds to a mutation in every 8th base pair of human DNA.
No consequences - neutral mutations
Many mutations lead to changes in DNA sections that have no consequences for the organism. This is the case when the mutated site in the genome is not used for genetically relevant information (see pseudogene , non-coding DNA ). Even if the changed position is used, the information content of the gene may not have changed because a number of amino acids are coded identically (see genetic code ). Therefore, these mutations are silent or silent mutations called. Even mutations that change the amino acid sequence of a protein can be neutral or almost neutral if this hardly changes the structure of the protein.
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, called polymorphisms , can be used to derive relationships between individuals or to estimate an average mutation rate.
In addition, it is also important that several genes code the same genetic properties, and not just in the diploid set of chromosomes , so that a mutation does not have to be immediately noticeable for this reason.
The neutral theory of molecular evolution holds that most genetic changes are neutral in nature. This hypothesis is controversial and the subject of current research.
There are various hereditary diseases that are either inherited or can appear as a result of mutations. Examples are:
- Sickle cell anemia : In this blood disease , the outer shape of the red blood cells is changed and the absorption of oxygen is reduced
- Phenylketonuria : impaired breakdown of the amino acid phenylalanine , which can damage the child's brain
- Cystic fibrosis ( cystic fibrosis ): the most common genetic disease in Northern Europe . The CFTR gene, which controls the consistency of the glandular secretions , is defective. If the secretion is too thick, it can (depending on the gland ) block the airways or the ducts of the glands.
- Forms of short stature in which the arms and legs are unusually short, while the body is otherwise built as usual
- Red Green weakness
- Hemophilia : impaired blood clotting
Mutations are one of the evolutionary factors and therefore jointly responsible for the development of life and the diversity of species on earth . Mutations with positive consequences are much less likely to occur than those with a neutral or negative effect. But when a positive mutation occurs, natural selection can help it spread through a population. For example, the consequences of malaria in heterozygous carriers of sickle cell anemia are less serious. This mutation is therefore more common in areas affected by malaria.
Humans make use of the genome-changing effect of ionizing radiation to artificially trigger mutations. One application is the irradiation of flower and plant seeds in order to create previously unknown shapes and to use them economically. The procedure usually has a very low success rate due to the widespread, extensive and untargeted change in the genetic material.
- Manx cats were created through gene mutation as a result of extreme inbreeding . In addition to the taillessness, there are skeletal malformations and other malformations. Manx cats are never purebred in this mutated gene M, so they have the combination Mm, i. That is, there is an autosomal imperfectly dominant inheritance with variable expressivity (expression). In animals with the hereditary gene combination MM, the fetuses die in the womb.
- The Sphynx cat has no fur. This breed has been bred by humans since 1966 from a naturally mutated cat born in Canada.
- Nude mice , also called thymus aplastic mice or athymic mice, are genetic mutants of the house mouse with a missing thymus . They were created in Glasgow in 1961 as a result of a spontaneous mutation in albino mice and are an extremely important model organism for research .
- Mutations make great advances possible in plant breeding. High-yielding cereals were grown from grasses with small seeds. Without plant breeding and mutations, it would not be possible to feed the world's population.
- When Escherichia coli - long-term experiment (1988-2008) of Lenski bacteria were kept under constant conditions and the changes occurring in the genome regularly documented. The only sources of carbon in the glass vessel were glucose and citrate . E. coli uses glucose as a natural source of nutrition; The wild type of E. coli cannot metabolize citrate as a carbon source . In 2003 E. coli mutants suddenly appeared who can also metabolize citrate.
- Lactose tolerance in humans: Most humans, like all mammals, are genetically determined to be lactose intolerant in adulthood, so they can only digest lactose-containing food poorly or not at all. According to geneticists, a mutation occurred in a person in the Caucasian region around 8,000 to 10,000 years ago that extended the natural lactose tolerance of the infant and child beyond breastfeeding to the entire life span. Thus, none of the offspring of this person show any adverse health effects during their lifetime when consuming milk or milk sugar. On the other hand, such foods are not tolerated by adult Asians or Africans who are not affected by this mutation (see lactose intolerance ).
- Human brain development : The microcephalin and ASPM genes control the growth of the brain in humans. Researchers led by Bruce Lahn from the Howard Hughes Medical Institute at the University of Chicago (USA) have found that two mutations have proven to be beneficial in recent human tribal history. The haplogroup D as a result of a mutation of microcephalin originated in the human genome 37,000 years ago and spread around the same time as the oldest finds that testify to man's preoccupation with art, music and religion. This mutation is found in around 70% of all people today. In another mutation, haplogroup D of the ASPM arose around 5,800 years ago, around the same time as the first civilization in Mesopotamia , from which the oldest written finds in human history come. This second mutation has prevailed in 30% of the world's population to date. There are also regional differences. Haplogroup D of the ASPM gene occurs particularly in Europe and the bordering areas of Asia and Africa. The parallelism of the events described is interpreted by the scientists to the effect that both mutations must offer an evolutionary advantage.
- Disease risk in breast cancer : In the summer of 2006, researchers have to Naznee Rahman from the British Institute of cancer research in Surrey a new breast cancer gene called BRIP 1 identified . This gene codes for a protein that is involved in repairing DNA damage. A rare mutation of this gene that was discovered at the same time means that the BRIP-1 protein can no longer perform this protective function. If this mutation is present, women are twice as likely to have breast cancer as others with a normal version of this genetic makeup. Mutations of the long-known genes BRCA1 and BRCA2 , on the other hand, increase the risk of disease by a factor of 10 to 20.
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