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Genetic code

2007 Schools Wikipedia Selection. Related subjects: General Biology

   A series of codons in an short RNA molecule. Each codon consists of
   three nucleotides, representing a single amino acid.
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   A series of codons in an short RNA molecule. Each codon consists of
   three nucleotides, representing a single amino acid.

   The genetic code is the set of rules by which information encoded in
   genetic material (DNA or RNA sequences) is translated into proteins (
   amino acid sequences) by living cells. Specifically, the code defines a
   mapping between tri- nucleotide sequences called codons and amino
   acids; every triplet of nucleotides in a nucleic acid sequence
   specifies a single amino acid. Most organisms use a nearly universal
   code that is referred to as the standard genetic code. Even viruses,
   which are not cellular and do not synthesize proteins themselves, have
   proteins made using this standard code. For a time, therefore, the code
   was thought to be universal. However, there are notable exceptions. It
   is also possible for a single organism to translate different parts of
   the genome in different ways. For example, in humans, protein synthesis
   in mitochondria relies on a modified genetic code that varies from the
   standard one.

Cracking the genetic code

   After the structure of DNA was deciphered by James Watson, Francis
   Crick and Rosalind Franklin, serious efforts to understand the nature
   of the encoding of proteins began. George Gamov postulated that a
   three-letter code must be employed to encode the 20 different amino
   acids used by living cells to encode proteins. The first elucidation of
   a codon was done by Marshall Nirenberg and Heinrich J. Matthaei in 1961
   at the National Institutes of Health. They used a cell-free system to
   translate a poly-uracil RNA sequence (or UUUUU... in biochemical terms)
   and discovered that the polypeptide they had synthesized consisted of
   only the amino acid phenylalanine. They, thereby deduced from this
   poly-phenylalanine that the codon UUU specified the amino-acid
   phenylalanine. Extending this work, Nirenberg and his coworkers were
   able to determine the nucleotide makeup of each codon. In order to
   determine the order of the sequence, trinucleotides were bound to
   ribosomes and radioactivaly labeled aminoacyl-tRNA was used to
   determine, which amino acid corresponded to the codon. Nirenberg's
   group was able to determine the the sequences of 54 out of 64 codons.
   Subsequent work by Har Gobind Khorana identified the rest of the code,
   and shortly thereafter Robert W. Holley determined the structure
   transfer RNA, the adapter molecule that facilitates translation. In
   1968, Khorana, Holley and Nirenberg shared the Nobel Prize in
   Physiology or Medicine for their work.

Transfer of information via the genetic code

   The genetic information carried by an organism, its genome, is
   inscribed in one or more DNA, or in some cases RNA, molecules. Each
   functional portion of a DNA or RNA molecule is referred to as a gene.
   The gene sequence inscribed in DNA, and in RNA, is composed of
   tri-nucleotide units called codons, each coding for a single amino
   acid. Each nucleotide sub-unit consists of a phosphate, deoxyribose
   sugar and one of the 4 nitrogenous nucleotide bases grouped into 2
   categories, purine and pyrimidine. The purine bases adenine (A) and
   guanine (G) are larger and consist of two aromatic rings. The
   pyrimidine bases cytosine (C) and thymine (T) are smaller and consist
   of only one aromatic ring. The percentages of adenine and thymine in
   the molecule are always the same, as well as percentages of cytosine
   and guanine. This is due to the fact that hydogen bonds can only form
   between these nucleotides- this is known as base pairing. In RNA,
   however, thymine (T) is substituted by uracil (U), and the deoxyribose
   is substituted by ribose.

   Each protein-coding gene is transcribed into a short template molecule
   of the related polymer RNA, known as messenger RNA or mRNA. This in
   turn is translated on the ribosome into an amino acid chain or
   polypeptide, which will then fold, resulting in secondary and tertiary
   structures. The process of translation requires transfer RNAs specific
   for individual amino acids with the amino acids covalently attached to
   them, guanosine triphosphate as an energy source, and a number of
   translation factors. tRNAs have anticodons complementary to the codons
   in mRNA and can be "charged" covalently with amino acids at their 3'
   terminal CCA ends. Individual tRNAs are charged with specific amino
   acids by enzymes known as aminoacyl tRNA synthetases which have high
   specificity for both their cognate amino acids and tRNAs. The high
   specificity of these enzymes is a major reasons why the fidelity of
   protein translation is maintained.

