“A mutation is a change or alteration happens in a DNA, gene, or chromosome due to intrinsic or extrinsic factors such as an error in replication or exposure to UV light, respectively.”

In a simple language, we can say, a change occurs in a number or structure of a gene or a chromosome is referred to as a genetic mutation.

Quite complicated, Isn’t it?

Let me explain to you what it is,

The basic unit of life is a cell. A cell- a microscopic structure present in every organism. It has an even tinier nucleus in its center. The material present in the nucleus is known as nucleic acid– DNA or RNA.

Mostly DNA as nucleic acid present in almost every organism and made up of the long chain of nucleotides- a polynucleotide chain.

Nitrogenous bases- A, T, G and C are the main units of nucleotides besides the sugar and phosphate. A chain of nucleotides which encodes proteins is known as a gene. If it changes, the function of gene alters or losses.

The gene replicates and transcribes into an mRNA. A protein is formed from the mRNA by the process of translation. The process of transcription and translation is collectively called gene expression. We can define it as in which amount a particular gene expressed in a particular cell is gene expression.

A mutation can also change gene expression. Likewise, change or mutation in the structure or number of chromosomes also results in genetic abnormalities, for example, the Philadelphia chromosome– a type of translocation (structural mutation), trisomy 21– an extra copy of chromosome 21 (numerical mutation).

In the present article, we will try to understand one of the important topics of genetics and genomics– the mutation or genetic mutation. Also, we will discuss the mechanism, causative agents, and different types of mutations present in a gene or chromosome.

Related article: DNA story: The structure and function of DNA.

So let’s get into the world of mutation,

What is a mutation?

“Change in the nucleotide sequence of the DNA”, is a mutation.

The mutation is an important biological process in nature. It can be helpful or harmful. For instance, the mutation creates variations in nature by providing new alleles and hence helps in evolution. On the other side, a sudden or undesirable mutation can cause cancer and other harmful genetic disorders.

The role of mutation in evolution is best explained by the example of sickle cell anemia. We will understand why sickle cell anemia is important to us in the last segment of this article, so read this article till the end.

Let’s move ahead.

The word mutation was similar to the French word “mutacioun” which literally means “process of changing.”

Although the “mutation” world was originally derived from the Latin word “mutare”. The meaning of this is “to change.”

The term “mutation” was coined by Hugo De Vries in 1890. However, before him, Seth Wright, an English farmer, noticed mutation for the first time in his unusual short-legs male lambs during 1791. He fails to define the process.

After the findings of Hugo de Vries, the mechanism of mutation was studied by Morgan in 1910.

In 1927, H. J. Muller performed experiments of artificial mutagenesis. Using the X-rays he had introduced mutation in Drosophila. For that, he was awarded the Nobel prize in 1946.

“Artificial mutagenesis or site-directed mutagenesis is a process of introducing mutations into organisms artificially, for our use.”

Read our article on it: Site-Directed Mutagenesis: Methods and Applications.

Definition of mutation:

“Due to the replication errors, exposure to mutagens and viral infections changes or alterations occur in a DNA sequence which causes genetic abnormalities, is known as mutation.”

The genetic mutations are usually categorized broadly into two categories- gene mutations and chromosomal mutations.

Gene mutation:

Mutation or series of mutations occur in the polynucleotide sequence of a gene that changes the function of it is referred to as gene mutations.

Type of Gene mutations:

Point mutation– Change in the single base of the DNA. It’s often known as single nucleotide polymorphism. Read our amazing article on Point mutation.

Insertion– insertion or addition of a base into the gene sequence. Often known as addition mutation.

Deletion– When a base or some bases deleted from the gene sequence.

Inversion– When some gene sequences inverted and inserted back into the original sequence.

Substitution– When some bases of a gene sequence are replaced by other bases.

Duplication– when some bases or a base duplicated in a gene sequence.

Other types of gene mutations:

Forward mutation:

Genetic Mutation from wild-type to mutant or evolution of new mutation from wild-type allele is called a forward mutation. The forward mutation leads to the evolution of new traits in the population.

