Читать книгу Pet-Specific Care for the Veterinary Team - Группа авторов - Страница 227

We know that the genetic code is actually written with triplet codons, such that three nucleotide bases together code for a single amino acid. Thus, using the four bases, adenine (A), thymine (T), guanine (G), and cytosine (C), we can construct a chain of bases that code for amino acids that will form an enzyme, a protein, or a polypeptide. DNA is read three bases at a time, and these three bases correspond to specific amino acids. Accordingly, TATAGACAACAT would be read as tyrosine (TAT)–arginine (AGA)–glutamine (CAA)–histidine (CAT).

Redundancy is built into the system. For example, both TAC and TAT code for tyrosine, so if the T in position 3 happens to be replaced by the base C, the final product is not affected (a silent mutation). Now, given the previous sequence, imagine that a point mutation occurs that deletes the third base in the sequence (T). With the bases after that point shifting one to the left, the first codon becomes TAA, which is a stop codon and arrests the process. If the deletion were to occur to the fourth base (A), the resulting peptide would be changed to tyrosine (TAT)–aspartic acid (GAC)–asparagine (AAC), which is completely different from the peptide normally produced.

Even though DNA replication is remarkably efficient, mistakes occasionally do happen. A base substitution that results in a stop codon, prematurely halting the process, is called a nonsense mutation; the resulting polypeptide will be shorter than usual and probably not functional. Progressive retinal atrophy (PRA) in the Irish setter, for example, is the result of a nonsense mutation in the cGMP‐phosphodiesterase‐beta gene. A missense mutation occurs when one base is substituted for another, which potentially results in a different amino acid occurring in the chain.

In some cases, the resultant polypeptide may not be functional. In other cases, however, because of redundancy built into the system, a base substitution will not change the amino acid product (e.g., CAT and CAC both code for histidine). This substitution is referred to as a silent mutation. Hemophilia B is characterized by a substitution of A for G at nucleotide 1477 in the gene for canine factor IX, resulting in the substitution of glutamic acid for glycine at position 379 in the factor IX molecule, which decreases the efficiency of blood clotting.

In contrast to missense mutations, in which only one amino acid in a sequence is affected, if a base is inserted or deleted in the DNA strand, it has the potential to alter the reading of the entire coded sequence downstream because the triplet codons are now out of their original sequence. This mutation is known as a frameshift mutation, an example of which is X‐linked nephritis. In simple terms, take the phrase “how are you” and insert the letter b after the letter h in how to see how a simple insertion of one base can change expression. The shift results in “hbo war eyo u” which doesn't communicate the same message as “how are you.” You can imagine what would happen to a genetic sequence in the same circumstances.

Considering that a point mutation happens by chance, that it can affect any bases in a DNA sequence for a peptide, and it then passes to future generations, it should not be surprising that similar disorders in different breeds can result from very different gene mutations. That is why the DNA test for PRA in Irish setters will not work in miniature poodles. Although the final clinical result of PRA is similar, the underlying genetic disorder could not be more different. When the incidence of mutations is combined with the fact that about 70% of all mutations are recessive, it is not difficult to see how they can be propagated.