   Theoretically, there are 4³ = 64 different codon combinations possible
   with a triplet codon of three nucleotides. In reality, all 64 codons of
   the standard genetic code are assigned for either amino acids or stop
   signals during translation. If, for example, an RNA sequence, UUUAAACCC
   is considered and the reading-frame starts with the first U (by
   convention, 5' to 3'), there are three codons, namely, UUU, AAA and
   CCC, each of which specifies one amino acid. This RNA sequence will be
   translated into an amino acid sequence, three amino acids long.

   The standard genetic code is shown in the following tables. Table 1
   shows what amino acid each of the 64 codons specifies. Table 2 shows
   what codons specify each of the 20 standard amino acids involved in
   translation. These are called forward and reverse codon tables,
   respectively. For example, the codon AAU represents the amino acid
   asparagine, and UGU and UGC represent cysteine {standard three-letter
   designations, Asn and Cys respectively).

Table 1: RNA codon table

   CAPTION: This table shows the 64 codons and the amino acid each codon
   codes for. The direction is 5' to 3'.

   2nd base
   U C A G
   1st
   base U

   UUU (Phe/F) Phenylalanine
   UUC (Phe/F)Phenylalanine
   UUA (Leu/L) Leucine
   UUG (Leu/L)Leucine

   UCU (Ser/S) Serine
   UCC (Ser/S)Serine
   UCA (Ser/S)Serine
   UCG (Ser/S)Serine

   UAU (Tyr/Y) Tyrosine
   UAC (Tyr/Y)Tyrosine
   UAA Ochre (Stop)
   UAG Amber (Stop)

   UGU (Cys/C) Cysteine
   UGC (Cys/C)Cysteine
   UGA Opal (Stop)
   UGG (Trp/W) Tryptophan
   C

   CUU (Leu/L)Leucine
   CUC (Leu/L)Leucine
   CUA (Leu/L)Leucine
   CUG (Leu/L)Leucine

   CCU (Pro/P) Proline
   CCC (Pro/P)Proline
   CCA (Pro/P)Proline
   CCG (Pro/P)Proline

   CAU (His/H) Histidine
   CAC (His/H)Histidine
   CAA (Gln/Q) Glutamine
   CAG (Gln/Q)Glutamine

   CGU (Arg/R) Arginine
   CGC (Arg/R)Arginine
   CGA (Arg/R)Arginine
   CGG (Arg/R)Arginine
   A

   AUU (Ile/I) Isoleucine
   AUC (Ile/I)Isoleucine
   AUA (Ile/I)Isoleucine
   AUG (Met/M) Methionine, Start

   ACU (Thr/T) Threonine
   ACC (Thr/T)Threonine
   ACA (Thr/T)Threonine
   ACG (Thr/T)Threonine

   AAU (Asn/N) Asparagine
   AAC (Asn/N)Asparagine
   AAA (Lys/K) Lysine
   AAG (Lys/K)Lysine

   AGU (Ser/S) Serine
   AGC (Ser/S)Serine
   AGA (Arg/R) Arginine
   AGG (Arg/R)Arginine
   G

   GUU (Val/V) Valine
   GUC (Val/V)Valine
   GUA (Val/V)Valine
   GUG (Val/V)Valine

   GCU (Ala/A) Alanine
   GCC (Ala/A)Alanine
   GCA (Ala/A)Alanine
   GCG (Ala/A)Alanine

   GAU (Asp/D) Aspartic acid
   GAC (Asp/D)Aspartic acid
   GAA (Glu/E) Glutamic acid
   GAG (Glu/E)Glutamic acid

