Mutation

I.
Mutations are permanent changes in the DNA.
A.
most mutations are neutral; they either make no change in the expression of any gene, or the changes made do not affect the function of any gene product.
1.
A large percentage of DNA is not part of any gene, and has no known function. Changes in these portions of the DNA do not alter any gene and are thus silent.
2.
Because of the wobble concept, the exact identity of the third base of a codon often makes no difference, and if it does, the two amino acids coded for by the old the the new codon are often quite similar in nature, so a change in the DNA of a gene which affects one of these bases will often have no effect on the function of the gene product. This genearlly includes 1/4-1/5 of the bases in the gene. These would be silent or neutral mutations.
3.
Not all portions of a protein are equally important for the function of that protein. Even a mutation which changes an amino acid in the final gene product may not make a difference in the function of the protein, or may alter the precise nature of the function of the gene product without alter the usefulness of that product. These would be neutral mutations.
B.
Of those mutations which do make a difference, most have a negative effect.:
1.
If an amino acid is altered in the active site region of a protein, it may decrease or destroy the ability of the protein to perform its function. This kind of mutation often leads to a classic recessive allele--an allele which does not produce a functional gene product.
2.
Alterations in key portions of a protein may lead to changes in the specificities of the protein (conditional mutations). The most common example of this is a temperature sensitive mutation. Proteins are all heat labile (they "melt" if you expose them to too high a temperature). A temperature sensitive mutation lowers the critical melting temperature for the protein, thus making it denature at a lower temperature than the normal gene product.
C.
A small percentage of mutations may actually improve the function of the gene product or may convey a new or expanded function to that product. These mutations provide the "grist" for the evolutionary mill.

II.
Mutations can occur in two different directions.
A.
A forward mutation is a mutation which changes a wild type allele into a new allele (for example, a mutation in one of the genes coding for color producing enzymes may change a wild type [normal color] allele into an albino allele).
B.
A true reversion (reverse mutation) is a mutation which changes a mutant allele back into a wild type allele (for example, in the previous example, a reversion would be anohter mutation at exactly the same location of the first mutation, hwich simply reverses the change made the first time, changing the albino allele back into a wild type [normal] allele). As you might expect, true reversions are much less common than forward mutations because the "target area" is much smaller. A typical gene is hundreds of bases long; a forward mutation can be achieved by altering any one of many of those bases. But a reversion must hit exactly the previously altered base, and must alter it in such a way as to change it back to what was originally in that position.
C.
A suppressor mutation seems like a reversion, but is actually a second change in the same gene, at a different site in the gene, which compensates for the forward mutation in the behavior of the gene product. The gene actually now has two differences when compared to the original wild type, but the protein made following its instructions works just like the original, wild type protein.

III.
Mutations can occur in several different places.
A.
A mutation in the DNA of a somatic cell will produce a clone of cells in one individual which are genetically slightly different from teh rest or the cells in the body. This might produce, for instance, a streak of different color in the iris of the eye (eg, a streak of blue in a person's otherwise brown eye). In some cases, a somatic mutation may lead to the development of cancer.
B.
A germ line mutation changes a gene in a gemete or a cell which will produce a gamete. This kind of mutation may be passed on to offspring. For example, England's Queen Victoria apparently had a germ line mutation which introduced the hemophilia allel into a number of the royal families of Europe.
C.
Mutations may also occur in the DNA of mitochondria or chloroplasts, producing changes in cytoplasmic traits

