I got a little confused about the difference between a mutation and polymorphism that people use in genetics.
I disagree with all those using frequency as the difference. Frequency is a useful tool to try and extract useful/robust polymorphisms from data but 1% is entirely arbitrary and actually dates back to a time where data was much thinner on the ground. In a population of 1 billion, a genetic variant shared by 1 million is still a polymorphism, even though it is only 0.1% of the population.
A *mutation* is a physical event in a single individual/cell. A polymorphism is a population attribute. Unless they are lethal or somatic*, mutations can give rise to polymorphism following increases in frequency due to either selection or genetic drift. In this case, one might refer to the "mutation" spreading or an individual "carrying a mutation" but this is just short-hand for "the mutant allele", i.e. "the genetic variant generated by the mutation" - it is not ACTUALLY a mutation unless it arose de novo since the previous generation. (*In some cases, it might even be useful to consider polymorphisms within populations of somatic cells.)
When the new variant has some kind of affect, such as causing a human disease, it is obviously useful to use such short-hand but we should not confuse convenience/utility/convention with reality. (Or, to put it another way, one possible reason that the difference between polymorphism and mutation confuses some people is that "mutation" is being over-used in a rather lazy fashion to mean something that it does not. There is nothing wrong with "low frequency variant" if that is what you mean.)
If the question is what do people mean when they say "mutation" or "polymorphism" then frequency might be important, depending on who that person is and in what field they work. (I think the 1% thing is a much more fixed convention in human genetics than genetics in general.) If the question is what is the actual biological difference between a mutation and polymorphism, it is not. (That's my pedantic geneticist opinion, anyway.)
Mutation is any change that occurs in a DNA sequence where as a polymorphism refers to the situation when two or more mutations are segregating at the same locus in a population. Locus here is rather general and could be anything from a single nucleotide to a whole stretch of DNA nucleotides (e.g. a CDS of gene).
I would mostly agree with Pär except to clarify that a polymorphism has two or more "alleles" not mutations - one of the alleles is usually the ancestral state. One often comes across people referring to an individual "carrying a mutation" but this is really short-hand for "carrying the mutant allele", which itself is really slang for "carrying the derived allele".
Having said that, I think that in humans, a polymorphism needs a minor allele frequency of at least 1% to be considered a SNP (Single Nucleotide Polymorphism), so you will still find some community-specific variations of the language.
Mutation is a change that is present in less than 1% of the population, and a polimorphism is present in more than 1% of the population.
A genetic polymorphism is a variant of the DNA sequence or of an entire chromosome thought not to have pathogenic consequences. In contrast, a mutation is a change in the DNA or a chromosomal aberration (change) with a pathogenic effect.
For the geneticist, polymorphism (from the Greek meaning "multiple forms") are mutations in the genotype, such as SNPs that have no adverse effects on the individual and occur with high frequency in the general population (more than 1% of the population). While a mutation mutation is a change in the genome that might lead to a pathogenic effect. Be aware that some mutations might be present in more than 1% of the population.
The old population geneticist's definition that specifies that a polymorphism has to occur in at least 1% of alleles is somewhat redundant, as there are many sequence changes that occur at less than 1% and are still considered polymorphisms. The term 'polymorphism' - as opposed to a mutation - has come to mean a sequence change that is largely benign, whereas a mutation is harmful (disease-causing). As a definition, though, it's not particularly helpful, as it has become clear that disease-causing status is not black-and-white. In the example of cystic fibrosis (CF), one can see a complete spectrum of disease-causing potential, from completely benign to severely disease-causing. Even the existence of a sequence change on the same allele (in cis) as a classic disease-causing mutation does not preclude it from being completely benign and there are many examples of so-called 'complex alleles' (two or more sequence changes in one CF allele) in cystic fibrosis. Finally, be aware that this is still a contentious area!
When a mutation frequency is more than 1% in the population it is called as polymorphism
A mutation is any change in the DNA sequence, whether it has a phenotypic correlate or not. A polymorphism is any such a change which segregates in a natural population, usually without any phenotypic effect. I say usually because a phenotypic effect may appear if the environmental or genomic context changes (see the beautiful work of Susan Lindquist on the latter). You can say that the process of mutation is the cause of the polymorphism. But a mutation can also be induced in the laboratory by random or directed mutagenesis (that what some of us spent part of our life doing). Those mutations are obviously not polymorphisms.
In a nutshell:
All polymorphism are mutations (even if we may not be able to establish which is the ancestral form). Not all mutations are polymorphisms
All the confusion comes from the fact that we are talking about different contexts.
1. At the most basic level, molecular genetics, the only relevant concept is mutation: when there is a change as a result of errors in replication, mutagenesis, recombination, etc., there is a mutation.
2. At the population genetics or medical genetics levels we can decide to clasify mutations according to their relative frequency, effect on the function of the gene, etc. Therefore we may distinguish between disease-causing mutations and polymorphissms. But the concept of polymorphism can be different according to field of genetics.
The last two answers are coming to the point:
A mutation is any change of the nucleotide sequence - leading to SNPs (single nucleotide polymorphisms) or RFLPs (restriction fragment length polymorphisms) or AFLPs (amplified fragment length polymorphisms), e.g. methods to detect polymorphisms in a genome.