   GGU (Gly/G) Glycine
   GGC (Gly/G)Glycine
   GGA (Gly/G)Glycine
   GGG (Gly/G)Glycine

Table 2: Reverse codon table

   This table shows the 20 standard amino acids used in proteins, and the
   codons that code for each amino acid.
   Ala A GCU, GCC, GCA, GCG           Leu L UUA, UUG, CUU, CUC, CUA, CUG
   Arg R CGU, CGC, CGA, CGG, AGA, AGG Lys K AAA, AAG
   Asn N AAU, AAC                     Met M AUG
   Asp D GAU, GAC                     Phe F UUU, UUC
   Cys C UGU, UGC                     Pro P CCU, CCC, CCA, CCG
   Gln Q CAA, CAG                     Ser S UCU, UCC, UCA, UCG, AGU,AGC
   Glu E GAA, GAG                     Thr T ACU, ACC, ACA, ACG
   Gly G GGU, GGC, GGA, GGG           Trp W UGG
   His H CAU, CAC                     Tyr Y UAU, UAC
   Ile I AUU, AUC, AUA                Val V GUU, GUC, GUA, GUG
   Start AUG                          Stop  UAG, UGA, UAA

Salient features

Reading frame of a sequence

   Note that a codon is defined by the inital nucleotide from which
   translation starts. 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. Partial codons have been
   ignored in this example. Every sequence can thus be read in three
   reading frames, each of which will produce a different amino acid
   sequence (in the given example, Gly-Lys-Pro, Gly-Asp, 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, or on the opposite strand.

   The actual frame a protein sequence is translated in is defined by a
   start codon, usually the first AUG codon in the mRNA sequence.
   Mutations that disrupt the reading frame by insertions or deletions of
   one or two nucleotide bases are known as frameshift mutations. These
   mutations may impair the function of the resulting protein, if it is
   formed, and are thus rare in in vivo protein-coding sequences. Often
   such misformed proteins are targeted for proteolytic degradation. One
   reason for the rareness of frame-shifted mutations being inherited 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 lethality before the organism is viable.

Start/stop codons

   Translation starts with a chain initiation codon ( start codon). Unlike
   stop codons, the codon alone is not sufficient to begin the process.
   Nearby sequences and initiation factors are also required to start
   translation. The most common start codon is AUG, which also codes for
   methionine, but other start codons are also used.

   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
   after its discoverer Harris Bernstein, whose last name means "amber" in
   German. The other two stop codons were named 'ochre" and "opal" in
   order to keep the "colour names" theme. Stop codons are also called
   termination codons and they signal release of the nascent polypeptide
   from the ribosome due to binding of release factors in the absence of
   cognate tRNAs with anticodons complementary to these stop signals.

Degeneracy of the genetic code

   Many codons are redundant, meaning that two or more codons can code for
   the same amino acid. Degenerate codons may differ in their third
   positions; e.g., both GAA and GAG code for the amino acid glutamic
   acid. A codon is said to be four-fold degenerate if any nucleotide at
   its third position specifies the same amino acid; it is said to be
   two-fold degenerate if only two of four possible nucleotides at its
   third position specify the same amino acid. In two-fold degenerate
   codons, the equivalent third position nucleotides are always either two
   purines (A/G) or two pyrimidines (C/T). Only two amino acids are
   specified by a single codon; one of these is the amino-acid methionine,
   specified by the codon AUG, which also specifies the start of
   translation; the other is tryptophan, specified by the codon UGG. The
   degeneracy of the genetic code is what accounts for the existence of
   silent mutations.

   Degeneracy results because a triplet code designates 20 amino acids and
   a stop codon. Because there are four bases, triplet codons are required
   to produce at least 21 different codes. For example, if there were two
   bases per codon, then only 16 amino acids could be coded for (4²=16).
   Because at least 21 codes are required, then 4³ gives 64 possible
   codons, meaning that some degeneracy must exist.

