Although the initial change may not occur in the template strand of the double-stranded DNA molecule for that gene, after replication, daughter DNA molecules with mutations in the template strand will segregate and appear in the population of organisms.

Some Mutations Occur by Base Substitution

 Single-base changes (point mutations) may be transitions or transversions. In the former, a given pyrimidine is changed to the other pyrimidine or a given purine is changed to the other purine. Transversions are changes from a purine to either of the two pyrimidines or the change of a pyrimidine into either of the two purines, as shown in Figure 1.

Fig1. Diagrammatic representation of transition and transversion mutations.

When the DNA nucleotide sequence of a protein-coding gene containing the mutation is transcribed into an mRNA molecule, then the RNA molecule will of course possess the base change at the corresponding location.

Single-base changes in the mRNA may have one of several effects when translated into protein:

1. There may be no detectable effect because of the degeneracy of the code; such mutations are often referred to as silent mutations. This would be most likely if the changed base in the mRNA molecule were to be at the third nucleotide of a codon. Because of wobble, the translation of a codon is least sensitive to a change at the third position.

2. A missense effect will occur when a different amino acid is incorporated at the corresponding site in the protein molecule. This mistaken amino acid—or missense, depending on its location in the specific protein—might be accept able, partially acceptable, or unacceptable to the function of that protein molecule. From a careful examination of the genetic code, one can conclude that most single-base changes would result in the replacement of one amino acid by another with rather similar functional groups. This is an effective genetic “buffering” mechanism to avoid drastic change in the physical properties of a protein molecule. If an acceptable missense effect occurs, the resulting protein molecule may not be distinguishable from the normal one. A partially acceptable missense will result in a protein molecule with partial but abnormal function. If an unacceptable missense effect occurs, then the protein molecule will not be capable of functioning normally.

3. A nonsense codon may appear that would then result in the premature termination of translation and the production of only a fragment of the intended protein molecule. The probability is high that a prematurely terminated protein molecule or peptide fragment will not function in its nor mal role. Examples of the different types of mutations, and their effects on the coding potential of mRNA are presented in Figures 2 and 3.

Fig2. Examples of three types of missense mutations resulting in abnormal hemoglobin chains. The amino acid alterations and possible alterations in the respective codons are indicated. The hemoglobin Hikari β-chain mutation has apparently normal physiologic properties but is electrophoretically altered. Hemoglobin S has a β-chain mutation and partial function; hemoglobin S binds oxygen but precipitates when deoxygenated; this causes red blood cells to sickle, and represents the cellular and molecular basis of sickle cell disease. Hemoglobin M Boston, an α-chain mutation, permits the oxidation of the heme ferrous iron to the ferric state and so will not bind oxygen at all.

Fig3. Examples of the effects of deletions and insertions in a gene on the sequence of the mRNA transcript and of the polypeptide chain translated therefrom. The arrows indicate the sites of deletions or insertions, and the numbers in the ovals indicate the number of nucleotide residues deleted or inserted. Colored type indicates the correct amino acids in the correct order.

Frameshift Mutations Result From Deletion or Insertion of Nucleotides in DNA That Generates Altered mRNAs

 The deletion of a single nucleotide from the coding strand of a gene results in an altered reading frame in the mRNA. The machinery translating the mRNA does not recognize that a base was missing, since there is no punctuation in the reading of codons. Thus, a major alteration in the sequence of polymerized amino acids, as depicted in Example 1, Figure 3, results. Altering the reading frame results in a garbled translation of the mRNA distal to the single nucleotide deletion. Not only is the sequence of amino acids distal to this deletion garbled, but reading of the message can also result in the appearance of a nonsense codon and thus the production of a polypeptide both garbled and prematurely terminated (Example 3, Figure 3).

If three nucleotides or a multiple of three nucleotides are deleted from a coding region, translation of the corresponding mRNA will generate a protein that is missing the corresponding number of amino acids (Example 2, Figure 3). Because the reading frame is a triplet, the reading phase will not be disturbed for those codons distal to the deletion. If, however, deletion of one or two nucleotides occurs just prior to or within the normal termination codon (nonsense codon), the reading of the normal termination signal is disturbed. Such a deletion might result in reading through the now “mutated” termination signal until another nonsense codon is encountered (not shown here).

Insertions of one or two or nonmultiples of three nucleotides into a gene result in an mRNA in which the reading frame is distorted on translation, and the same effects that occur with deletions are reflected in the mRNA translation. This may result in garbled amino acid sequences distal to the insertion and the generation of a nonsense codon at, or distal to the insertion, or perhaps reading through the normal termination codon. Following a deletion in a gene, an insertion (or vice versa) can reestablish the proper reading frame (Example 4, Figure 3). The corresponding mRNA, when translated, would contain a garbled amino acid sequence between the insertion and deletion. Beyond the reestablishment of the reading frame, the amino acid sequence would be correct. One can imagine that different combinations of insertions or deletions (ie, indels), or of both, would result in formation of a protein wherein a portion is abnormal, but this portion is surrounded by the normal amino acid sequences. Such phenomena have been demonstrated convincingly in a number of human diseases.

Suppressor Mutations Can Counteract Some of the Effects of Missense, Nonsense, & Frameshift Mutations

The discussion of the altered protein products of gene mutations is based on the presence of normally functioning tRNA molecules. However, in prokaryotic and lower eukaryotic organisms, abnormally functioning tRNA molecules have been discovered that are themselves the results of mutations. Some of these abnormal tRNA molecules are capable of binding to and decoding altered codons, thereby suppressing the effects of mutations in distinct mutated mRNA-encoding structural genes. These suppressor tRNA molecules, usually formed as a result of alterations in their anticodon regions, are capable of suppressing certain missense mutations, nonsense mutations, and frameshift mutations. However, since the suppressor tRNA molecules are not capable of distinguishing between a normal codon and one resulting from a gene mutation, their presence in the cell usually results in decreased viability. For instance, the nonsense suppressor tRNA molecules can suppress the normal termination signals to allow a read-through when it is not desirable. Frameshift suppressor tRNA molecules may read a normal codon plus a component of a juxtaposed codon to provide a frameshift, also when it is not desirable. Suppressor tRNA molecules may exist in mammalian cells, since read-through of translation has on occasion been observed. In the laboratory context, such sup pressor tRNAs, coupled with mutated variants of aminoacyl tRNA synthetases, can be utilized to incorporate unnatural amino acids into defined locations within altered genes that carry engineered nonsense mutations. The resulting labeled proteins can be used for in vivo and in vitro cross-linking and biophysical studies. This new tool adds significantly to biologists interested in studying the mechanisms of a wide range of biologic processes.

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مواضيع ذات صلة

Posttranslational Processing Affects the Activity of many Proteins

Like Transcription, Protein synthesis can be described in three phases: Initiation, Elongation, & Termination

The Genetic Code is Degenerate, Unambiguous, Nonoverlapping, Without Punctuation, & Universal

RNAs can be Extensively Modified

RNA Molecules are Extensively Processed Before They Become Functional

Phosphorylation Activates Pol II

Formation of the Pol II Transcription Complex

Eukaryotic Promoters Are More Complex

Bacterial Promoters Are Relatively Simple

RNA Synthesis is A Cyclical Process that Involves RNA Chain Initiation, Elongation, & Termination

RNA is Synthesized From A DNA Template by RNA Polymerases

DNA & Chromosome Integrity Is Monitored Throughout the Cell Cycle