Spontaneous mutations, mechanisms of their occurrence. Induced mutations Spontaneous mutations examples
Spontaneous mutation
Mutations.
Viruses, like all living organisms, are characterized by heredity and variability. Early research into the genetics of animal viruses primarily involved the collection and subsequent genetic and physiological characterization of viral mutants. Recently, viral mutants have been used as specific tools for studying the genetic and biochemical events occurring in an infected cell. Work of this kind with animal viruses has generally lagged behind similar work on prokaryotic systems.
Some viruses produce a significant proportion of mutants when passaged in the absence of any known mutagens. These spontaneous mutations accumulate in viral genomes and lead to phenotypic variation that is subject to selective pressure during viral evolution.
The rate of spontaneous mutagenesis in DNA genomes is significantly lower (10 -8 - 10 -11 for each included nucleotide) than in RNA genomes (10 -3 - 10 -4 for each included nucleotide). A higher frequency of spontaneous mutations is associated with low fidelity of replication of RNA genomes, which is likely due to the lack of corrective activity in RNA replicases, characteristic of enzymes that replicate DNA. Most often, spontaneous mutations are observed in retroviruses, which is associated with a higher frequency of failures in reverse transcription that are not capable of self-correction.
Thus, while the genomes of DNA viruses are relatively stable, the same cannot be said for RNA viruses. Unfortunately for geneticists, a number of factors stimulate disequilibrium in the population of genomes, and these factors often contribute to the accumulation of mutants in the population. Due to spontaneous mutagenesis, it is difficult to maintain homogeneity of the virus population. To circumvent this difficulty, viruses are periodically recloned, but mutants often arise both during plaque formation and during virus growth, so it can be difficult to obtain genetically homogeneous high-titer virus preparations.
Induced mutations in viruses are obtained through the action of various chemical and physical mutagens, which are divided into those acting in vivo and in vitro.
Most of the mutants isolated in animal virus research are derived from wild-type populations treated with mutagens. Mutagens are usually used to increase the frequency of mutations in a population, after which the mutants are screened using suitable selective pressure. The main problem associated with the use of mutagens is the selection of an appropriate dose. In general, it is desirable to obtain mutants that differ from the wild type by only one mutation. To do this, selection is carried out at the lowest dose of mutagen that gives a sufficient frequency of mutations with the desired phenotype.
Many different mutagens have been used in animal virus systems, but they all fall into a small number of classes defined by the mechanism of mutagenesis.
One class of mutagens, usually called in vitro mutagens, act by chemically modifying the nucleic acid contained in the viral particle. Nitrous acid deaminates bases, primarily adenine, to form hypoxanthine, which pairs with cytosine during subsequent replication. As a result of the action of nitrous acid on adenine, a transition occurs from the AT pair to the GC pair. Nitrous acid also deaminates cytosine, leading to the CG->-TA transition. Another in vitro mutagen is hydroxylamine; it reacts specifically only with cytosine and causes the CG->-TA transition. A large class of mutagens in vitro is represented by alkylating agents that act at many positions in bases. Alkylating agents - nitrosoguanidine, ethanemethane sulfonate and methylmethane sulfonate - are powerful mutagens.
The second class includes in vivo mutagens that require a metabolically active nucleic acid for their action.
One group of in vivo mutagens contains base analogues that are incorporated into the nucleic acid during synthesis according to the rules of normal pairing. Once switched on, these analogues are able to undergo tautomeric transitions that lead them to pair with different bases, thus causing transitions and transversions. Analogs that are often used are 2-aminopurine, 5-bromodeoxyuridine and 5-azacytidine.
Another group of in vivo mutagens includes intercalating agents, which insert into a base stack that results in insertions or deletions during subsequent nucleic acid replication.
Examples of intercalating agents are acridine dyes such as proflavine.
Ultraviolet light is also sometimes used as a mutagen. The main products of ultraviolet action are pyrimidine dimers. In DNA, pyrimidine dimers are excised. For RNA, the mechanism of ultraviolet mutagenesis is unknown.
Most mutations have the property of returning (reversion) to the wild type. Each mutation has a characteristic reversion frequency that can be accurately measured.
Classification of viral mutations.
Viral mutations are classified according to changes in phenotype and genotype. Based on phenotypic manifestations, viral mutations are divided into four groups:
· Mutations that do not have phenotypic manifestations.