Backward mutation:

A mutation is a unidirectional process, but sometimes some mutation gives the original (wild-type) allele back to the population, such mutation is known as a backward or back mutation.

Back mutation is a very rare and unusual phenomenon in nature.

It gives the original phenotype back into the population by true back mutation or by the occurrence of a secondary mutation.

In true back mutation, a mutation occurred at the same location as it occurred during forward-mutation. In simple words, it gives the wild-type codon back to the population.

In secondary mutation, an occurrence of a new mutation in any place in the sequence of the gene which gives the original function back or sometimes the new mutation suppressed the effect of the previous forward mutation.

Copying error:

Copying error occurs during cell division while replication. If it remains un-repaired, such mutations will change the genetic code.

Silent mutation:

It is non-expressive. In silent mutation, a new codon codes for the same amino acid as the wild-type one.

Mis-sense mutation:

A codon originated from a nucleotide change that will code for different amino acids. It can lead to alteration or loss of function in protein.

Nonsense mutation:

A stop codon added to the DNA sequence that stops protein translation.

It stops protein synthesis because a stop codon ends the protein synthesis results in a premature protein or truncated protein.

Frameshift mutation:

Base pair alteration causes abnormal reading frames which ultimately results in an abnormal protein formation.

A specific reading frame has a start codon and a stop codon. In between both codons, a definite coding sequence is present.

In a frameshift mutation, alteration in DNA leads to shifting of this reading frame from one place to another in a genome. So the position of start or stop codon changes.

See the image,

In addition to this, some mutations are different from mutations enlisted above.

For instance,

Some of the mutations are extra-large; in fragile X syndrome, an alteration in triple repeat number results in an abnormal protein.

In the case of DMD, an entire exon is deleted from the DMD gene.

Some mutations can alter the expression of other genes. For example, a mutation in the SOX9 somatic gene changes the expression of SRY gene.

Some mutations are stable, they can be inherited from generation to generation. Some mutations are non-stable, may occur for some time in a single generation.

Stable mutations are generally congenital, and non-stable mutations arise after birth.

If a stable mutation is incorporated into the genome it can never be repaired, while unstable mutation can be repaired and passes the wild-type allele back to the population.

Chromosome mutation:

Change or alteration into the structure or number of chromosomes is known as chromosomal mutation.

Insertion– When a large section of a chromosome arm is inserted in a chromosome.

Deletion– when a section of a chromosome is removed or deletion from the chromosome.

Duplication– When a section or arm of the chromosome duplicated.

Translocation– when a section or arm or some portion of chromosome translocated to another chromosome. Three major types of translocation are commonly found.

Balanced translocation: when two segments (nearly same) are exchanged, resulting in balanced translocation.

Here, roughly both segments are nearly same-sized. Even using the cytogenetic analysis it can’t be detected.

Advanced molecular cytogenetic techniques such as DNA microarray and FISH are required to find it.

Read more on Cytogenetics: A Brief Introduction To Cytogenetics [Karyotyping, FISH and Microarray]

Balance translocation is one of the major reason for recurrent abortion in females.

Reciprocal translocation: Reciprocal translocations are more commonly found in nature. It occurs between two non-homologous chromosomes.

Robertsonian translocation: Robertsonian translocation occurs between two acrocentric chromosomes. Acrocentric chromosomes are small-short chromosomes with one long q-arm and a short or very smaller p-arm.

In humans 13, 14, 15, 21, 22 and Y chromosomes are acrocentric. When translocation between two acrocentric chromosomes happens, one (nearly) metacentric and one “only centromeric” chromosome are formed.

Here long arms of both chromosomes are fused together. Therefore, one chromosome becomes larger metacentric and another chromosome remains without any arms or only with centromere.

Though the “only centromeric” chromosome does not have any arm, still it contains many genes of both chromosomes.

The Robertsonian translocation isn’t so common, it is found in some cases of recurrent abortion. It’s not observed in any other genetic abnormality.