For many people working in the evolutionary biology, a *mutation* is a general word to describe a change in nucleotides or amino acid sequences. This change may increase in frequency (or even get) fixed in the population if it carries selective advantages, or it may get purged from population if it is detrimental. But even if mutation is neutral for the fitness, its frequency may still increase due to random drift (although not as quickly as in the selection scenario. Mutations at different sites thus lead to us observing molecular differences in populations - these are referred to as *polymorphisms*. Some polymorphisms have very low frequency (eg,
Here is how I think about this distinction, which at least partly incorporates the prior answers. For biochemistry, a polymorphism is one of multiple alternative forms within a protein or nucleic acid sequence. For genetics, a polymorphism refers to genetic variants within the population that allow evolution by natural selection. A mutation is a change in nucleic acid sequence, such as in the sequence of a gene or its regulatory elements. Mutations originate from unrepaired DNA damage caused by replication errors and lesions from endogenous or exogenous mutagens as well as from insertion or deletion of DNA segments of DNA by mobile elements. Mutant proteins or nucleic acids that cause inherited diseases are considered mutations rather than polymorphisms even though they may exist in the population at significant levels – e.g. higher than the 1% level noted. A mutation may create a polymorphism in the population if the resulting variant form is transmitted to subsequent generations without causing major defects in biological functions.
Logically a mutation leads to polymorphism (irrespective to its effect!) which sometimes is not considered to be able to be maintained in a population if its frequency is too low, e.g.
Mutation is a genetic change anywhere in the genome however, a mutation is considered SNP if it is present in > or 1% population.
I feel that both terms are interchangeable when you are at the DNA level. Any mutation will generate variation and hence the polymorphism. However, not all polymorphisms are caused by mutations. Look for example on alternatively spliced genes. There is no apparent mutation in the gene, but the protein products can be vastly different having different, size, structure, enzyme activity and functions. Isn´t it a great polymorhism? In addtion, a whole bonanza of polymorphisms exists at the epigenetic level.. Cheers.
I think that Ales' answer is not correct. Of course, etymologically you can use polymorphism in any of the above senses. But the term has a specific meaning in population genetics and I think we should keep at that to avoid confusion. Different forms of a protein, resulting from alternative splicing are called isoforms. Which can also be used for similar proteins encoded by paralogue genes, which can also be confusing.
The term ˇpolymoprhismˇ should be viewed from different angles as already pointed out by John Tainer. As to the Claudio's answer, I feel feel that proteins encoded by paralogs usually differ genetically since paralogs are homologous genes located at different loci often harbouring specific SNPs.
To me polymorphism is any change in DNA that may or may not cause problem. Usually a DNA change accounts for more than 1% population then it will be called polymorphism. The changes include any kind of mutaion. But, practically we like to describe mutation as DNA changes that lead to dramatical phenotypical changes or diseases. A clear-cut distinction between polymorphism and mutaion is very difficult to me. Especially when a mutaion leads to improved biological fundtion how should we call it?
Simply speaking, mutations that do not change the function of a protein are referred to as polymorphism, e.g. the color of the eyes. Mutations changing or inactivating the protein are referred to as mutations, e.g. conversion of proto-oncogenes to oncogenes
All answers are awesome and to the point. Here i am going to make it more brief; A polymorphism is a change in the DNA sequence that is prevalent in a population more than one percent, while mutation is the variation in the genome whose frequency in a population is less than one percent. good luck
It largely depends on who you ask.
Referring to DNA level, used among users of DNA variant databases and in journals such as Human Mutation, the terms are defined as follows (similar to what Ulrich and Dimiter already mentioned):
- DNA (sequence) variant or allelic variant: general term to describe a variation on DNA level compared to the reference sequence.
- Polymorphism: regardless of frequency in any population, a polymorphism is a DNA variant that does not cause a disease (non-pathogenic).
- (DNA) Mutation: regardless of frequency in any population, a mutation is a DNA variant that causes a disease (pathogenic).
The Human Genome Variation Society (HGVS) describes this issue on their website:
``In some disciplines the term "mutation" is used to indicate "a change" while in other disciplines it is used to indicate "a disease-causing change". Similarly, the term "polymorphism" is used both to indicate "a non disease-causing change" or "a change found at a frequency of 1% or higher in the population". To prevent this confusion we do not use the terms mutation and polymorphism (including SNP or Single Nucleotide Polymorphism) but use neutral terms like "sequence variant", "alteration" and "allelic variant",,
A polymorphism is a mutation, the frequency of which in the population cannot be explained by mutation alone (e.g. mistakes in DNA synthesis). In other words, polymorphisms are explained by mutation plus demographic forces, such as founder effects, natural selection, genetic drift, population expansions and admixture. Mutations are typically rare, private to individuals or small families. Polymorphisms are more widely distributed amongst unrelated individuals in a population.
The term genetic polymorphism was originally coined by Ford in the 1940s. This is what he had to say: "Genetic polymorphism is the simultaneous occurrence in the same locality of two or more discontinuous forms in such proportions that the rarest of them cannot be maintained just by recurrent mutation or immigration".
I'm with Nabi...
A mutation is a genetic variant in the DNA. If that mutation occurs in more than 1% of the population, it is considered polymorphic and thus a polymorphism.
