What is the definition of a mutation?

Question

There are two alleles that determine the sensitivity of a person to Coumadin (a medicine for blood thinners used to treat a stroke etc). Sometimes you encounter the terminology that one has a mutation on both alleles (father's and mother's side). But why is that called a mutation and not just a variation? Does a mutation mean that it changed during lifetime, or is the difference between mutation and variation arbitrarily defined? Or is there really a kind of standard taken where deviations are considered to be mutations?

Answer 1

Good question!

The term mutation can be used with two different meanings. Each definition can further be split into two different more detailed definitions. The reason for this slight mess is mainly historical. In short, a mutation can refer to

• An event
  • narrow sense
  • broad sense
• An allele
  • definition based on ancestral/derived states
  • definition based on frequency

Before going into the details of these definitions, it is important to first define a few other terms.

A few other definitions

The terms I want to define here are Locus, polymorphic locus, allele, nucleotide and phenotype.

In short (simplified version), a phenotype is the way an individual look. The variations of phenotypes of the individuals in a population depends upon the variation of genotypes and the variation of environments that they encounter. This concept is very much related to the concept of heritability. You may want to read more about it here.

The DNA sequence is made of four nucleotides. It is the sequence of these nucleotides that affect the phenotype of an individual

A locus is refers to the position of a DNA sequence of arbitrary length. At a given locus different types of sequence can exist, such a coding or non-coding sequence, a gene or just an intron, only a few codons, etc..

An allele is one variant of a sequence (often a gene) at a given locus. If, in the population, more than one allele exists at a given locus, than the locus is said to be polymorphic. Most polymorphic loci have only two alleles. In such case we can talk about bi-allelic loci.

Mutation as an event

A mutation can refer to an event.

Narrow definition

A mutation may refer to the event of a spontaneous change in the nucleotide sequence of an individual such as typically an indel (insertion or deletion of one or few nucleotides) or a substitution (substitution of a nucleotide by another one). In other words, a mutation can refer to the event of changing allele (eventually making up a new one) at a given locus.

Broad definition

The broad definition is similar to the narrow one expect that it encompass more types of genetic changes. In the broad sense, a mutation may refer more globally to any genetic spontaneous change. For example a whole chromosome deletion or a full genome duplication are examples of mutations.

In my experience, most often when the term "mutation" is used, it is to refer to the broad definition of mutation.

Mutation as an allele

A mutation can refer to an allele. Note however that very often we prefer using the terms "mutant allele", "mutant state" or just "mutant" as synonym to refer to this allele. Pretty much the only circumstance in which we would use the term mutation here is in sentences of the kind "Individual A carries the mutation.".

Definition based one ancestral/derived states

A mutation can refer to the allele that is derived from a more ancestral allele. Consider for example, a given locus was NOT polymorphic in the past. A mutation (in the sense of "event") occurs and the locus is now polymorphic. The allele that has been created by the mutation (in the sense of "event") is sometimes called "mutation".

Definition based on frequency

A mutation can refer to the allele that is at the lowest frequency in the population. For example, consider a bi-allelic locus with two alleles A and B. If the frequency of the allele B is lower than $\frac{1}{2}$ (that is lower than the frequency of the allele A), then the allele B can be referred to as the mutation. The reason for calling "mutation" the allele that is at low frequency is that most mutations are deleterious and as a consequence the mutant allele is often at low frequency. As a consequence, using the Definition based on frequency and Definition based one ancestral/derived states is often not important.

To address your question specifically

It is a little hard to directly address your question as it seems to have several misunderstanding on the concept of mutation. In the same time however, it feels like you are turning around the realization that there are several definitions in use.

Sometimes you encounter the terminology that one has a mutation on both alleles (father's and mother's side). But why is that called a mutation and not just a variation?

The term mutation (whichever definition you pick) is intrinsically related to the concept of variation in the population but not so much to variation within a single individual (homozygote vs heterozygote).

If an individual "has a mutation on both allele", refers to the term mutation as an allele (in the narrow sense probably) and not as an event. More specifically it refers to one allele at a polymorphic locus (probably a locus of only one nucleotide) within the allele considered at the larger polymorphic locus considered.

Does a mutation mean that it changed during lifetime

A mutation (in the sense of event) is a change that if often view at the moment of reproduction but the mutation may have occurred anytime in the lineage of the germ cells. Note, one may consider also mutation that occurred (during the lifetime of the individual) but in the soma cells. Such mutation will NOT be transmitted to the offspring.

Or is there really a kind of standard taken where deviations are considered to be mutations?