Imbalanced Robertsonian translocation results in mental retardation, trisomy and other structural abnormalities.

Inversion– When a section of a chromosome is inverted and inserted back to the chromosome.

Here if the inversion occurs in only one arm of the chromosome, this type of inversion is called a paracentric inversion. The centromere is not involved in paracentric inversion.

If the inversion occurs between two arms of a chromosome, this type of inversion is called a pericentric inversion. The centromere is involved in pericentric inversion.

Ring chromosome: when both ends of a chromosome are fused together, it creates a ring-like structure and so-called as ring chromosome.

A ring chromosome is generally observed in the long metacentric chromosomes. It happens because of the loss of telomeric sequences.

Telomeres of each chromosome have specific sequences which prevent them to fuse together. When some of these sequences (telomeric sequences) are lost, it results in the fusion of chromosomal ends.

Read more on Telomer- definition, structure, and function.

Phenotypic abnormalities like microcephaly, mental retardation and epilepsy are associated with ring chromosomes.

Aneuploidy– Change in the number of the chromosome which results in genetic abnormality is known as aneuploidy.

For instance, the trisomy. We will discuss “ploidy” in some other articles. Now let’s go ahead in the present topic.

How do mutations occur?

Replication error and error in DNA repairing are the intrinsic factors which induce mutations. While UV rays, X-rays, base analogous, teratogens, and carcinogens are some of the extrinsic or environmental factors which cause mutations.

Error in replication:

Replication is a process of copying the entire DNA. It creates the exact copy of DNA using the DNA polymerase. However, sometimes or at the end of replication, some DNA sequences can’t copy properly.

Thus gene or DNA sequence can’t replicate properly and hence it causes mutation.

Error in DNA repairing:

Replication errors are repaired by cell’s DNA repair mechanism, however, some mutations even skip DNA repair.

Mutagens:

Agents that cause mutations are known as mutagens. For example, UV rays, base analogous, and chemicals.

Broadly, mutagens interfere with the base-pairing or nucleotide structure and result in mutation.

We have covered an amazing article on the mechanism of how different mutagens cause an alteration in the DNA sequence. You can read it here: Mutagens: definition, types, and mechanism.

Different types of Genetic Mutations:

Spontaneous vs Induced mutation

Spontaneous mutations happen without any known reasons.

It occurs by metabolic, replication, and developmental errors. Spontaneous mutations are rare and occur without any reason. It originated by birth.

Larger genes are more prone to spontaneous mutation because the chance of replication error is higher in larger genes. The rate of spontaneous mutation is 10-5 per gene per generation during replication.

On the other side,

An induced mutation is resulting from exposure of an organism to mutagenic agents. The general mutagenic agents are radiation, UV light and chemicals.

The UV light is responsible for xeroderma pigmentation and skin cancer, it causes uncontrolled cell division by penetrating into the skin.

Due to the lower energy of the UV light, it can’t penetrate into other tissues but it can easily penetrate the skin cells and activate oncogenes.

Chemicals such as alkylating agents and base analogs are common chemical mutagens. However, every chemical is somehow mutagenic to our DNA.

Furthermore, climate change and lifestyle play a major role in acquiring mutations.

Spontaneous mutations are stable, inherited and occur infrequently in populations. The inheritance rate is dependent on the inheritance pattern.

Spontaneous mutations are miraculous. It remains recessive in the parental organism and does not show off symptoms. Its effect shows in consecutive generations.

In contrast, induced mutations immediately show its effect on the target organism.

Somatic vs germ-line mutation:

Somatic mutations occur in the somatic cells only.

It doesn’t follow any specific pattern of inheritance, still, it is lethal. Notably, Only germ cells can undergo fertilization therefore those mutations which are present in germ cells can only be inherited.

Somatic mutation is restricted to some tissue or bodily organs.

But if it occurs in progenitor cells it can be spread to other daughter cells. Progenitor cells are the group of cells which have the capacity to divide further. Commonly somatic mutations cause cancer, in most cases.