The 1% cutoff definition is a practical definition but it is arbitrary. It reflects the idea that mutation is rare and only present in families, whilst polymorphisms are mutations that are common amongst unrelated individuals. We all harbour mutations that are only found in ourselves or immediate family members. Polymorphisms on the other hand are the product of population history plus mutation.
Super set to sub set. A mutation can be used to refer to a change. It also depends on the discipline where the term is used. Strictly speaking a mutation is a change in DNA sequence, with or without an expressed variation in the phenotype. These changes can be spontaneous or conserved within a genome, they can give rise to no observed variation, a benign/beneficial variation or negative/pathogenic variation and it is important to distiguish between a single organism, clonal expansion or group amongst other groups. A polymorphism can be considered a conserved mutation that is observed with a given frequency amongst a population, possibly linked or correlated with other changes.
Within medicine, given its focus, expressed mutations (phenotypic variations) tend to be pathogenic or confer benefit.
The main difference here is that every polymorphism can be viewed as a mutation originally, as it had to result from a change in the DNA sequence at some point. A mutation is a change in the DNA sequence. A polymorphism is a term used for how we index these changes within a genome of interest, cross-sectionally rather than longitudinally (indexed by time).
I hope that was not too garbled. Please let me know if you would like to discuss.
A mutation is defined as any change in a DNA sequence away from normal. This implies there is a normal allele that is prevalent in the population and that the mutation changes this to a rare and abnormal variant.
In contrast, a polymorphism is a DNA sequence variation that is common in the population. In this case no single allele is regarded as the standard sequence. Instead there are two or more equally acceptable alternatives.
I would like to caution the interpretation of polymorphism as a mutation without change protein function or causing disease. There are many studies demonstrating cetrain polymorphism may not cause acute disease but lead to higher chance of dysfunction. I personally agree that polymorphism is a kind of mutation that happen in more than 1% of the population. The 1% is an arbitarily defined number.
There is also the semantic aspect. Whereas "polymorphism" implies some previous comparison of sequences or mapping of loci on a subpopulation, i.e. in SPACE, the term "mutation" does not invoke any such idea, and if so, it is a change happening in TIME, rather than in space. This is meant as an addition to the previous statements, not a correction.
Polymorphism is any change in DNA and mutation is a change which in some manner influense the expression of the gene (usually in exons)
All polymorphisms are in a way a mutation but not all cause mutations in the protein. Some are silent or code for the same protein. The polymorphism is a place where not all of the population shares the same sequence in turn there could be a number of versions or alleles.
i am not so sure that the question ment polymorphism WRT chromosome. polymorphism, in a general sense, means present in more than one form simultaneously. for example, Carbon can take the form of graphite, diamond,...etc.
as to the biology arena, i think polymorphism can be the result of crossing over between chromosome, or deletion of a piece from one chromosome without affecting the developmental process of the organism. i see polymorphism possiblity to happen in lower forms that rely on fewer number of chromosome, where little chromosomal change can be detected in the phenotype.
mutation has been tackled enough in other comments
polymorphism is defined as DNA or chromosome have in many variant form which may or may not caused disease but in case of mutation only some part or segment of DNA changed which further effects on protein expression
Mutation is the event of changing one or more nucleotides in an organisms' DNA sequence. If this mutation is spread to the population since it is not or not strongly selected against then it contributes to genetic variation of the population and is called polymorphism.
A mutation is a change in the sequence of a gene compared to that of the population. A polymorphism is a "variant" that is present in the population with a frequency of 1% or greater. Then, a random mutation is presented in the population with a frequency of less than 1%, when this percentage is equal or higher than 1% is called polymorphism or variant.
a variant does not necessarily create a different protein. these definitions are closely related to the DNA sequence. Therefore two individuals that produce the same protein (which therefore have the same amino acid sequence) can have 2 different variants (the nucleotide sequence is different in a nucleotide base).
Dear Pfeffer,
little confusion from your text, the extreme case of mutation is polymorphism so if mutation is not spread to that extent to make a variant in popolation then it is not polymorphism. if it is possible the mutations make variant then give example????
Dear Pfeffer,
A mutation is defined as any change in a DNA sequence away from normal. This implies there is a normal allele that is prevalent in the population and that the mutation changes this to a rare and abnormal variant.
In contrast, a polymorphism is a DNA sequence variation that is common in the population. In this case no single allele is regarded as the standard sequence. Instead there are two or more equally acceptable alternatives. The arbitrary cut-off point between a mutation and a polymorphism is 1 per cent. That is, to be classed as a polymorphism, the least common allele must have a frequency of 1per cent or more in the population. If the frequency is lower than this, the allele is regarded as a mutation.
Best Regards
Mutation is a change in DNA sequence. Polymorphism is consequence of this mutation so if the mutation is spread to the population then it contributes to genetic variation of the population and is called “polymorphism”.
A mutation is any alteration or change in the genetic information and therefore produces a conformational change in the characteristics of the genomic structure of an individual, can occur spontaneously, is transmitted hereditarily and it can be classified as pathological. Furthermore, a polymorphism is a normal variation in the DNA sequence between various individuals who come to appear more frequently than mutations in at least 1% of the population, most polymorphisms are from silent mutations or not changes in phenotype.