· Lethal mutations, i.e. completely disrupting the synthesis or function of vital proteins and leading to loss of reproductive ability. A mutation is lethal if, for example, it disrupts the synthesis or function of a vital virus-specific protein, such as viral polymerase.
· Conditionally lethal mutations, i.e. mutations that cause loss of the ability to synthesize a specific protein or impair its function only under certain conditions. In some cases, mutations are conditionally lethal, since the virus-specific protein retains its functions under certain optimal conditions and loses this ability under nonpermissive conditions. A typical example of such mutations are temperature sensitive (ts) mutations, in which the virus loses the ability to reproduce at elevated temperatures (39-42 ° C), retaining this ability at normal growing temperatures (36-37 ° C).
· Mutations that have a phenotypic manifestation, for example, changes in the size of plaques under an agar coating or thermostability, changes in the host spectrum, resistance to inhibitors and chemotherapy.
For the first time, an increase in the frequency of hereditary variability under the influence of external agents was discovered in 1925 by Soviet microbiologists G.A. Nadson and G.S. Filippov. They observed an increase in the diversity of hereditary forms - salypants- after exposure to “radium rays” on lower fungi.
In 1927, G. Möller reported on the effect of X-rays on the mutation process in Drosophila. Some compounds (iodine, acetic acid, ammonia) are capable of inducing recessive lethals in the L chromosome. In 1939, S.M. Gershenzon discovered the strong mutagenic effect of exogenous DNA in Drosophila. Powerful chemical mutagens were discovered in 1946. I.A. Rapoport (ethylenimine) in the USSR and S. Auerbach and J. Robson (nitrogen mustard) in England.
Since then, the arsenal of mutagenic factors has included a variety of chemical compounds: analogues of bases that are incorporated directly into DNA, agents such as nitrous acid or hydroxylamine, modifying bases, compounds that alkylate DNA (ethyl methanesulfonate, methyl methanesulfonate, etc.), compounds that intercalate between DNA bases (acridines and their derivatives), etc.
Along with mutagens, antimutagen substances were found.
The ability to change the rate of the mutation process served as a decisive incentive to elucidate the causes of spontaneous mutations. One of the first attempts to explain the causes of spontaneous mutations came down to the assumption that they were actually induced by a natural background of radioactivity. However, it turned out that this way can explain the occurrence of only about 0.1% of all spontaneous mutations in Drosophila. The hypothesis about the thermal movement of atoms as the main cause of spontaneous mutations was also not confirmed. There have been attempts to explain spontaneous mutations as a result of the action of metabolic products of the cell and organism.
The modern point of view on the causes of spontaneous mutations was formed in the 1960s. thanks to the study of the mechanisms of reproduction, repair and recombination of genes and the discovery of enzyme systems responsible for these processes. There has been a tendency to explain gene mutations as errors in the functioning of DNA template enzymes. This hypothesis is now generally accepted. The attractiveness of the hypothesis also lies in the fact that it allows us to consider the induced mutation process as a result of the intervention of external factors in the normal reproduction of carriers of genetic information, i.e. it provides a unified explanation of the causes of spontaneous and induced mutations. The development of the theory of the mutation process was greatly influenced by the study of its genetic control. Genes have been discovered whose mutations can increase or decrease the frequency of both spontaneous and induced mutations. Thus, the existence of common causes of induced and spontaneous mutation processes is confirmed.
The first explanation of the mechanism of mutational changes (gene mutations and chromosomal aberrations) was proposed in 1935 by N.V. Timofeev-Resovsky, K. Zimmer and M. Delbrück based on an analysis of radiation mutagenesis in higher organisms, primarily in Drosophila. Mutation was considered as the result of an instantaneous rearrangement of atoms in a complex gene molecule. The reason for such a restructuring was considered to be the direct entry of a quantum or ionizing particle into the gene (the principle of entry) or random vibrations of atoms. The subsequent discovery of the effect of the consequences of ionizing radiation showed that mutations arise as a result of a process that lasts over time, and not directly at the moment of passage of an energy quantum or ionizing particle through a gene.
Spontaneous- These are mutations that occur spontaneously, without intervention from the experimenter.
Induced– these are those mutations that are caused artificially, using various factors mutagenesis.
In general, the process of mutation formation is called mutagenesis, and the factors causing mutations are mutagens.