Contrary, germline mutations are inherited and more dangerous than a somatic one.

Mutations occur in egg or sperm (germ cells), it’s known as germline mutations.

In somatic mutation, if the mutation occurs in cells after metaphase, it can not be spread to the other cells. The somatic mutation occurs during the mitosis whereas germline mutation occurred during meiosis.

Germline mutations may or may not affect the parental organism but it will surely affect the offsprings. Also, the germline mutations are generally non-curable.

All the disorders which follow the Mendelian pattern of inheritance are germline mutations.

Actually, the germline mutations help in evolution by providing new alleles, yet, it may harmful too.

On the other hand, somatic mutations affect only the organism having the mutation. It doesn’t have any role in evolution.

Somatic mutations are restricted to an individual, if it is lethal, an individual may die but it can’t transmit to other organisms in the population.

Whereas germline mutations are silent, it remains in a recessive condition in some organisms and steadily spreads throughout the population.

Chromosomal mutation vs mitochondrial mutation:

Mitochondria are the powerhouse organelle of our cell. Mitochondrial DNA (mtDNA) is present in mitochondrial (not in the nucleus), and it has its own replication and transcription machinery.

Genomic mutations may be either syndromic or Mendelian while the mitochondrial mutations are neither syndromic nor Mendelian.

Because it inherited from the maternal organism only, it is known as maternally inherited DNA. Thus, if any mutation is induced in the mtDNA and is inherited to male offspring, it can’t further be transmitted.

Read further,

On the other side,

Chromosomal DNA is inherited from both the parents. notably, not all chromosomal mutations are inherited in Mendelian fashion.

For instance, Cry du chat syndrome, Down syndrome, and Patau syndrome are some of the common types of chromosomal disorders that do not follow Mendelian inheritance.

Mitochondrial DNA is inherited maternally, it is rarest among rare.

Kearns- syre syndrome, Leigh syndrome and non-syndromic hearing loss are some of the mitochondrial disorders which arise due to the mutation in mtDNA.

Deletion, duplication, translocation and inversion are some of the common types of mutations observed in mtDNA, same as genomic DNA.

Morphological mutation:

The Genetic mutation which affects the outer characteristic or physical characteristic or phenotype of an organism is called a morphological mutation.

This type of mutation alters the physical properties like shape, size, and color of an organism.

Lethal mutation:

A Genetic mutation that causes the death of an organism or affects the survival of an organism is called a lethal mutation.

If a mutation causes death in a certain environment then the mutation is known as a conditional lethal mutation.

Conditional mutation:

In this type of genetic mutations, the mutant allele causes mutant phenotype in a certain specific environment or conditions and remains wild type in some other environment.

Let’s take the example of bacteria,

The conditions which favor the growth of mutant colonies are called restrictive conditions.

In contrast, conditions which cause the growth of wild-type phenotype (having wild-type allele) are called permissive conditions.

In this experiment, if some special type of essential amino acid is given into the culture medium, then and then, the mutant bacteria will grow otherwise in the lack of it, only wild type bacteria can grow.

See the figure,

Conditional mutation is very important in genetic studies. We can study the characteristics of an allele, and how it behaves in different adverse conditions. We can estimate the time duration of gene action as well.

Biochemical mutation:

Each cell required energy and nutrients for differentiation and survival. Different biochemical pathway inside the cell provides that essential requirement.

For mutation study, bacteria are the most suitable model organism because of their unique properties.

Bacteria or microbial culture which can grow on minimal media (only simple inorganic salts) are called prototrophic.

In contrast, the mutant bacterial culture which requires all the essential nutrients like amino acids and other organic salts, are called auxotrophic.

Wild-type cultures are prototrophic while biochemical mutants are auxotrophic in nature because biochemical mutant doesn’t have some metabolites which they require to grow.

Hence they need all types of nutrients.

Auxotrophic mutants are unable to synthesize essential nutrients like amino acid, vitamins and nitrogenous bases whereas wild-type strains of bacteria can synthesize all the essential metabolites.

