1. MUTATIONS Questo documento è pubblicato sotto licenza Creative Commons
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2. Genetic mutations
A mutation is a heritable 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

3. 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.

4. 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 fact, the golden Delicious apple originally arose as a mutant branch on a red Delicious tree.

5. Germinal mutations Somatic mutations are never 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 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.

6. 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.

7. 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.

8. Functional consequences of base changes
We first 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 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.

9. 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.

10. Examples of point mutations

11. 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.

12. 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.

13. 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.

14. Base mismatches
Mismatched bases. (a) Mispairs resulting from rare tautomeric forms of the pyrimidines; (b) mispairs resulting from rare tautomeric forms of the purines.

15. 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.