Topic 3: Mutations

In the living cell, DNA (deoxyribonucleic acid) undergoes frequent chemical change, especially when it is being replicated (in S phase of the eukaryotic cell cycle). Most of these changes are quickly repaired; those that are not result in a mutation. Thus, a mutation is a failure of DNA repair. Mutations are changes in genes or chromosomes. They are the ultimate source of genetic variation and therefore evolution. There are several types of mutations: single-base substitutions, deletions and insertions, chromosomal mutations, duplications, translocations, and somatic versus germline mutations. There are also different causes for mutations and their rates, methods to measure them as well how often they may appear. In addition studies have even shown that males contribute more mutations than females.

Mutations can come in different forms. One of these forms is the single-base substitution, which is also known as a point mutation. In base substitutions, transitions (replaced by the other) and transversions (replaced by each other) occur. For example, the four nucleotide bases are A (adenine), T (thymine), C (cytosine), and G (guanine). In normal circumstances, A will pair with T, while C will pair with G. However, nothing and no one are perfect; so mutations will arise. Therefore, occasionally A might pair with G, and/or A with C. Sometimes the genetic code may even be redundant, so different codons can code of the same amino acid. These kinds of mutations that affect the codons are known as synonymous mutations or silent mutations, while those that affect the specific amino acid are called nonsynonymous mutations. The single-base substitution includes missense, nonsense, silent, and splice-site mutations.

In a missense mutation, the new nucleotide alters the codon to produce an altered amino acid in the protein product. An example of this is sickle-cell disease, shown above. The beta chain of hemoglobin changes the original codons.

In comparison to a missense mutation, a nonsense mutation is where a new nucleotide changes a codon that specified an amino acid to one of the STOP codons (TAA, TAG, TGA). Thus, translation of the messenger RNA transcribed from this mutant gene wills top prematurely. The earlier in the gene that this occurs, the more truncated the protein product and the more likely that it will be unable to function. An example is cystic fibrosis, where in comparison to sickle-cell disease, no single mutation is responsible; defects in the protein cause the various symptoms of the disease.

A third form of the single-base substitution is the silent mutation. In these kinds of mutations, no changes in the products of codons can be detected without sequencing the gene or its RNA.

The final type of the single-base substitution is the splice-site mutation, which is the removal of intro sequences (the portion of a gene that is transcribed into RNA but is removed during the formation of the mature RNA molecule). Nucleotide signals at the splice sites guide the enzymatic equipment. If a mutation alters one of these signals, then the intron is not removed and remains as part of the final RNA molecule. The translation of its sequence alters the sequence of the protein product.

Other types of mutations could be deletions and insertions. Just as they are implied by the words themselves, deletions mean loss of genetic material, while insertions are an addition of genetic material. Both of these mutations eventually result in frameshift mutations: when the number of nucleotides inserted or deleted is not a multiple of three, every codon beyond the point of insertion or deletion is read incorrectly during translation. Naturally, they generate new STOP codons, eventually creating nonsense mutations. The consequences of insertions may be deadly. A number of inherited human disorders are caused by the insertion of many copies of the same triplet of nucleotides. Examples of such trinucleotide repeat diseases are Huntington's disease (hereditary disorder with mental and physical deterioration leading to death) and the fragile X syndrome (an inherited disorder caused by a defective gene on the X-chromosome, leading to mental retardation, enlarged testes, and facial abnormalities in males and mild or possibly even no effects in heterozygous females).

A third major type of mutation is a chromosomal mutation. These consist of inversions, which are chromosomal defects where a segment of the chromosome breaks off and reattaches in the reverse direction and translocations, a transfer of a chromosomal segment to a new position, especially on a nonhomologous chromosome.

The next type of mutation is the duplication. The meaning of this word, just like insertions and deletions, can already be implicated by the word itself. It is the doubling of a section of the genome. In meiosis (sexual reproduction), crossing over between sister chromatids that are out of alignment produces a