When nutrients and metabolites rich media are given to auxotrophic mutants, the condition has become permissive for them and mutant colonies can grow faster.

Loss of function mutation:

In simple terms, a mutation that causes functional loss of the gene is called a loss of function mutation. Loss of function mutation depends on the condition of inheritance of that mutation. Generally, it remains recessive.

If the wild-type normal allele is dominant and expressed over mutant allele then even in heterozygous condition, the loss of function mutation remains recessive. It is also called a null mutation.

Mutant allele is expressed in a condition where both the recessive alleles (homozygous recessive) are overexpressed as compared to the normal wild-type allele.

Gain of function mutation:

Loss of function Genetic mutations are most common in nature, but some mutation gives a new function to the gene or gives the original function back to the gene. This type of mutation is a gain of function mutation.

However, these types of mutation are rare. Remember, sickle allele.

In sickle cell anemia-heterozygous condition, individuals remain unaffected but mutation gives one additional benefit. It protects against the malaria parasite. Despite, in the homozygous mutant condition, it causes anemia.

Temperature-sensitive mutant:

Mutant that is growing at one temperature and remains suppressed at another temperature, is called a temperature-sensitive mutation.

Most enzyme-coding genes are temperature sensitive because enzymes are activated at a once specific temperature.

Examples of genetic mutations:

Here in the last segment of this article, I am enlisting some of the examples of gene and other mutations in tabular form.

Type of mutation Example Description Deletion (Point mutation) Cystic fibrosis A single gene, autosomal recessive condition. Base substitution Sickle cell anemia Read the article for more detail. (link) Insertion Beta thalassemia A single gene, autosomal recessive condition. Chromosomal deletion Cry-do-chat Deletion on the p arm of chromosome 5. Chromosomal translocation Philadelphia chromosome Translocation between 4 and 17. Chromosomal duplication A type of cancer Some amount of chromosomes duplicated. Trisomy 21 Down syndrome An extra copy of chromosome 21. Frameshift mutation Crohn’s disease Insertion of a premature stop codon.

Are mutations helpful?

Not always but not harmful always, even.

Any alteration in nature occurs to make us survive on earth. New alleles originate due to change in the sequence of a gene. Which probably happens in our favor.

Now coming to our question regarding sickle cell anemia. The SCD is a type of autosomal recessive genetic condition. This means, a single allele isn’t enough to cause disease.

The sickle allele (HbS) is, in fact, originated to make us survive against malaria. In the case of sickle cell, RBCs become sickle cells, instead of the normal doughnut shape. Hence the malaria parasite can’t identify it.

It is an evolutionary gift for us, especially, in the African subcontinent where malaria is more prevalent.

On the other side, some random mutations can cause cancer like a lethal condition.

Thus, we can say, “mutations are helpful but not always or mutations are harmful but not always.”

Perhaps what I think, random cancer-causing mutations are lethal because it helps to spread the mutant harmful allele in the population. In this context also, the mutations are helpful.

Besides, using the artificial mutagenesis techniques, any new mutations can be introduced into the DNA sequence of our interest.

By this, we can create new genetically modified organisms for some experimental purposes.

Pleiotropy:

Pleiotropy is the mechanism in which the mutation in one gene influences more than one trait or phenotype.

Again recall the situation in sickle cell anemia. Mutant HBS allele results in anemic condition as well as protects the heterozygous individual from the malaria parasite. We will discuss pleiotropy broadly in other articles.

Conclusion:

Different types of Genetic mutations randomly occur in the population.

It creates allelic variation in a genome and the new allele originates in the population.

Polymorphism is a natural phenomenon. A genetic mutation occurs to make us adaptive in any adverse environment but it may be harmful sometimes. Scientifically we can say, “what we are today, is a result of millions of mutations in the past”.

Source

Griffiths AJF, Gelbart WM, Miller JH, et al. Modern Genetic Analysis. New York: W. H. Freeman; 1999. The Molecular Basis of Mutation.