Gene mutation

MUTATIONS 

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Genetica per Scienze Naturali 

a.a. 08-09 prof S. Presciuttini

Genetic mutations 

 

 

A mutation is a herita 

table 

change of the genetic material 

Geneticists recognize three different levels at which mutation takes 

place. 

 

 

 

In gene mutation, , an allele of a gene changes, becoming a different allele. 

Because such a change takes place within a single gene and maps to one 

chromosomal locus ("point"), a gene mutation is sometimes called a point 

mutation. 

In chromosome mutations, , the structure of one or more chromosome is altered. 

Gene mutation is not necessarily a part of such a process; the effects of 

chromosome mutation are due more to the new arrangement of chromosomes and 

of the genes that they contain. Nevertheless, some chromosome mutations, in 

particular those proceeding from chromosome breaks, are accompanied by gene 

mutations caused by the disruption at the breakpoint. 

In genome mutations, , whole chromosomes, or even entire sets of chromosomes, 

change. Duplications of entire genomes in the course of evolution are particularly 

important as a mechanism resulting in sudden expansions in gene number 



Basic terminology about gene mutation 

The ultimate source of genetic variation is gene mutation 

To consider change, we must have a fixed reference point, or standard. In genetics, 

the wild type provides the standard (the wild-type allele may be either the form 

found in nature or the form found in a standard laboratory stock). 

Any change away from the wild-type allele is called forward mutation; any 

change back to the wild-type allele is called reverse mutation. 

The non-wild-type allele of a gene is often called a mutation. . To use the same word 

for the process and the product may seem confusing, but in practice little confusion 

arises. 

Thus, we can speak of a dominant mutation or a recessive mutation. Consider, 

however, how arbitrary these definitions are; the wild type of today may have been a 

mutation in the evolutionary past, and vice versa. 

Another useful term is mutant. . A mutant organism or cell is one whose changed 

phenotype is attributable to the possession of a mutation. Sometimes the noun is left 

unstated; in this case, a mutant always means an individual or cell with a phenotype 

that shows that it bears a mutation. 

Two other useful terms are mutation event, , which is the actual occurrence of a 

mutation, and mutation frequency, , the proportion of mutations in a population of 

cells or individual organisms. 



Somatic mutations 

A somatic mutation occurs in a single cell of developing somatic tissue in an 

individual organism; that cell may become the progenitor of a population of 

identical mutant cells, all of which have descended from the cell that mutated; ; this 

phenomenon is particularly important in cancer. 

A population of identical cells derived asexually from one progenitor cell is called a 

clone. . Because the members of a clone tend to stay close to one another during 

development, an observable outcome of a somatic mutation is often a patch of 

phenotypically mutant cells called a mutant sector. The earlier in development the 

mutation event, the larger the mutant sector will be. 

Somatic mutation in the red Delicious apple. The 

mutant allele determining the golden color arose in a 

flower's ovary wall, which eventually developed into 

the fleshy part of the apple. The seeds are not mutant 

and will give rise to red-appled trees. In n fact, the 

golden Delicious apple originally arose as a mutant 

branch on a red Delicious tree. 



Germinal mutations 

Somatic mutations are never n 

passed on to progeny. 

On the contrary, mutations that occurs in the germ line, special tissue 

that is set aside in the course of development to form sex cells, will be 

passed on to the next generation. . These are called germinal 

mutations. 

An individual of perfectly normal phenotype and of normal ancestry 

can harbor undetected mutant sex cells. These mutations can be 

detected only if they are included in a zygote. 

 

For example, the t 

X-linked hemophilia mutation in European royal families is 

thought to have arisen in the germ cells of Queen Victoria or one of her parents. 



Hemophilia 

The original hemophilia mutation in the pedigree of the royal families of Europe arose 

in the reproductive cells of Queen Victoria's parents or of Queen Victoria herself. 



Point mutations: base substitutions 

Point mutations typically refer to alterations of single base pairs of 

DNA or of a small number of adjacent base pairs. 

At the DNA level, there are two main types of point mutational 

changes: base substitutions and base additions or deletions. 

Base substitutions are those mutations in which one base pair is 

replaced by another. Base substitutions again can be divided into two 

subtypes: transitions and transversions. 

Addition or deletion mutations are actually of nucleotide pairs; 

nevertheless, the convention is to call them base-pair additions or 

deletions. The simplest of these mutations are single-base-pair 

additions or single-base-pair deletions. Gene mutations may arise 

through simultaneous addition or deletion of multiple base pairs at 

once. 



Functional consequences of base changes 

We first f 

consider what happens when a mutation arises in a polypeptide coding part 

of a gene. Depending on the consequences, single-base substitutions are classified 

into: 

Silent or synonymous mutations: the mutation changes one codon for an amino acid 

into another codon for that same amino acid. 

Missense mutations: the codon for one amino acid is replaced by a codon for another 

amino acid. 