Within Cancer research, polymorphism refers to germline (inherited) genotypes, while mutation refers to a somatic event within the malignancy. To account for both, best tumour sequencing studies include matched normal DNA (e.g. blood samples) to differentiate the tumour-specific mutations from the background polymorphic genotype.
I would exercise caution linking either polymorphism or mutation to functional consequences. There are plenty of somatic silent mutations, and plenty of functional polymorphisms underlying the variation in our appearances, skills and predisposition to various diseases.
For me, a particular biochemical event or MUTATION occurs once, producing a variant at a particular locus that would not have been produced by assortment from the parental genomes. All of the descendents then carry one variant of the POLYMORPHISM, or one of several possible sequences at that locus, in their unique genomes.
I agree with Sibtain Afzal. It's all about % of prevalence in population. Less than 1% would imply the change considered as mutation!
simple answer frequency. By convention, >1% in the population being studied: polymorphism. Mutation often used int eh context of a rare deleterious change but could equally reply to any change form the "normal" sequence. Some researchers have tried to coin the term "paucimorphism" , allele freq. 0.05 to 0.0005 (Day et al 2004, Current Genomics 5; 431-438).
"normal", "threshold", "common" are all very subjective and they won't give a clear definition of polymorphism and mutation.
In molecular biology, meaning of "mutation" suggests that the scientist has detected the substitution of a single nuclei acid within a defined period.
In medical biology, we are referring to "mutation" to correlate DNA variations with diseases regardless their prevalence and their nature: somatic or inherited (i.e BRAC1 and breast cancer). However, in this case this should be defined as a polymorphism, but we are inferring that a mutation is a bad event since polymorphism is either neutral or good for health. This is not a very rational definition for mutation.
"Polymorphism" is a variation in DNA which happened to an undetermined time and has been selected in a species over generations. Polymorphism belongs to "normal" DNA sequences, and is characterized by its prevalence in a population.
Therefore, I agree with Anna Git perception, polymorphism should be applied to inherited DNA variations among a population, while mutation is a DNA variation presents in some cells but is not representative to the inherited DNA of a single organism.
As others already have mentioned - the only difference is the frequency in the population with the arbitrary 1% cuttoff (http://genome.wellcome.ac.uk/doc_WTD020780.html).
Has anybody a publication/source introducing this cuttoff?
I disagree with all those using frequency as the difference. Frequency is a useful tool to try and extract useful/robust polymorphisms from data but 1% is entirely arbitrary and actually dates back to a time where data was much thinner on the ground. In a population of 1 billion, a genetic variant shared by 1 million is still a polymorphism, even though it is only 0.1% of the population.
A *mutation* is a physical event in a single individual/cell. A polymorphism is a population attribute. Unless they are lethal or somatic*, mutations can give rise to polymorphism following increases in frequency due to either selection or genetic drift. In this case, one might refer to the "mutation" spreading or an individual "carrying a mutation" but this is just short-hand for "the mutant allele", i.e. "the genetic variant generated by the mutation" - it is not ACTUALLY a mutation unless it arose de novo since the previous generation. (*In some cases, it might even be useful to consider polymorphisms within populations of somatic cells.)
When the new variant has some kind of affect, such as causing a human disease, it is obviously useful to use such short-hand but we should not confuse convenience/utility/convention with reality. (Or, to put it another way, one possible reason that the difference between polymorphism and mutation confuses some people is that "mutation" is being over-used in a rather lazy fashion to mean something that it does not. There is nothing wrong with "low frequency variant" if that is what you mean.)
If the question is what do people mean when they say "mutation" or "polymorphism" then frequency might be important, depending on who that person is and in what field they work. (I think the 1% thing is a much more fixed convention in human genetics than genetics in general.) If the question is what is the actual biological difference between a mutation and polymorphism, it is not. (That's my pedantic geneticist opinion, anyway.)
Regardless of what various books may or may not say, I think it is useful for multiple reasons to distinguish mutations as changes in genes that result in defective, disease-causing phenotypes whereas polymorphisms are relatively benign, i.e. even if they cause variable phenotypes they do not cause disease. Furthermore I do not think the 1% threshold holds up from known data. I consider genetic disorders to result from mutations that cause defects in gene function. In the Ashkenazim group, for example, women have a high (2.5%) prevalence of BRCA1 and BRCA2 gene mutations resulting in breast and ovarian cancer, and ~1 in 25 Ashkenazim are carriers for these mutations.
@John, what's the problem with calling an allele a "disease-causing allele" or "risk factor"? It is entirely plausible for an allele to be entirely benign in most of the population and only have an effect on certain genetic backgrounds. Is this a "mutation"? What if, like the famous sickle-cell Glu6->Val Hb allele, the "mutation" is both beneficial and disease-causing in an environment- and/or genotype-specific fashion? Personally, I think that we need to move AWAY from trying to think of everything as "Wildtype" versus "Mutant" - the reality is lot more complicated and variable than this dichotomy implies. It is useful for inbred laboratory model organisms (and teaching concepts) but not for real populations.
