Stop codon

In the standard genetic code, there are three different termination codons:

There are variations on the standard genetic code, and alternative stop codons have been found in the mitochondrial genomes of vertebrates,[2] Scenedesmus obliquus,[3] and Thraustochytrium.[4]

The nuclear genetic code is flexible as illustrated by variant genetic codes that reassign standard stop codons to amino acids.[5]

In 2007, the UGA codon was identified as the codon coding for selenocysteine (Sec) and found in 25 selenoproteins located in the active site of the protein. Translation of this codon is enabled by the proximity of the SECIS element (SElenoCysteine Incorporation Sequence).[6]

The UAG codon can translate into pyrrolysine (Pyl) in a similar manner.

Distribution of stop codons within the genome of an organism is non-random and can correlate with GC-content.[7][8] For example, the E. coli K-12 genome contains 2705 TAA (63%), 1257 TGA (29%), and 326 TAG (8%) stop codons (GC content 50.8%).[9] Also the substrates for the stop codons release factor 1 or release factor 2 are strongly correlated to the abundance of stop codons.[10] Large scale study of bacteria with a broad range of GC-contents shows that while the frequency of occurrence of TAA is negatively correlated to the GC-content and the frequency of occurrence of TGA is positively correlated to the GC-content, the frequency of occurrence of the TAG stop codon, which is often the minimally used stop codon in a genome, is not influenced by the GC-content.[11]

Recognition of stop codons in bacteria have been associated with the so-called 'tripeptide anticodon',[12] a highly conserved amino acid motif in RF1 (PxT) and RF2 (SPF). Even though this is supported by structural studies, it was shown that the tripeptide anticodon hypothesis is an oversimplification.[13]

They were the first set of nonsense mutations to be discovered, isolated by Richard H. Epstein and Charles Steinberg and named after their friend and graduate Caltech student Harris Bernstein, whose last name means "amber" in German (cf. Bernstein).[14][15]

Viruses with amber mutations are characterized by their ability to infect only certain strains of bacteria, known as amber suppressors. These bacteria carry their own mutation that allows a recovery of function in the mutant viruses. For example, a mutation in the tRNA that recognizes the amber stop codon allows translation to "read through" the codon and produce a full-length protein, thereby recovering the normal form of the protein and "suppressing" the amber mutation.[16] Thus, amber mutants are an entire class of virus mutants that can grow in bacteria that contain amber suppressor mutations. Similar suppressors are known for ochre and opal stop codons as well.

It was the second stop codon mutation to be discovered. Reminiscent of the usual yellow-orange-brown color associated with amber, this second stop codon was given the name of "ochre", a orange-reddish-brown mineral pigment.[15]

Ochre mutant viruses had a property similar to amber mutants in that they recovered infectious ability within certain suppressor strains of bacteria. The set of ochre suppressors was distinct from amber suppressors, so ochre mutants were inferred to correspond to a different nucleotide triplet. Through a series of mutation experiments comparing these mutants with each other and other known amino acid codons, Sydney Brenner concluded that the amber and ochre mutations corresponded to the nucleotide triplets "UAG" and "UAA".[17]

The third and last stop codon in the standard genetic code was discovered soon after, and corresponds to the nucleotide triplet "UGA".[18]

To continue matching with the theme of colored minerals, the third nonsense codon came to be known as "opal", which is a type of silica showing a variety of colors.[15] Nonsense mutations that created this premature stop codon were later called opal mutations or umber mutations.

Nonsense mutations are changes in DNA sequence that introduce a premature stop codon, causing any resulting protein to be abnormally shortened. This often causes a loss of function in the protein, as critical parts of the amino acid chain are no longer created. Because of this terminology, stop codons have also been referred to as nonsense codons.

A nonstop mutation is a point mutation that occurs within a stop codon. Nonstop mutations cause the continued translation of an mRNA strand into what should be an untranslated region. Most polypeptides resulting from a gene with a nonstop mutation are nonfunctional due to their extreme length.

Nonstop mutations differ from nonsense mutations in that they do not create a stop codon but, instead, delete one. Nonstop mutations also differ from missense mutations, which are point mutations where a single nucleotide is changed to cause replacement by a different amino acid.

Nonstop mutations have been linked with several congenital diseases including congenital adrenal hyperplasia,[19] variable anterior segment dysgenesis,[20] cystic fibrosis[21] and mitochondrial neurogastrointestinal encephalomyopathy.[22]