Page 141 - Genetics_From_Genes_to_Genomes_6th_FULL_Part2

300 Chapter 8 Gene Expression: The Flow of Information from DNA to RNA to Protein

Figure 8.27 How mutations in a gene can affect its The mutant polypeptide will be unable to function if it re­
expression. (a) Mutations in a gene’s coding sequences. Silent quires the missing amino acids for its activity.
mutations do not alter the protein’s primary structure. Missense
mutations replace one amino acid with another. Nonsense mutations Frameshift mutations
shorten a polypeptide by replacing a codon with a stop signal.
Frameshift mutations change the reading frame downstream of the Frameshift mutations result from the insertion or deletion
addition or deletion. (b) Mutations outside the coding region can of nucleotides within the coding sequence. As discussed
also disrupt gene expression. earlier, if the number of extra or missing nucleotides is not
(a) Types of mutation in a gene's coding sequence divisible by 3, the insertion or deletion will skew the read­
ing frame downstream of the mutation. As a result, frame­
Wild-type mRNA 5' ATG GGA GCA CCA GGA CAA GAU GGA 3' shift mutations usually result in the formation of truncated
Wild-type polypeptide N Met Gly Ala Pro Gly Gln Asp Gly C
proteins (because of the appearance of premature stop co­
Silent mutation ATG GGA GCC CCA GGA CAA GAU GGA dons) with incorrect amino acids at their C termini.
–
Met Gly Ala Pro Gly Gln Asp Gly
Missense mutation ATG GGA GCA CCA AGA CAA GAU GGA Mutations Outside the Coding Sequence
–
Met Gly Ala Pro Arg Gln Asp Gly
Can Also Alter Gene Expression
Nonsense mutation ATG GGA GCA CCA GGA UAA GAU GGA
–
Met Gly Ala Pro Gly Stop Mutations that produce a variant phenotype are not re­
stricted to alterations in codons. Because gene expression
Frameshift mutation ATG GGA GCC ACC AGG ACA AGA UGG A depends on several signals other than the actual coding se­
–
Met Gly Ala Thr Arg Thr Arg Trp
quence, changes in any of these critical signals can disrupt
the process (Fig. 8.27b).
(b) Mutations outside the coding sequence We have seen that promoters and termination signals
Ribosome binding Transcription in the DNA of a gene instruct RNA polymerase to start and
site or 5' UTR termination
Start codon stop transcription. Changes in the sequence of a promoter
Sites needed (ATG) 3' UTR
Enhancer Promoter for splicing Stop codon (TAG) that make it hard or impossible for RNA polymerase to as­
sociate with the promoter diminish or prevent transcrip­
tion. Likewise, mutations in enhancers that disrupt them
Exon Intron Exon from being recognized by transcription factors also dimin­
ish the transcription of eukaryotic genes. Mutations in a
Missense mutations termination signal can diminish the amount of mRNA pro­
Mutations that change a codon into a mutant codon that duced and thus the amount of gene product.
specifies a different amino acid are called missense muta- In eukaryotes, most primary transcripts have splice­
tions. If the substituted amino acid has chemical properties acceptor sites, splice­donor sites, and branch sites that
similar to the one it replaces, then this change may have allow splicing to join exons together with precision in the
little or no effect on protein function. Such mutations are mature mRNA. Changes in any one of these sites can
conservative substitutions. For example, a mutation that obstruct splicing. In some cases, the result will be the
alters a GAC codon for aspartic acid to a GAG codon for absence of mature mRNA and thus no polypeptide. In other
glutamic acid is a conservative substitution because both cases, the splicing errors can yield aberrantly spliced
amino acids have acidic R groups. mRNAs that encode altered forms of the protein.
By contrast, nonconservative substitutions, missense Mature mRNAs have ribosome binding sites and in­
mutations that cause substitution of an amino acid with frame stop codons indicating where translation should start
very different properties, are likely to have more noticeable and stop. Mutations affecting a ribosome binding site would
consequences. A change of the same GAC codon for aspar­ lower the affinity of the mRNA for the small ribosomal
tic acid to GCC, a codon for alanine (an amino acid with an subunit; such mutations are likely to diminish the efficiency
uncharged, nonpolar R group), is an example of a noncon­ of translation and thus the amount of polypeptide product.
servative substitution. Mutations in a stop codon would produce longer­than­
The effect on phenotype of any missense mutation is dif­ normal proteins that might be unstable or nonfunctional.
ficult to predict because it depends on how a particular amino
acid substitution changes a protein’s structure and function.
Most Mutations that Affect Gene

Nonsense mutations Expression Reduce Gene Function
Nonsense mutations change an amino acid–specifying co­ Mutations affect phenotype by changing either the amino
don to a premature stop codon. Nonsense mutations there­ acid sequence of a protein or the amount of the gene product
fore result in the production of truncated proteins lacking produced. Any mutation inside or outside a coding region
all amino acids between the amino acid encoded by the mu­ that reduces or abolishes protein activity in one of the many
tant codon and the C terminus of the normal polypeptide. ways previously described is a loss-of-function mutation.