To take your example, do the Ashkenazim group actually have an elevated mutation rate in BRCA1 and BRCA2? If not, the language is confusing - they actually have a high prevalence of disease-associated change-of-function alleles due (presumably) to population founder affects. The origin of deleterious alleles is important - a high prevalence of *mutations* (i.e. de novo genetic alterations) would imply that there is an environmental element to the problem beyond ancestry, with tremendously different implications for treatment, screening etc.
"The only solution would be an international agreement in which the term are clearly defined."
A more immediate/pragmatic solution is that everyone makes it clear what they mean by particular terms when they use them, especially if they deviate from the "correct" specific technical definitions. I may not agree that a "mutation" is a "disease-causing genetic variant" but at least I will be able to follow your paper if you write something like "the high frequency of mutations (i.e. disease-causing genetic variants) this population..." or "X polymorphic sites (minor allele frequency >=1%)..." or "in this paper we refer to polymorphisms with a minor allele frequency under 1% as 'rare genetic variants'..." etc.
Community-specific conventions and field-specific definitions will always be with us and, as science gets increasingly interdisciplinary, it is increasingly important to make those clear to people outside those communities/fields. Getting *everyone* to agree on a harmonized definition... good luck with that one! :op
Historically in Population Genetics, E.B. Ford (1940) defined polymorphism as the occurrence together of two or more discontinuous forms of a species in such proportions that the frequency of the rarest form is above the mutation rate.
In the 1960s Harry Harris, gave it numerical values thus:
a locus or a gene is defined as being polymorphic if the frequency of the most common allele is less than 0.99 if the sample size is large (N=100 or more) or less than 0.95 if the sample size is small.
In molecular genetics you will be probably concerned only with the mutation concept. But in population genetics you will certainly be intrested in which of all posible mutations of a gene are fixed in the population. This means that you want to know which mutations are carried with frequency different from cero across all individuals of that population. Alternatively stated, polymorphism means that in a population more than one gene are distributed across the population. Mutation is the mechanism by which such variety is originated, natural selection is then the mechanism by which the variant gene gets fixed or sorted out.
Both terms are not very useful. In clinical diagnostics both terms are therefore to be avoided. A pathogenic mutation is a genomic variant that may cause or causes a disease. Polymorphism is generally regarded as a variant with a frequency over 1%. However, that does not exclude pathogenicity. It is therefore better to use the phrase 'neutral variant' if you mean a variant that is proven to be not causal.
I agree that it is best to avoid the term "mutation" if one simply means a "disease-causing variant" because it is ambiguous and gives the impression that all changes to DNA are necessarily damaging.
Even the concept of a "disease-causing variant" is fuzzy since many variants have multiple effects which can be either harmful or beneficial depending on the circumstance. Richard Edwards above mentioned the classic sickle-cell variant. Another more recent example could be the Leu vs Pro variant in GCKR (rs1260326) which is associated both with increased triglyceride levels and decreased glucose levels. This table shows many polymorphisms with differing effects on different glucose-related traits: http://circgenetics.ahajournals.org/content/5/2/242/F2.large.jpg
Perhaps in human biology, mutation is best reserved for either "somatic mutations" where one has sequenced the tumor tissue and adjacent healthy tissue, or for "private mutations" where one has sequenced the patient/proband and the parents.
In addition to being arbitrary, a frequency cutoff is also ambiguous as the frequency of a given variant can vary widely from population to population. Consider this variant in the ABO gene:
http://alfred.med.yale.edu/alfred/mvograph.asp?siteuid=SI610970X
The frequency ranges from 0% in an African population to 100% in a South African population, with other groups having every value in between. As human sequencing data continues to explode, this observation is likely to apply to more and more polymorphisms.
In Population Genetics it is the norm for a gene to be polymorphic in one population but idiomorphic (i.e. frequency of the most common allele being more than 0.99 or 0.95 depending on sample size) in another. This applies to all species not only to humans and to all categories of genetic markers.
I do not agree on the definition of Ghazala Rubi. this definition of polymorphism is not complete because it takes account only of polymorphisms RFLP (Restriction fragment length polymorphisms) that are only a small part of existent polymorphisms. Most polymorphisms are SNPs (single nucleotide polymorphism) that are not identifiable with restriction enzymes.
The main differences between the mutation and polymorphism: mutation is rare and deleterious, while polymorphism is common and tolerated.
Mutation is the basis of some polymorphisms. Here I compare it with SNP (single nucleotide polymorphism). When a mutation occurs in DNA sequence, it has a long way to become a SNP. It must not be deleterious enough to kill the organism (for this reason non-coding polymorphisms are well spread among spices). It must be stable and reaches to a minimal frequency among the entire population then become a SNP.
Consider missence mutations, which are point mutations whereby a single nucleotide change codes for a different amino acid. Such missense mutations can occur at several sites within a protein and are responsible for multiple diseases including SOD1 mediated ALS (see Science 1993 261, 1047-51). Whereas in some sense these are polymorphic variants within the population, the notable feature of these changes is that they are disease-causing mutations.
Polymorphism is a set of mutation variants. Moreover, genetic mutations can occur in a gene (such as SNP transition, transversion, insertions, deletions), in a chromosome (such as translocation, inversion, interstitial deletion, duplication mutations) and in a genome (polyploidy, aneuploidy). Also, it is important to keep in mind that mutations can be negative, neutral and positive. Additionally, a polymorphism may be evolutionary fixed in a population with a frequency more than 1 per cent. It can also be not fixed but found in DNA.