Mutagenic factors are divided into physical,chemical And biological.
Spontaneous mutation rate makes up one gene, for each gene of each organism it is different.
Causes of spontaneous mutations not entirely clear. Previously they were thought to be caused by natural background of ionizing radiation. However, it turned out that this was not the case. For example, in Drosophila, the natural background radiation causes no more than 0.1% of spontaneous mutations.
WITH age consequences from exposure to natural background radiation can accumulate, and in humans, 10 to 25% of spontaneous mutations are due to this.
Second reason spontaneous mutations are accidental damage to chromosomes and genes during cell division and DNA replication due to random errors in the functioning of molecular mechanisms.
The third reason spontaneous mutations are moving by genome mobile elements, which can invade any gene and cause a mutation in it.
American geneticist M. Green showed that about 80% of mutations that were discovered as spontaneous arose as a result of the movement of mobile elements.
Induced mutations first discovered in 1925. G.A. Nadson And G.S. Filippov in USSR. They irradiated mold cultures with X-rays. Mucorgenevensis and received a splitting of culture “into two forms or races, differing not only from each other, but also from the original (normal) form.” The mutants turned out to be stable, since after eight successive subcultures they retained their acquired properties. Their article was published only in Russian, and the work did not use any methods for quantitatively assessing the effect of X-rays, so it remained little noticed.
IN 1927 G. G. Möller reported the effect of X-rays on the mutation process in Drosophila and proposed quantitative method accounting for recessive lethal mutations on the X chromosome ( ClB), which has become a classic.
In 1946, Möller was awarded the Nobel Prize for the discovery of radiation mutagenesis. It has now been established that practically all types of radiation(including ionizing radiation of all types - , , ; UV rays, infrared rays) cause mutations. They are called physical mutagens.
Basicmechanisms their actions:
1) disruption of the structure of genes and chromosomes due to direct action on DNA and protein molecules;
2) education free radicals, which enter into chemical interaction with DNA;
3) thread breaks spindles;
4) education dimers(thymine).
In the 30s was opened chemical mutagenesis in Drosophila: V.V. Sakharov (1932 ), M. E. Lobashev And F. A. Smirnov (1934 ) showed that some compounds, such as iodine, acetic acid, ammonia, are capable of inducing recessive lethal mutations on the X chromosome.
IN 1939 G. Sergei Mikhailovich Gershenzon(student of S.S. Chetverikov) discovered a strong mutagenic effect of exogenous DNA in Drosophila. Under the influence of the ideas of N.K. Koltsov that the chromosome is a giant molecule, S.M. Gershenzon decided to test his assumption that DNA is such a molecule. He isolated DNA from the thymus and added it to the food of Drosophila larvae. Among 15 thousand control flies (i.e., without DNA in the food) there was not a single mutation, and in the experiment, 13 mutants were found among 13 thousand flies.
IN 1941 Charlotte Auerbach And J. Robson showed that nitrogen mustard induces mutations in Drosophila. The results of work with this chemical warfare agent were published only in 1946, after the end of World War II. In the same 1946 G. Rapoport(Joseph Abramovich) in the USSR showed mutagenic activity formaldehyde.
Currently to chemical mutagens include:
A) natural organic and inorganic substances;
b) industrial products processing of natural compounds– coal, oil;
V) synthetic substances, previously not found in nature (pesticides, insecticides, etc.);
d) some metabolites human and animal bodies.
Chemical mutagens cause mainly genetic mutations and act during DNA replication.
Mechanisms of their action:
1) modification of the base structure (hydroxylation, deamination, alkylation);
2) replacement of nitrogenous bases with their analogues;
3) inhibition of the synthesis of nucleic acid precursors.
In recent years, so-called supermutagens:
1)base analogues;
2) connections, DNA alkylating(ethyl methanesulfonate, methyl methanesulfonate, etc.);
3) connections, intercalating between DNA bases (acridines and their derivatives).
Supermutagens increase the frequency of mutations by 2-3 orders of magnitude.
TO biological mutagens relate:
A) viruses(rubella, measles, etc.);
b) non-viral infectious agents(bacteria, rickettsia, protozoa, helminths);
V) mobile geneticelements.