IV.
Mutations occur at two different levels.
A.
Gross (chromosome) mutations are changes in chromosome structure.
1.
Translocations occur when two non-homologous chromosomes exchange segments (reciprocal translocation) or when a piece of one chromosome becomes attached to a non-homologous chromosome, with no segments moving in the the other direction (unidirectional or unilateral).
a.
An individual may be a translocation heterozygote (carry one normal set of chromosomes along with one translocated set), or a translocation homozygote (carry two sets of chromosomes which have the translocation).
b.
An individual who has a balanced translocation carries one set of normal chromosomes and one set of chromosomes which have a translocation. There are no genes missing or damaged, and the genetic function of this individual is unimpaired.
c.
Translocation heterozygotes become a problem during meiosis when homologous chromosomes attempt to synapse. Synapsis occurs on a gene by gene basis, and the two pairs of chromosomes do not carry the same sets of genes. The pairing attempt leads to a characteristic cross-shaped formation as four chromosomes attempt to sort themselves out. Crossing over among these four chromosomes can lead to duplications and deficiencies and to dicentric and acentric chromosomes.
d.
Even without crossing over, the gametes of a translocation heterozygote can easily contain only part of a translocation set of chromosomes, thus leading to imbalance if involved in fertilization.
e.
Despite the problems they can cause, translocations have obviously been an important part of the evolutionary process. This is clearly evident when chromosomes of closely related species are compared. Typically, the actual genetic contents of those chromosomes are very similar, but they differ by having significant rearrangements of parts of chromosomes--translocations and inversions.
2.
Inversions occur when segments of chromosome become reversed.
a.
As in translocation, inversions may be present in heterozygous or homozygous arrangements.
b.
For the individual with teh inversion, there are not necessarily any genetic consequences. As long as there are no missing or damaged genes, the unusual arrangement of DNA is no problem.
c.
Again, as in translocations, problems arise when meiosis occurs in an inversion heterozygote. Because chromosomes pair in sysnapsis on a gene by gene basis, the synapsis between a normal chromosome and a chromosome carrhing an inversion creates a characteristic inversion loop. Crossing over within the loop will lead to duplications and deficiencies. Potentially more problematic, if the centromere of the chromosome is outside the inversion loop, crossing over inside the loop will lead to one dicentric and one acentric chromosome.
D.
Like translocations, inversions have clearly been an important part of the evolutionary process.
3.
Duplications occur when a chromosome acquires an extra copy of a chunk of the chromosome.
a.
There are a nubmer of ways duplications can occur. See above for two.
b.
The severity of the result varies, depending upon the size f the duplication and the genes in the duplicated region.
c.
Many relatively small duplicaitons are apparently harmless. In fact, it is evident that there have been many, many duplications in the history of our own species which have actually become fixed in our chromosomes. Apparently all eukaryotic chromosome sets have many duplicated regions.
D.
Duplications have apparently been an important part of the evolutionary process in eukaryotes. many of our genes are very similar to each other, and are obviously members of the same gene family. (For example, myoglobin and the globin genes of hemoglobin, of which there are at least three types, are obviously all descended from copies of the same gene). Small duplications provide extra copies of genes. This allows point mutatin chnages in one copy would jeopardizing the performance of the other copy and thus losing a vital function.
4.
Deficiencies occur when a chromosome loses a portion of its DNA.
a.
See above for two of the ways that deficiencies can come about.
b.
The severity of a deficiency depends upon the amoung of lost DNA and the genes which are lost; however, deficiencies are apparently never beneficial (though a small deficiency can easily be neutral).
c.
A deficiency is always more harmful than duplication of the same portion of DNA.
B.
Point Mutations are changes involving only one base pair of the DNA. (Very small mutations--ie, two or three base pairs--are generally also considered point mutations, although they don't strictly meet the definition.)
1.
Base substitutions involve the replacement of one base (and its complementary partner) by one of the other bases (and its complementary partner). Base subsitutions affect only the amino acid coded for by the codon affected.
a.
Transition mutations involve replacing a purine with another purine (and its partnering pyrimidine with another pyrimidine), or replacing a pyrimidine with a pyrimidine (and its partnering purine with another purine). For example, if an A-T pair is replaced by a G-C pair, this is a transition.
b.
Transversion mutations involve replacing a purine with a pyrimidine (and its partnering pyrimidine with a purine), or replacing a pyrimidine with a puring (and its partnering purine with a pyrimidine). For example, if an A-T pair is replaced by either a T-A pair or a C-G pair, this is a transversion.
2.
Frame shifts are created when one or a few bases are inserted or deleted, thus altering the ultimate reading frame of the ribosome. Frame shift mutations affect all of the protein following the position of the inserted or deleted base. Ribosomes read in a strict 3-base-codon frame, regardless of whether the final amino acid sequence "makes sense."

V.
Mutations have a variety of causes.
A.
Many mutations have purely natural, spontaneous causes. All of the bases in DNA exist in more than one tautomeric form, although each has one tautomer which is overwhelmingly most common. Some of the uncommon tautomers have different base pairing characteristics from their more common alternatives. When a base is unpaired (as in during DNA replication, which is when most mutations occur), it will shift spontaneously from one tautomeric form to another, although most of the time it will assume its common form. If at the moment of base pairing during replication the base is caught in an uncommon form, it may be given the incorrect partner (for example, A may accidentally be paired with C instead of T). When the same molecule replicates again, the A will almost certainly revert to its common form as soon as it is separated from the C, but the C is fixed in the other strand and will pair with its normal partner, a G. Thus, this final strand will have acquired a transition base substitution.
B.
Agents which cause non-spontaneous mutations are called mutagens.
1.
Some kinds of radiations are mutagens. For instance, ultraviolet (UV) radiation can cause mutations. During a time when the DNA is single stranded, UV can excite the electons in side-by-side Tymines. This can cause these Thymines to bond covalently to each other, forming a Thymine dimer. (This can also happen to side-by-side Cytosines, or to a Thymine and a Cytosine which are beside each other, but these are less common). Wehn the DNA polymerase reaches the point wehre it shoudl be inserting Adenines to pair with the two Thymines, they are not available for base pairing. The polymerase will generally insert two (or sometimes just one) bases at random, thus producing at least a base subsitution, and sometimes a frame shift. There is a UV-activated DNA repair mechanism which finds and repairs Thymine dimers during DNA replication, but the repair mechanism is not 100% effective. Other kinds of radiation, such as gamm radiation, can actually cause breaks in the DNA backbones, leading to gross mutations in chromosomes.
2.
There are a lot of chemical mutagens.
a.
Some kinds of molecules mimic the appearance of the bases of DNA. These are called base analogs. For example, 5-bromo-Uracil is very much like Thymine, except that instead of a methyl group attached to its fifth carbon, it has a bromine. 5-bromo-Uracil is sometimes incorporated into DNA instead of Thymine, which wouldn't of itself be a problem, except that it is not as faithful in base pairing as Thymine is, and often leads to transition mutations.
b.
There is a group of substances which are called intercalary agents. These become inserted (intercalated) in between the bases in a polynucleotide. They can distort the shape of teh molecule so that during replication extra bases are inserted or bases are left out of the new strand, thus creating frame shift mutations.
c.
There are other kinds of chemical mutagens as well.