@Maxat, when we describe a genetic variant as "fixed" in a population, we normally mean that it has essentially reached a frequency of 100%. (Mutations etc. will keep it just under 100% in reality.) By definition, polymorphisms are NOT fixed variants unless you are considering different levels of population, e.g. a genotype may be fixed in a sub-population but polymorphic in the population as a whole.
@Richard, yes of course, if the frequency of the allele is at 100% it is said to be "fixed genetic variant" in the population. But I mean evolutionary fixed mutation as a "genetic polymorphic allele with appreciable frequency" in population (Cavalli-Sforza & Bodmer). We can find a mutation with frequency of less than 1% in the population. It is just a one-off de novo mutation. It will probably not passed on to the next generation and will disappear without becoming as polymorphism in the population.
Polymorphism originated as a mutation. This mutation did not markedly affect the health. In some cases the mutation may be beneficial to the carrier; thus the mutation spreads. If it reaches to a certain threshold, set by some as 5% of the population, others lower it, the mutation would be considered as a polymorphism. Thus the main difference is in the number of the people have the mutation/polymorphism in population.
"The only solution would be an international agreement in which the term are clearly defined"
This is an interesting discussion but it is sad that people are constantly trying to reinvent the wheel. This question and many related to 'mutations' and 'polymorphisms' has been debated discussed and to some extent agreed upon over the past 20 years or more. Indeed, an international body was set up some 20 years ago to consider and make recommendations on such questions. Please see the extensive resources available at the Human Genome Variation Society (http://www.hgvs.org/).
Polymorphism is a term mainly to describe the structural aspect of a gene, whereas mutation is more meaningfully used to describe the functional aspect of a gene. Can you use your own words to explain them, instead of throwing to others an org-link which is not your own knowledge? Whatever the agreement over 20 years ago was and it is still unclear and confusing to the person who raises the question. Use the current scientific concept to explain more clearly to everyone, please.
I am surprised by the answers here. Mutation is a genetic term that refers to a heritable change or phenotype different from the wild-type. Many mutations in flies and mice were described morphologically, before we even knew that DNA was the genetic material. Polymorphisms or SNPs are variants that are NOT mutations unless they result in a measurable change in phenotype and function. For the vast majority of polymorphisms we do not know whether they have an effect at all. Remember, when it comes to humans or any outbred population, we really do not know what is the reference genome, so any variation in sequence that does not affect phenotype is a polymorphisms, not a mutation.
Dear MH Zhou,
My apologies to you and anyone else who thought my answer was dismissive; I certainly did not want to fob anyone off with a link to a web site. Those who know me know that I am only too happy to offer my own opinion but on this occasion, for brevity, I thought it would be helpful to offer the combined wisdom of a very large number of Geneticists who have considered these issues over a very long period. I will offer my opinion but I would also recommend the Human Genome Variation Society as a source of combined wisdom of numerous eminent human geneticists on this and other issues related to Human genetic variants. The HGVS evolved out of the efforts of several prominent human geneticists who initially formulated recommendations on a standard system for naming human “mutations” see (Antonarakis, 1998; Beaudet and Tsui, 1993).
My opinion:
The term mutation has been used in human genetics to mean a pathogenic DNA variant. Although I am sure people will continue to use this meaning, I believe it is erroneous and misleading. There are some well accepted definitions for mutation and polymorphism:
Polymorphism: Two or more alleles that can exist at a locus (with significant frequency, usually > 1% allele frequency).
Mutation: A de novo (new) change of the DNA sequence within a gene or chromosome in the somatic or germline tissues of an individual (once it is passed to an offspring it is no longer a mutation, rather it is an inherited DNA variant).
Based on these definitions the current usage is totally incorrect. I would suggest the use of the term “pathogenic DNA variant”.
Trying to distinguish polymorphisms and mutations based on whether they alter function or cause disease is also totally incorrect. It has been apparent for decades that common polymorphic variants can contribute to or even cause significant disease (usually in combination with other ‘harmless’ DNA variants). Just look at the massive amount of data being published on the role of polymorphisms in complex genetic traits such as schizophrenia, diabetes, heart disease, etc.
They are all just DNA variants, some are common, some are rare, some alter function others do not (that is why the HGVS uses “Variation” in their name not mutation or polymorphism).
Anyhow, that is my two bob's worth (apologies to those not familiar with pre-decimal British currency jargon)!
Antonarakis SE. (1998) Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat 11: 1-3.
Beaudet AL, Tsui LC. (1993) A suggested nomenclature for designating mutations. Hum Mutat 2: 245-248.
Genome wide association studies do show that there are correlations between some polymorphisms and complex traits like hypertension or diabetes. But, often the contribution of any single allele is very small, on the order of 1-5% increased risk. I think this makes it difficult to conclude that this allele or variant is a mutation. Indeed the risky allele may even have been the founder allele and may have had some benefit to reproductive fitness in more primitive populations.
WOW. This is a great discussion.
The interest for this topic maybe is a sign that we have to rethink something that before the era of NGS we took as a dogma.