Well...yes! A deviation is a deviation to a reference. In other words, we can replace "deviation" by "one allele of a polymorphic locus" in your question. And yes, a mutation (in the sense of a given allele) can refers to one allele of a polymorphic locus.

Answer 2

What I was taught by people in genomics is that "variation" is preferred for an allele that was not private to just one individual or family, but was found in pretty much unrelated individuals, while "mutation" is preferred for a very recently changed allele that is private to one individual or their family. Sometimes, it seems the "mutation" is preferred when you mean to imply a clinically relevant difference caused by that different allele (as opposed to a polymorphism, which is usually what we call a survival-neutral different allele) I would say that the term "mutation" is being used incorrectly in your case unless the variant just appeared de novo, but maybe they do mean it in the second sense, because this difference clearly has a clinical phenotype associated with it.

Answer 3

Sometimes you encounter the terminology that one has a mutation on both alleles (father's and mother's side). But why is that called a mutation and not just a variation?

To answer this question, we first need to define a few terms:

What is a Genetic Mutation?

A genetic mutation is a permanent modification to the DNA of an organism, such that the modification causes differences in the DNA that are not "typically" found amongst other members of the organism's population. These mutations can be classified into two major categories, and are defined by the means in which the organism obtained the mutation(s): hereditary mutations, and acquired (somatic) mutations.

• Inherited mutations are prevalent throughout virtually every cell within the organism's body, and are most commonly referred to as germline mutations. The primary causes of germline mutations are cell replication errors, cell age, and environmental factors; however, there is still little data on this, and as a result, it is still widely debated as to which of these is most to blame. An example of an inherited mutation is Sickle Cell Disease.

• Acquired mutations are located only within affected somatic cells, and are caused by environmetal factors, such as UV radiation (see Xeroderma pigmentosum), or by DNA replication errors during mitosis.

The fundamental difference between inherited and acquired mutations is that inherited mutations are passed down from parent to offspring, whereas acquired mutations are not.

With both inherited and acquired mutations, they can occur in any of the following ways:

• Missense mutation
• Nonsense mutation
• Insertion
• Deletion
• Duplication
• Frameshift mutation

See here (page 7) for a brief description of each.

What is Genetic Variation?

Genetic variation is a descriptive term that encapsulates the comparision of a DNA sequence belonging to an organism with respect to the composite, genetic "profile" of the population that the organism is a member of. For each expressed (phenotypic) trait of an organism, and of a population, there are a collection of possiblities with respect to how that trait is in fact expressed. Examples of variation for a given trait, when considering humans, are:

• Ear lobe shape - free; attached
• Hairline - widow's peak; straight
• Hair color - black; brown; blonde; red/orange

It's important to note that genetic variation is not (commonly) brought about by the occurrence of mutations, but in fact, is caused by polymorphisms.

So, how do the two differ?

Does a mutation mean that it changed during lifetime, or is the difference between mutation and variation arbitrarily defined?

A genetic mutation occurs after a normal allele has been transferred from parent to offspring, and then that allele is altered into an "abnormal" state. Implicitely speaking, a mutation is referencing a single individual.

Conversely, a polymorphism is a DNA sequence that is acquired (inherited) from the parent, remains unaltered, and is commonly found within the organism's population. Again, implicitely speaking, genetic variation maintains the perspective of the population, and not of a single individual.

Or is there really a kind of standard taken where deviations are considered to be mutations?

The cutoff for if an allele is considered to be a polymorphism or a mutation is 1%. Which is to say that 1% or more of the population must carry that variation of the allele for to be considered a polymorphism; otherwise, it's a mutation (see here and here). Note though that this cutoff is completely arbitrary.

Now, to answer your overarching question...

The reason why an allele may be described as a variation or a mutation is due to the kind of cell that the allele is contained within (germ vs somatic) upon aleration, when the allelic DNA sequence was defined (before/after inheritance), and how prevalent within the organism's population that allele is (cutoff).

In the case of Coumadin (Warfarin), according to the National Institutes of Health, it would seem that a person's sensativity to Coumadin is dictated by autosomal dominant polymorphisms, and so, the alleles involved would be considered a variation, and not a mutation.

Many genes are involved in the metabolism of warfarin and in determining the drug's effects in the body. Certain common changes (polymorphisms) in the CYP2C9 and VKORC1 genes account for 30 percent of the variation in warfarin metabolism due to genetic factors. Polymorphisms in other genes, some of which have not been identified, have a smaller effect on warfarin metabolism.