StemCell Therapy

The genetic code is the set of rules by which information encoded within genetic material (DNA or mRNA sequences) is translated into proteins by living cells. Translation is accomplished by the ribosome, which links amino acids in an order specified by mRNA, using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.

The code defines how sequences of nucleotide triplets, called codons, specify which amino acid will be added next during protein synthesis. With some exceptions,[1] a three-nucleotide codon in a nucleic acid sequence specifies a single amino acid. Because the vast majority of genes are encoded with exactly the same code (see the RNA codon table), this particular code is often referred to as the canonical or standard genetic code, or simply the genetic code, though in fact some variant codes have evolved. For example, protein synthesis in human mitochondria relies on a genetic code that differs from the standard genetic code.

While the "genetic code" determines a protein's amino acid sequence, other genomic regions determine when and where these proteins are produced according to a multitude of more complex "gene regulatory codes".

Serious efforts to understand how proteins are encoded began after the structure of DNA was discovered in 1953. George Gamow postulated that sets of three bases must be employed to encode the 20 standard amino acids used by living cells to build proteins. With four different nucleotides, a code of 2 nucleotides would allow for only a maximum of 42 = 16 amino acids. A code of 3 nucleotides could code for a maximum of 43 = 64 amino acids.[2]

The Crick, Brenner et al. experiment first demonstrated that codons consist of three DNA bases; Marshall Nirenberg and Heinrich J. Matthaei were the first to elucidate the nature of a codon in 1961 at the National Institutes of Health. They used a cell-free system to translate a poly-uracil RNA sequence (i.e., UUUUU...) and discovered that the polypeptide that they had synthesized consisted of only the amino acid phenylalanine.[3] They thereby deduced that the codon UUU specified the amino acid phenylalanine. This was followed by experiments in Severo Ochoa's laboratory that demonstrated that the poly-adenine RNA sequence (AAAAA...) coded for the polypeptide poly-lysine[4] and that the poly-cytosine RNA sequence (CCCCC...) coded for the polypeptide poly-proline.[5] Therefore, the codon AAA specified the amino acid lysine, and the codon CCC specified the amino acid proline. Using different copolymers most of the remaining codons were then determined. Subsequent work by Har Gobind Khorana identified the rest of the genetic code. Shortly thereafter, Robert W. Holley determined the structure of transfer RNA (tRNA), the adapter molecule that facilitates the process of translating RNA into protein. This work was based upon earlier studies by Severo Ochoa, who received the Nobel Prize in Physiology or Medicine in 1959 for his work on the enzymology of RNA synthesis.[6]

Extending this work, Nirenberg and Philip Leder revealed the triplet nature of the genetic code and deciphered the codons of the standard genetic code. In these experiments, various combinations of mRNA were passed through a filter that contained ribosomes, the components of cells that translate RNA into protein. Unique triplets promoted the binding of specific tRNAs to the ribosome. Leder and Nirenberg were able to determine the sequences of 54 out of 64 codons in their experiments.[7] In 1968, Khorana, Holley and Nirenberg received the Nobel Prize in Physiology or Medicine for their work.[8]

A codon is defined by the initial nucleotide from which translation starts and sets the frame for a run of uninterrupted triplets, which is known as an "open reading frame" (ORF). For example, the string GGGAAACCC, if read from the first position, contains the codons GGG, AAA, and CCC; and, if read from the second position, it contains the codons GGA and AAC; if read starting from the third position, GAA and ACC. Every sequence can, thus, be read in its 5' 3' direction in three reading frames, each of which will produce a different amino acid sequence (in the given example, Gly-Lys-Pro, Gly-Asn, or Glu-Thr, respectively). With double-stranded DNA, there are six possible reading frames, three in the forward orientation on one strand and three reverse on the opposite strand.[9]:330 The actual frame from which a protein sequence is translated is defined by a start codon, usually the first AUG codon in the mRNA sequence.

In eukaryotes, ORFs in exons are often interrupted by introns.