   These properties of the genetic code make it more fault-tolerant for
   point mutations. For example, in theory, four-fold degenerate codons
   can tolerate any point mutation at the third position, although codon
   usage bias restricts this in practice in many organisms; two-fold
   degenerate codons can tolerate one out of the three possible point
   mutations at the third position. Since transition mutations (purine to
   purine or pyrimidine to pyrimidine mutations) are more likely than
   transversion (purine to pyrimidine or vice-versa) mutations, the
   equivalence of purines or that of pyrimidines at two-fold degenerate
   sites adds a further fault-tolerance.

   A practical consequence of redundancy is that some errors in the
   genetic code only cause 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. Even so, it is a single point mutation that causes a
   modified hemoglobin molecule in sickle-cell disease. The hydrophilic
   glutamate (Glu) is substituted by the hydrophobic valine (Val), which
   reduces the solubility of ß-globin. In this case, this mutation causes
   hemoglobin to form linear polymers linked by the hydrophobic
   interaction between the valine groups causing sickle-cell deformation
   of erythrocytes. Sickle-cell disease is generally not caused by a de
   novo mutation. Rather it is selected for in malarial regions (in a
   similar way to thalassemia), as heterozygous people have some
   resistance to the malarial Plasmodium parasite ( heterozygote
   advantage).

   These variable codes for amino acids are allowed because of modified
   bases in the first base of the anticodon of the tRNA, and the base-pair
   formed is called a wobble base pair. The modified bases include inosine
   and the Non-Watson-Crick U-G basepair.

Variations

   Numerous variations of the standard genetic code are found in
   mitochondria, which are energy-producing organelles that are found
   inside eukaryotic cells. Mycoplasma translate the codon UGA as
   tryptophan. Ciliate protozoa also have some variation in the genetic
   code: UAG and often UAA code for glutamine (a variant also found in
   some green algae), or UGA codes for cysteine. Another variant is found
   in some species of the yeast, Candida, where CUG codes for serine. In
   addition in some rare cases certain proteins may also use alternate
   initiation (start) codons.

   In certain proteins, non-standard amino acids are substituted for
   standard stop codons, depending upon associated signal sequences in the
   messenger RNA: UGA can code for selenocysteine and UAG can code for
   pyrrolysine as discussed in the relevant articles. A detailed
   description of variations in the genetic code can be found at the NCBI
   web site. However, there may be other non-standard interpretations that
   are not yet known. Sequencing of genomes may reveal unique genetic
   codes that allow the incorporation of other novel amino acids into
   proteins.

Origin of the genetic code

   Despite the variations that exist, the genetic codes used by all known
   forms of life on Earth are very similar. Since there are many possible
   genetic codes that are thought to have similar utility to the one used
   by Earth life, the theory of evolution suggests that the genetic code
   was established very early in the history of life.

   One can ask the question: is the genetic code completely random, just
   one set of codon-amino acid correspondences that happened to establish
   itself and be "frozen in" early in evolution, although functionally any
   of the many other possible transcription tables would have done just as
   well? Already a cursory look at the table shows patterns that suggest
   that this is not the case.

   There are three themes running through the many theories that seek to
   explain the evolution of the genetic code (and hence the origin of
   these patterns). One is illustrated by recent aptamer experiments which
   show that some amino acids have a selective chemical affinity for the
   base triplets that code for them. This suggests that the current,
   complex transcription mechanism involving tRNA and associated enzymes
   may be a later development, and that originally, protein sequences were
   directly templated on base sequences. Another is that the standard
   genetic code that we see today grew from a simpler, earlier code
   through a process of "biosynthetic expansion". Here the idea is that
   primordial life 'invented' new amino acids (e.g. as by-products of
   metabolism) and later back-incorporated some of these into the
   machinery of genetic coding. Although much circumstantial evidence has
   been found to indicate that originally the number of different amino
   acids used may have been considerably smaller than today, precise and
   detailed hypotheses about exactly which amino acids entered the code in
   exactly what order has proved far more controversial. A third is that
   natural selection organized the codon assignments of the genetic code
   to minimize the effects of genetic errors ( mutations).
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