The use of a simple percentage (1%) to distinguish between mutations from a SNP is clearly not acceptable anymore. This threshold does not make sense for the reasons mentioned above. It is also extremely difficult to make predictions on the consequences of a SNP/Mutation. So I also agree that a functional distinction between SNP/Mutation is not a feasible path. Indeed, there are SNP associated to diseases and there are mutations which do not change the phenotype of an individual.
Whatever was written 15 or 20 years ago by the most prominent scientists was driven by the knowledge available at the time. Now our analytic power is magnitude higher and our coverage of the human genome is showing genetic differences with a level of detail simply not conceivable even five years ago. Now this kind of depth can get inside not only the single individuals but the single cells.
With the current knowledge for me it makes sense to define as a mutation something which is acquired in a somatic cell line and differs from the germ line sequence of an individual. All the rest for me are polymorphisms including SNPs acquired during the evolution and responsible or not for phenotypic changes, including the possible development of a disease.
From a practical perspective this makes very important in oncology to sequence both germ line and cancer in order to focus only on those DNA changes which are real mutations acquired in somatic cells and not polymorphisms.
Cristiano, you make an excellent point about germline versus somatic variation. Indeed, with single cell sequencing we now know that the rate of somatic "variation" is much higher than we thought. We are accumulating changes in DNA sequence over a lifetime. Fortunately, most will not be passed on to the next generation. I would agree that it is time to retire the term "mutation".
Gregory,
I am not sure I would use GWAS as a good example (their success rate has hardly been spectacular). Nevertheless there are numerous clear examples of "polymorphisms" causing pathology even for monogenic disorders like cystic fibrosis. There is also very good evidence that many polymorphisms significantly affect protein function (often by as much as 90% reduction in activity without necessarily producing pathology). So I still say that linking the term "mutation" to pathology or function is wrong.
The frequency of DNA sequence variation and its effect on protein products determines the change as polymorphism or mutation. if a change is frequently present in a population and is not associated with any disease phenotype is considered polymorphism and in other case as mutation.
When I teach genetics (e.g. Useful Genetics on Coursera) I say that a mutation is an event that changes a DNA sequence in a cell or organism, or the specific change that results from such an event.
The terms sequence variant and polymorphism refer to DNA sequence differences in populations, with variant referring to any sequence difference, regardless of type or frequency. By convention the term polymorphism refers to variants that are present in at least 1% of the population being considered.
Single-nucleotide variants (SNVs) and single-nucleotide polymorphisms (SNPs) refer to variants in which the difference is only the identity of a single nucleotide of the sequence.
All of these terms are formally independent of the effect of the mutation or variant on phenotype. However in casual usage the term mutation is often used to mean sequence changes that have harmful phenotypic effects. Polymorphisms are commonly not harmful; otherwise they wouldn't be able to persist in the population.
What does it mean "Polymorphisms are commonly not harmful"?
Think about type II diabetes and SNP RS7903146 just to make an example. This SNP is really robust in predicting the risk of developing the disease and validated in a very consistent number of studies (PMID: 16415884). In particular the TT phenotype is associated with increased risk. It is likely that 2,000 years ago having this SNP in a time when food was scarce was an advantage in evolutionistic terms. But now with all the sugars present in our tables to have this SNP is a trait which increases the probability to develop type II diabetes of around 60% (Hazard Ratio 1.6 in Caucasians).
Is that a mutation? According to the dogma, No, since its expression is higher than 1%. Is it harmful? The answer is Yes since there is an increase of developing type II diabetes.
I fully agree with Phillip. The functional criterion cannot be used to distinguish a polymorphism from a mutation. Actually, if some SNPs are so present in the population is because they conferred in the past an evolutionistic advantage. Therefore, it is possible that they have an impact on the phenotype. The sense of the impact (harmful or not) is not predictable and dependent on the interaction with other factors genetic or not as in the above mentioned example.
It is time to rethink the concept of mutation and conveniently adapt the terminology.
As mentioned above, the discussion is not trivial since practical consequences originate. What is normal and what is pathologic? As I discussed for me every individual has a reference in the germ line cells. A mutation is a deviation of the reference in a somatic cells All the differences in the germ line as compared to another germ line or a pooled population of germ lines is a polymorphism.
@Cristiano, there is also such a thing as germline mutation. (I think that Rosie Redfield's definition of mutation is a good one.)
@Oliver, I am not entirely sure what a white paper will achieve. It seems more like the kind of thing for an opinions piece in a relevant journal - and perhaps a bit more pedantry during peer review.
@Richard
In my assumption germ line mutation does not exist. Mutation will be defined as a difference in a somatic cell as compared with germ line cells of the same individual. A difference in a germ line cell as compared with a reference formed by a population of germ line cells will be always a polymorphism. If then the polymorphism in a specific locus produce a variant linked to a disease this would be defined as pathogenetic polymorphism and not mutation just to differentiate the two kinds. You correctly pointed out above that the use of the frequency 1% does not make sense, since at the end more genomes we will sequence more rare events in the genome we will find which with the current nomenclature we don`t know how to label.
@Oliver
The debate and the different opinions noticed in this thread make clear that we would need a new way to define "mutations" and "polymorphisms".
Otherwise we will continue to use definition which are anachronistic such as a SNP is a mutation present in >1% of the population
First, I would like to crystallize the problem before I offer my opinion.