Mechanisms of their action:
1) the genomes of viruses and mobile elements are integrated into the DNA of the host cells;
Induced mutagenesis , starting from the late 20s of the 20th century, have been used for the selection of new strains, breeds and varieties. The greatest success has been achieved in the selection of strains of bacteria and fungi that produce antibiotics and other biologically active substances.
So, we managed to increase activity antibiotic producers by 10-20 times, which made it possible to significantly increase the production of appropriate antibiotics and sharply reduce their cost. Activity of the radiant mushroom - vitamin B producer 12 managed to increase 6 times, and the activity of the bacteria - producer amino acids lysine- 300-400 times.
Using Mutations dwarfism in wheat allowed in the 60-70s to sharply increase the yield of grain crops, which was called “ green revolution" Dwarf wheat varieties have a shortened thick stem that is resistant to lodging; it can withstand increased load from a larger ear. The use of these varieties has made it possible to significantly increase yields (several times in some countries).
An American breeder and geneticist is considered the author of the “green revolution” N. Borlauga, who in 1944, at the age of 30, settled and began working in Mexico. For his success in breeding highly productive plant varieties, he was awarded the Nobel Peace Prize in 1970.
What mutations are called spontaneous? If we translate the term into accessible language, then these are natural errors that arise during the interaction of genetic material with the internal and/or external environment. Such mutations are usually random. They are observed in the reproductive and other cells of the body.
Exogenous causes of mutations
Spontaneous mutation can occur under the influence of chemicals, radiation, high or low temperatures, rarefied air or high pressure. Every year, on average, a person absorbs about one tenth of a rad of ionizing radiation, which constitutes the natural background radiation. This number includes gamma radiation from the Earth’s core, the solar wind, and the radioactivity of elements located deep in the earth’s crust and dissolved in the atmosphere. The dose received also depends on where exactly the person is located. A quarter of all spontaneous mutations occur precisely due to this factor.
Ultraviolet radiation, contrary to popular belief, plays a minor role in causing DNA damage, since it cannot penetrate deep into the human body. But the skin often suffers from excessive sun exposure (melanoma and other types of cancer). However, single-celled organisms and viruses mutate when exposed to sunlight. Too high or low temperatures can also cause changes in genetic material.
Endogenous causes of mutations
The main reasons for which a spontaneous mutation can occur remain endogenous factors. These include metabolic by-products, errors in the process of replication, repair or recombination, and others.
- spontaneous transitions and inversions of nitrogenous bases;
- incorrect arrangement of nucleotides due to errors in DNA polymerases;
- chemical replacement of nucleotides, for example, guanine-cytosine with adenine-guanine.
- mutations in genes responsible for the repair of individual sections of the DNA chain after they are broken under the influence of external factors.
- failures in the crossing over processes during meiosis or mitosis lead to the loss and completion of bases.
These are the main factors causing spontaneous mutations. The causes of failures may include the activation of mutator genes, as well as the conversion of safe chemical compounds into more active metabolites that affect the cell nucleus. In addition, there are structural factors. These include repeats of the nucleotide sequence near the site of chain rearrangement, the presence of additional DNA sections similar in structure to the gene, as well as mobile elements of the genome.
Pathogenesis of mutation
Spontaneous mutation occurs as a result of the influence of all the factors listed above, acting together or separately during a certain period of the cell’s life. There is such a phenomenon as sliding disruption of pairing of daughter and mother DNA strands. This often results in the formation of loops of peptides that have not been able to integrate adequately into the sequence. After removing excess DNA sections from the daughter strand, loops can be either resected (deletions) or inserted (duplications, insertions). Changes that appear are consolidated in subsequent cycles of cell division.
The rate and number of mutations that occur depend on the primary structure of DNA. Some scientists believe that absolutely all DNA sequences are mutagenic if they form bends.
Most common spontaneous mutations
Why do spontaneous mutations most often appear in genetic material? Examples of such conditions are the loss of nitrogenous bases and the removal of amino acids. Cytosine residues are considered especially sensitive to them. It has been proven that today more than half of vertebrates have mutations at cytosine residues. After deamination, methylcytosine changes to thymine. Further copying of this section repeats the error or deletes it, or doubles it and mutates it into a new fragment. Another reason for frequent spontaneous mutations is considered to be a large number of pseudogenes. Because of this, uneven homologous recombinations can form during the process of meiosis. The consequence of this is rearrangements in genes, rotations and duplication of individual nucleotide sequences.