Nonsense mutations: the codon for one amino acid is replaced by a translation 

termination (stop) codon. 

The severity of the effect of missense and nonsense mutations on the polypeptide 

may differ. If f a missense mutation causes the substitution of a chemically similar 

amino acid (conservative substitution), 

then it is likely that the alteration will have 

a less-severe effect on the protein's structure and function. Alternatively, chemically 

different amino acid substitutions, called nonconservative substitutions, are more 

likely to produce severe changes in protein structure and function. 

Nonsense mutations will lead to the premature termination of translation. Thus, they 

have a considerable effect on protein function. Unless they occur very close to the 

3’ end of the open reading frame, so that only a partly functional truncated 

polypeptide is produced, nonsense mutations will produce inactive protein products. 



Functional consequences of frameshift mutations 

On the other hand, single-base additions or deletions have 

consequences on polypeptide sequence that extend far beyond the site 

of the mutation itself, like nonsense mutations. 

Because the sequence of mRNA is "read" by the translational 

apparatus in groups of three base pairs (codons), the addition or 

deletion of a single base pair of DNA will change the reading frame 

starting from the location of the addition or deletion and extending 

through to the carboxy terminal of the protein. Hence, these lesions 

are called frameshift mutations. 

These mutations cause the entire amino acid sequence translationally 

downstream of the mutant site to bear no relation to the original 

amino acid sequence. 

Thus, frameshift mutations typically exhibit complete loss of normal 

protein structure and function. 



Examples of point mutations 



Mutations in non-coding regions 

Now let's turn to those mutations that occur in regulatory and other non-coding 

sequences. Those parts of a gene that are not protein coding contain a variety of 

crucial functional sites. At the DNA level, there are sites to which specific 

transcription-regulating proteins must bind. At the RNA level, there are also 

important functional sequences such as the ribosome-binding sites of bacterial 

mRNAs and the self-ligating sites for intron excision in eukaryote mRNAs. 

The consequences of mutations in parts of a gene other that the polypeptide-coding 

segments are difficult to predict. In general, the functional consequences of any 

point mutation (substitution or addition or deletion) in such a region depend on its 

location and on whether it disrupts a functional site. Mutations that disrupt these 

sites have the potential to change the expression pattern of a gene in terms of the 

amount of product expressed at a certain time or in response to certain 

environmental cues or in certain tissues. 

It is important to realize that such regulatory mutations will affect the amount of the 

protein product of a gene, but they will not alter the structure of the protein. 



Mechanisms of Spontaneous Mutation 

The origin of spontaneous hereditary change has always been a topic 

of considerable interest. It is known now that spontaneous mutations 

arise from a variety of sources, including errors in DNA replication, 

spontaneous lesions, and other more complex mechanisms. 

Spontaneous mutations are very rare, making it difficult to determine 

the underlying mechanisms. How then do we have insight into the 

processes governing spontaneous mutation? Even though they are 

rare, some selective systems allow numerous spontaneous mutations 

to be obtained and then characterized at the molecular level for 

example, their DNA sequences can be determined. From the nature of 

the sequence changes, inferences can be made about the processes that 

have led to the spontaneous mutations. 



Errors in DNA replication 

Mispairing in the course of replication is a source of spontaneous base substitution. 

Tautomers of bases 

Each of the bases in DNA can appear in one of several forms, called tautomers, 

which are isomers that differ in the positions of their atoms and in the bonds 

between the atoms. The forms are in equilibrium. The keto form of each base is 

normally present in DNA, whereas the imino and enol forms of the bases are rare. 

Mispairs resulting from the change of one tautomer into another are termed a 

tautomeric shift. 

Most mispairing mutations are transitions. . This is likely to be because an A·C or 

G·T mispair does not distort the DNA double helix as much as A·G or C·T base 

pairs do. An error in DNA replication can occur when an illegitimate nucleotide pair 

(say, AC) forms in DNA synthesis, leading to a base substitution. 

Mispairs can also result when one of the bases becomes ionized. . This type of 

mispair may occur more frequently than mispairs due to imino and enol forms of 

bases. 



Base mismatches 

Mismatched bases. (a) Mispairs resulting from rare tautomeric forms 

of the pyrimidines; (b) mispairs resulting from rare tautomeric forms 

of the purines. 



From mispairs to mutations 

(a) A guanine undergoes a tautomeric shift to its rare enol form (G*) at the time of 

replication. (b) In its enol form, it pairs with thymine. (c and d) In the next replication, 

the guanine shifts back to its more stable keto form. The thymine incorporated opposite 

the enol form of guanine, seen in part b, directs the incorporation of adenine in the 

subsequent replication. The net result is a GC→AT mutation. . If a guanine undergoes 

a tautomeric shift from the common keto form to the rare enol form at the time of 

incorporation (as a nucleoside triphosphate, rather than in the template strand 

diagrammed here), it will be incorporated opposite thymine in the template strand and 

cause an AT →GC mutation.

Gene mutation

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