Translation starts with a chain initiation codon or start codon. Unlike stop codons, the codon alone is not sufficient to begin the process. Nearby sequences such as the Shine-Dalgarno sequence in E. coli and initiation factors are also required to start translation. The most common start codon is AUG, which is read as methionine or, in bacteria, as formylmethionine. Alternative start codons depending on the organism include "GUG" or "UUG"; these codons normally represent valine and leucine, respectively, but as start codons they are translated as methionine or formylmethionine.[10]

The three stop codons have been given names: UAG is amber, UGA is opal (sometimes also called umber), and UAA is ochre. "Amber" was named by discoverers Richard Epstein and Charles Steinberg after their friend Harris Bernstein, whose last name means "amber" in German.[11] The other two stop codons were named "ochre" and "opal" in order to keep the "color names" theme. Stop codons are also called "termination" or "nonsense" codons. They signal release of the nascent polypeptide from the ribosome because there is no cognate tRNA that has anticodons complementary to these stop signals, and so a release factor binds to the ribosome instead.[12]

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can affect the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low1 error in every 10100million basesdue to the "proofreading" ability of DNA polymerases.[14][15]

Missense mutations and nonsense mutations are examples of point mutations, which can cause genetic diseases such as sickle-cell disease and thalassemia respectively.[16][17][18] Clinically important missense mutations generally change the properties of the coded amino acid residue between being basic, acidic, polar or non-polar, whereas nonsense mutations result in a stop codon.[9]:266

Mutations that disrupt the reading frame sequence by indels (insertions or deletions) of a non-multiple of 3 nucleotide bases are known as frameshift mutations. These mutations usually result in a completely different translation from the original, and are also very likely to cause a stop codon to be read, which truncates the creation of the protein.[19] These mutations may impair the function of the resulting protein, and are thus rare in in vivo protein-coding sequences. One reason inheritance of frameshift mutations is rare is that, if the protein being translated is essential for growth under the selective pressures the organism faces, absence of a functional protein may cause death before the organism is viable.[20] Frameshift mutations may result in severe genetic diseases such as Tay-Sachs disease.[21]

Although most mutations that change protein sequences are harmful or neutral, some mutations have a beneficial effect on an organism.[22] These mutations may enable the mutant organism to withstand particular environmental stresses better than wild type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection.[23]Viruses that use RNA as their genetic material have rapid mutation rates,[24] which can be an advantage, since these viruses will evolve constantly and rapidly, and thus evade the defensive responses of e.g. the human immune system.[25] In large populations of asexually reproducing organisms, for example, E. coli, multiple beneficial mutations may co-occur. This phenomenon is called clonal interference and causes competition among the mutations.[26]

Degeneracy is the redundancy of the genetic code. This term was given by Bernfield and Nirenberg. The genetic code has redundancy but no ambiguity (see the codon tables below for the full correlation). For example, although codons GAA and GAG both specify glutamic acid (redundancy), neither of them specifies any other amino acid (no ambiguity). The codons encoding one amino acid may differ in any of their three positions. For example, the amino acid leucine is specified by YUR or CUN (UUA, UUG, CUU, CUC, CUA, or CUG) codons (difference in the first or third position indicated using IUPAC notation), while the amino acid serine is specified by UCN or AGY (UCA, UCG, UCC, UCU, AGU, or AGC) codons (difference in the first, second, or third position).[27]:102117:521522 A practical consequence of redundancy is that errors in the third position of the triplet codon cause only a silent mutation or an error that would not affect the protein because the hydrophilicity or hydrophobicity is maintained by equivalent substitution of amino acids; for example, a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. NCN yields amino acid residues that are small in size and moderate in hydropathy; NAN encodes average size hydrophilic residues. The genetic code is so well-structured for hydropathy that a mathematical analysis (Singular Value Decomposition) of 12 variables (4 nucleotides x 3 positions) yields a remarkable correlation (C = 0.95) for predicting the hydropathy of the encoded amino acid directly from the triplet nucleotide sequence, without translation.[28][29] Note in the table, below, eight amino acids are not affected at all by mutations at the third position of the codon, whereas in the figure above, a mutation at the second position is likely to cause a radical change in the physicochemical properties of the encoded amino acid.