Polymerase model of mutagenesis
According to this model, spontaneous mutations arise as a result of random errors in molecules that synthesize DNA. For the first time, such a model was presented by Bresler. He suggested that mutations appear as a result of the fact that polymerases in some cases insert non-complementary nucleotides into the sequence. Years later, after lengthy tests and experiments, this point of view was approved and accepted in the scientific world. Certain patterns have even been deduced that allow scientists to control and direct mutations by exposing certain sections of DNA to ultraviolet light. For example, they found that adenine is most often inserted opposite the damaged triplet.
Tautomeric model of mutagenesis
Another theory that explains spontaneous and artificial mutations was proposed by Watson and Crick (discoverers of the structure of DNA). They proposed that mutagenesis is based on the ability of some DNA bases to convert into tautomeric forms, which change the way the bases join together.
After publication, the hypothesis was actively developed. New forms of nucleotides were discovered after ultraviolet irradiation. This gave scientists new research opportunities. Modern science is still debating the role of tautomeric forms in spontaneous mutagenesis and its impact on the number of identified mutations.
Other models
Spontaneous mutation is possible when the recognition of nucleic acids by DNA polymerases is impaired. Poltaev and co-authors elucidated the mechanism that ensures compliance with the principle of complementarity during the synthesis of daughter DNA molecules. This model made it possible to study the patterns of spontaneous mutagenesis. The scientists explained their discovery by saying that the main reason for changes in DNA structure is the synthesis of non-canonical nucleotide pairs. They suggested that base sweeping occurs through deamination of DNA sections. This results in a change from cytosine to thymine or uracil. Due to such mutations, pairs of incompatible nucleotides are formed. Therefore, during the next replication, a transition occurs (point replacement of nucleotide bases).
Classification of mutations: spontaneous
There are different classifications of mutations depending on what specific criterion underlies them. There is a division based on the nature of the change in gene function: - hypomorphic (mutated alleles synthesize fewer proteins, but they are similar to the original);
- amorphous (the gene has completely lost its functions);
- antimorphic (the mutated gene completely changes the trait it represents);
- neomorphic (new signs appear). But a more common classification is one that divides all mutations proportionally by variable structure. There are: 1. Genomic mutations. These include polyploidy, that is, the formation of a genome with a triple or more set of chromosomes, and aneuploidy - the number of chromosomes in the genome is not a multiple of the haploid one.
2. Chromosomal mutations. Significant rearrangements of individual chromosome sections are observed. There is loss of information (deletion), doubling (duplication), change in the direction of nucleotide sequences (inversion), as well as reversal of chromosome sections to another location (translocation).
3. Gene mutation. The most common mutation. Several random nitrogenous bases are replaced in the DNA chain.
Consequences of mutations
Spontaneous mutations are the causes of tumors, storage diseases, dysfunctions of organs and tissues of humans and animals. If a mutated cell is located in a large multicellular organism, then with a high degree of probability it will be destroyed by triggering apoptosis (programmed cell death). The body controls the process of preserving genetic material and, with the help of the immune system, gets rid of any possible damaged cells. In one case out of hundreds of thousands, T lymphocytes do not have time to recognize the affected structure, and it gives rise to a clone of cells that also contain the mutated gene. The conglomerate of cells has other functions, produces toxic substances and negatively affects the general condition of the body. If the mutation occurred not in the somatic cell, but in the reproductive cell, then changes will be observed in the descendants. They turn out to be congenital organ pathologies, deformities, metabolic disorders and storage diseases.
Spontaneous mutations:
In some cases, mutations that previously seemed useless can be useful for adapting to new living conditions. This introduces mutation as the measure of natural selection. Animals, birds and insects wear camouflage colors that match their locale to protect themselves from predators. But if their habitat changes, then with the help of mutations nature tries to protect the species from extinction. In new conditions, the fittest survive and pass this ability on to others. The mutation can occur in inactive regions of the genome, and then no visible changes in the phenotype are observed. A “breakdown” can only be identified with the help of specific studies. This is necessary for studying the origin and related species of animals and compiling their genetic maps.
