2 THE INTERRUPTED GENE (Full Edition)
8 Some DNA sequences code for more than one protein
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- The use of alternative initiation
or termination codons allows two proteins to be generated where one is equivalent
to a fragment of the other.
- Nonhomologous protein sequences can
be produced from the same sequence of DNA when it is read in different reading frames
by two (overlapping) genes.
- Homologous proteins that differ by
the presence or absence of certain regions can be generated by differential (alternative)
splicing, when certain exons are included or excluded. This may take the form of
including or excluding individual exons or of choosing between alternative exons.
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Most genes consist of a sequence of DNA that is devoted solely to the purpose of
coding for one protein (although the gene may include noncoding regions at either
end and introns within the coding region). However, there are some cases in which
a single sequence of DNA codes for more than one protein.
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Figure 2.17
Two proteins can be generated from a single gene by starting (or terminating) expression
at different points.
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Overlapping genes occur in the relatively simple situation in which one
gene is part of the other. The first half (or second half) of a gene is used independently
to specify a protein that represents the first (or second) half of the protein specified
by the full gene. This relationship is illustrated in Figure 2.17. The end result
is much the same as though a partial cleavage took place in the protein product
to generate part-length as well as full-length forms.
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Figure 2.18
Two genes may share the same sequence by reading the DNA in different frames.
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Two genes overlap in a more subtle manner when the same sequence of DNA is shared
between two nonhomologous proteins. This situation arises when the same
sequence of DNA is translated in more than one reading frame. In cellular genes,
a DNA sequence usually is read in only one of the three potential reading frames,
but in some viral and mitochondrial genes, there is an overlap between two adjacent
genes that are read in different reading frames. This situation is illustrated in
Figure 2.18. The distance of overlap is usually relatively short, so that most of
the sequence representing the protein retains a unique coding function.
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In some genes, alternative patterns of gene expression create switches
in the pathway for connecting the exons. A single gene may generate a variety of
mRNA products that differ in their content of exons. The difference may be that
certain exons are optional — they may be included or spliced out. Or there may be
exons that are treated as mutually exclusive — one or the other is included, but
not both. The alternative forms produce proteins in which one part is common while
the other part is different.
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Figure 2.19
Alternative splicing generates the a and
ß variants of troponin T.
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In some cases, the alternative means of expression do not affect the sequence of
the protein; for example, changes that affect the 5' nontranslated leader or the
3' nontranslated trailer may have regulatory consequences, but the same protein
is made. In other cases, one exon is substituted for another, as indicated in Figure
2.19.
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In this example, the proteins produced by the two mRNAs contain sequences that overlap
extensively, but that are different within the alternatively spliced region. The
3' half of the troponin T gene of rat muscle contains 5 exons, but only 4 are used
to construct an individual mRNA. Three exons, WXZ, are the same in both
expression patterns. However, in one pattern the a
exon is spliced between X and Z; in the other pattern, the ß exon is used. The a
and ß forms of troponin T therefore differ in the
sequence of the amino acids present between sequences W and Z, depending on which
of the alternative exons, a or
ß, is used. Either one of the a and ß exons can be used to form an individual mRNA,
but both cannot be used in the same mRNA.
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Figure 2.20
Alternative splicing uses the same pre-mRNA to generate mRNAs that have different
combinations of exons.
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Figure 2.20 illustrates an example in which alternative splicing leads to the
inclusion of an exon in some mRNAs, while it is left out of others. A single type
of transcript is made from the gene, but it can be spliced in either of two ways.
In the first pathway, two introns are spliced out, and the three exons are joined
together. In the second pathway, the second exon is not recognized. As a result,
a single large intron is spliced out. This intron consists of intron 1 + exon 2
+ intron 2. In effect, exon 2 has been treated in this pathway as part of the single
intron. The pathways produce two proteins that are the same at their ends, but one
of which has an additional sequence in the middle. So the region of DNA codes for
more than one protein. (Other types of combinations that are produced by alternative
splicing are discussed in Alternative splicing involves differential use of splice
junctions).
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Sometimes two pathways operate simultaneously, a certain proportion of the RNA being
spliced in each way; sometimes the pathways are alternatives that are expressed
under different conditions, one in one cell type and one in another cell type.
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So alternative (or differential) splicing can generate proteins with overlapping
sequences from a single stretch of DNA. It is curious that the higher eukaryotic
genome is extremely spacious in having large genes that are often quite dispersed,
but at the same time it may make multiple products from an individual locus. Alternative
splicing expands the number of proteins relative to the number of genes by ~15%
in flies and worms, but has much bigger effects in man, where ~60% of genes may
have alternative modes of expression (see The human genome has fewer genes than
expected). About 80% of the alternative splicing events result in a change
in the protein sequence.
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©Jones and Bartlett Publishers (2007)
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