The frequency of codons, also known as codon usage bias, can vary from species to species with functional implications for the control of translation. The following codon usage table is for the human genome.[30]

While slight variations on the standard code had been predicted earlier,[31] none were discovered until 1979, when researchers studying human mitochondrial genes discovered they used an alternative code.[32] Many slight variants have been discovered since then,[33] including various alternative mitochondrial codes,[34] and small variants such as translation of the codon UGA as tryptophan in Mycoplasma species, and translation of CUG as a serine rather than a leucine in yeasts of the "CTG clade" (Candida albicans is member of this group).[35][36][37] Because viruses must use the same genetic code as their hosts, modifications to the standard genetic code could interfere with the synthesis or functioning of viral proteins.[38] However, some viruses (such as totiviruses) have adapted to the genetic code modification of the host.[39] In bacteria and archaea, GUG and UUG are common start codons, but in rare cases, certain proteins may use alternative start codons not normally used by that species.[33]

In certain proteins, non-standard amino acids are substituted for standard stop codons, depending on associated signal sequences in the messenger RNA. For example, UGA can code for selenocysteine and UAG can code for pyrrolysine. Selenocysteine is now viewed as the 21st amino acid, and pyrrolysine is viewed as the 22nd.[33] Unlike selenocysteine, pyrrolysine encoded UAG is translated with the participation of a dedicated aminoacyl-tRNA synthetase.[40] Both selenocysteine and pyrrolysine may be present in the same organism.[41] Although the genetic code is normally fixed in an organism, the achaeal prokaryote Acetohalobium arabaticum can expand its genetic code from 20 to 21 amino acids (by including pyrrolysine) under different conditions of growth.[42]

Despite these differences, all known naturally occurring codes are very similar to each other, and the coding mechanism is the same for all organisms: three-base codons, tRNA, ribosomes, reading the code in the same direction and translating the code three letters at a time into sequences of amino acids.

Variant genetic codes used by an organism can be inferred by identifying highly conserved genes encoded in that genome, and comparing its codon usage to the amino acids in homologous proteins of other organisms. For example, the program FACIL[43] infers a genetic code by searching which amino acids in homologous protein domains are most often aligned to every codon. The resulting amino acid probabilities for each codon are displayed in a genetic code logo, that also shows the support for a stop codon.

The DNA codon table is essentially identical to that for RNA, but with U replaced by T.

The origin of the genetic code is a part of the question of the origin of life. Under the main hypothesis for the origin of life, the RNA world hypothesis, any model for the emergence of genetic code is intimately related to a model of the transfer from ribozymes (RNA enzymes) to proteins as the principal enzymes in cells. In line with the RNA world hypothesis, transfer RNA molecules appear to have evolved before modern aminoacyl-tRNA synthetases, so the latter cannot be part of the explanation of its patterns.[45]

A consideration of a hypothetical random genetic code further motivates a biochemical or evolutionary model for the origin of the genetic code. If amino acids were randomly assigned to triplet codons, there would be 1.51084 possible genetic codes to choose from.[46]:163 This number is found by calculating how many ways there are to place 21 items (20 amino acids plus one stop) in 64 bins, wherein each item is used at least once. [2] In fact, the distribution of codon assignments in the genetic code is nonrandom.[47] In particular, the genetic code clusters certain amino acid assignments. For example, amino acids that share the same biosynthetic pathway tend to have the same first base in their codons. This could be an evolutionary relic of early simpler genetic code with fewer amino acids, that later diverged to code for a larger set of amino acids.[48] It could also reflect steric and chemical properties that had another effect on the codon during its evolution. Amino acids with similar physical properties also tend to have similar codons,[49][50] reducing the problems caused by point mutations and mistranslations.[47]

Given the non-random genetic triplet coding scheme, it has been suggested that a tenable hypothesis for the origin of genetic code should address multiple aspects of the codon table such as absence of codons for D-amino acids, secondary codon patterns for some amino acids, confinement of synonymous positions to third position, a limited set of only 20 amino acids instead of a number closer to 64, and the relation of stop codon patterns to amino acid coding patterns.[51]

There are three main ideas for the origin of the genetic code, and many models belong to either one of them or to a combination thereof:[52]

Hypotheses for the origin of the genetic code have addressed a variety of scenarios:[56]

Since 2001, 40 non-natural amino acids have been added into protein by creating a unique codon (recoding) and a corresponding transfer-RNA:aminoacyl tRNA-synthetase pair to encode it with diverse physicochemical and biological properties in order to be used as a tool to exploring protein structure and function or to create novel or enhanced proteins.[71][72]

H. Murakami and M. Sisido have extended some codons to have four and five bases. Steven A. Benner constructed a functional 65th (in vivo) codon.[73]

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Genetic code - Wikipedia

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