The problem of spontaneity of mutations
In the forties of the last century, there was a theory that mutations are caused solely by the influence of external factors and help to adapt to them. In order to test this theory, a special test and repetition method was developed. The procedure was that a small amount of bacteria of one type was sown in test tubes and, after several inoculations, antibiotics were added to them. Some microorganisms survived and were transferred to a new medium. A comparison of bacteria from different test tubes showed that resistance arose spontaneously, both before and after contact with the antibiotic. The method of repetition was to transfer microorganisms to fleecy fabric and then transfer them to several clean media. New colonies were cultured and treated with antibiotic. As a result, bacteria located in identical areas of the medium survived in different test tubes.
The mutation process is characterized by the frequency of mutations and the direction of gene mutation.
The frequency of mutations is one of the defining features of each species of animals, plants and microorganisms: some species have higher mutational variability than others. These differences are due to the influence of many factors of general and particular importance: the genotypic structure of the species, the degree of its adaptation to environmental conditions, the place of its distribution, the strength of natural factors, etc. No matter how protected the organism is from the influence of the external environment, the processes occurring in it chemical processes associated with metabolism can be the cause of spontaneous mutational variability. Under this term we hide our ignorance of the specific causes of mutations.
At present, there is still no complete understanding of the frequency of mutations per generation. This is explained by the fact that mutations are extremely diverse both in phenotypic manifestation and genetic determination, and the methods for recording them are imperfect; Only in relation to the mutability of individual loci can a more or less accurate assessment be made. As a rule, only one of the members of an allelic pair mutates at the same time, which is explained by the rarity of the mutation itself; simultaneous mutation of both members is an unlikely event.
The established general patterns of spontaneous mutation frequency boil down to the following points:
- different genes in the same genotype mutate at different frequencies;
- Similar genes in different genotypes mutate at different rates.
These two provisions are illustrated by tables.
The first of them shows the frequency of mutation of different genes using the example of corn, the second compares mutation of genes in different species of animals, plants and humans, and in corn - mutation of the same genes in different lines with different genotypes.
So, different genes mutate at different frequencies, that is, there are mutable and stable genes. Each gene mutates relatively rarely, but since the number of genes in a genotype can be enormous, the total frequency of mutation of various genes turns out to be quite high. For Drosophila, this calculation shows one mutation per approximately 100 gametes per generation. However, such calculations are not yet very accurate, since it is actually impossible to distinguish a single change in a locus from complex small reorganizations in chromosomes; In addition, it is very difficult to establish simultaneous mutations in different chromosomes within the same cell.
Based on the rarity of the event itself - gene mutation, it is also necessary to explain the fact that a mutation is usually observed in only one of the loci. Genetics does not know a single reliable fact of simultaneous mutation of two alleles in homologous chromosomes. But it is possible that this is explained by the mechanism of mutation itself.
The reasons for spontaneous gene mutations remain far from clear. One of the main reasons causing different mutation rates is the genotype itself. The same R r gene in two lines of corn mutates to r r in different ways: in one - with a frequency of 6.2, and in the other - 18.2 per 10,000 gametes. It has also been established that the frequency of lethal mutations in different lines of Drosophila is different.
Through selection, it is possible to create lines that will have different spontaneous mutabilities. This is supported by the fact that there are special genes - mutators, which affect the rate of mutation of other genes. For example, in maize, near the left end of the short arm of chromosome IX, there is the Dt locus, which affects the mutability of the A locus, located in the long arm of chromosome III. However, it is still not entirely clear what the Dt locus is. Perhaps it is some kind of chromosomal rearrangement.
The influence of genotype on the spontaneous mutability of an individual gene is also manifested during hybridization. There are indications that the frequency of mutations at the same locus is higher in hybrid organisms than in the original forms.
The spontaneous mutation process is also caused by the physiological state and biochemical changes in cells.
For example, M. S. Navashin and G. Stubbe showed that during the aging process of seeds when stored for several years, the frequency of mutations, especially such as chromosomal rearrangements, increases significantly. A similar phenomenon is observed in relation to the frequency of lethal mutations in Drosophila during sperm storage in the seminal receptacles of females. These kinds of facts indicate that spontaneous gene mutation depends on physiological and biochemical changes in the cell associated with external conditions.
One of the possible reasons for spontaneous mutation may be the accumulation in the genotype of mutations that block the biosynthesis of certain substances, as a result of which there will be an excessive accumulation of precursors of such substances that can affect gene changes. This hypothesis is amenable to experimental testing.
If you find an error, please highlight a piece of text and click Ctrl+Enter.