There was never any confusion with these terms until very recently. The dilemma becomes obvious for the scientist who has the unenviable task of interpreting nucleotide variations found in a client's DNA test: is it just an innocent SNP or a potentially dangerous (or pathologic) change?
My opinion: I also believe the term "mutation", as presently defined (in Classical Genetics) should be rested, or redefined to mean what we all (the new "Genetic Generation") have taken it (albeit loosely) to mean; i.e. pathologic phenotype/import.
The obvious implication of this is that for every possible change (or variation) at any one locus, we need clinical annotations or correlations to make predictions of the prognostic import of each change. And some form of model (software) to predict risk summations.
Using this format, it would then mean that all nucleotide changes for which a pathogenic phenotype cannot be proven, should be "dismissed" as "benign" changes (or true polymorphisms/SNPs).
@Anthony. Everyone has the power to use a word however they like, but except in a classroom situation nobody has power to enforce their preferred usage on others.
The term 'mutation' is used very widely in a broad range of evolutionary, experimental, bioinformatic and clinical contexts. The meanings intended in these contexts have a great deal of overlap, but they're certainly not identical. If you would like to have a term that specifically means 'pathologic phenotype/import', using a new or underused term is likely to be more successful than using 'mutation'.
@Oliver: It may well be a good idea to review the usage of these terminologies from various disciplines, and find areas of common agreement. I will be interested to contribute a clinician's perspective to the article.
@Rosie: Thanks for your comments; they are noted. However, If you will, carefully go through my submission again and you will find that it was not intended "to enforce" my "preferred usage on others". I have only expressed opinions based on my experience, just as you (and everyone else) have done.
When we try to explain our "technical jargon" to laypersons, we will find that what is paramount to them is whether this change calls for concern. Is it just "one of those things" (i.e. a benign change, without any import) or something potentially harmful, requiring some form of action. And scientifically, I have come to believe that when we say polymorphism (whether single nucleotide or haplotype), we are in essence saying that it is one of the many options/variants that are recognized to be normal (or "wildtype") for that locus; and which should mean there is no cause for worry. On the contrary, when we say mutation, we are saying: this is "new" (either to the person/genome or science), is not one of the recognized variants; and calls for further scrutiny. Apologies to all those who may consider this an over-simplification of a rather grievous matter.
Cristiano, I fail to understand how you can assume that "germ line mutation does not exist" when it theoretically must do and empirically does! If you sequence sperm, you will find many germline mutations (in the true classical genetics sense) and it is increasingly common to perform whole exome or genome sequencing on the parents of a patient with a rare genetic disorder with no familial history in order to identify the germline mutation responsible for the disease. Furthermore, if you consider viruses or unicellular organisms, *all* mutation is (effectively) germline!
I completely disagree with Anthony (and agree with Rosie). There is no need to redefine mutation and drop its classical textbook (arguably "correct") definition. If anything needs to be dropped it is the mentality that sequence variants can be easily defined as pathogenic or benign and that "mutation" is a good word to use in this context.
In natural populations - including humans - polymorphisms (including rare genetic variants) can have a range of affects that are dependent on the genetic background in which the variant sits. We already have terminology to describe this (e.g. "risk factor") and whilst it might be that a more precise terminology to define different subsets of genetics variants is useful, I am personally convinced that "mutation" does not belong in that repertoire - in terms of population-level variation, it is a throwback to a naive idea that there exists a "wild-type" human or mouse or plant. Such thinking is neither accurate nor helpful. (Even in the lab, inbred "wild-type" strains are not really "wild-type" as they are not found in the wild and probably contain many fixed low-frequency variants that do not represent the wider population.)
@Oliver, I personally have neither the time nor the familiarity with the relevant literature to contribute. I think that common standards are best defined by international organisations rather than individuals.
Edit: PS. This was cross-posted with Anthony's comment above and is responding to the earlier one.
Anthony, would you not think it was more useful in the long term to make the layperson understand that the notion of "wild-type" and "mutant" is wrong? There is no such thing as a "normal" human. It is normal to be different to everyone else and carry a host of genetic variants that predispose to (or protect against) different diseases. It is true, there are a few strongly-deleterious rare variants kicking around in the population (either dominant de novo mutations or recessive alleles that hang around at low frequency) but these are surely the exception rather than the rule?
@Oliver
I created a google group snpvsmutations
Inside the group we may move forward the task of writing a white paper on this topic which I feel as excellent idea.
https://groups.google.com/d/forum/snpvsmutations
@All
I agree with Oliver and whoever wants to contribute please join the group. Let see if we can wrap up something. There are so many place where we can stimulate the discussion as we did here.
@ Richard
Germ line it means the two cells from which we originate. Each individual has a reference in the genome of the two gonadic cells coming from our parents. What you are mentioning is a a mutation in germ line cells which can be carried to your progeny and will be possibly a part of germ line of another individual.
As specialist in the cancer field, I can tell that it is very common to sequence the cancer but not the germ line (intended as above, namely from example from blood if you have lung cancer). We are missing important peculiarities which are linked to an individual simply because we are taking only the sequence of the cancer and not that of the germ line . We cannot be 100% sure that actually we are in front to a mutation cancer specific rather than a polymorphism.
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