Biology Reference
In-Depth Information
transcription-coupled repair (Bhatia
et al
., 1996; Drapkin
et al
., 1994; Hanawalt,
1994), a process that corrects lesions specifically on the transcribed DNA strand,
could also account for different mutation rates between transcribed and nontran-
scribed strands. Both these mechanisms would predict a higher mutation rate for
the nontranscribed as opposed to the transcribed DNA strand.
Finally, in their dataset of pathological substitutions, Krawczak
et al
. (1998)
found that thermodynamic stability of DNA triplets was positively correlated
with the average relative rate at which the central nucleotide of a triplet under-
went substitution. At first sight, this finding might appear to be counterintuitive
since it implies that higher rather than lower DNA duplex stability would render
a gene region more prone to single base-pair substitution. However, the consistent
absence of flanking repeat elements noted for the mutations analyzed here sug-
gests that extensive strand slippage (which would require the DNA to be single-
stranded) is unlikely to play an important role in the generation of single
base-pair substitutions. Nevertheless, a high degree of thermodynamic stability
could in principle impair DNA replication in various ways. First, the likelihood
that DNA helicases would be incapable of unwinding the two DNA strands cor-
rectly or efficiently may be expected to be higher in more stable regions (Chen
et
al
. 1992). Second, temporary reannealing of the two native DNA strands during
replication might be favored and could be more enduring in such regions. In both
cases, DNA polymerase activity would be seriously impeded by localized double-
stranded DNA structures, which could result in either a cessation of polymeriza-
tion or the skipping of one or more nucleotides, leaving a gap in the nascent DNA
strand. Miscorrection during the post-replicative repair of such nicks would then
introduce a single base-pair substitution. Alternatively, the observed correlation
could reflect the increased stability of at least some slippage-mediated misalign-
ments during replication of the native and nascent DNA strands, allowing
enough time for misincorporation of a noncomplementary nucleotide. In this
case, however, the thermodynamic stabilities of the misaligned structures must be
comparable to those of the wild-type triplets, an assumption for which there is
currently no evidence.
7.5.2 Single base-pair substitutions in evolution which have altered the
function of specific amino acid residues
Natural selection is a mechanism for generating an exceedingly high degree of
improbability.
R.A. Fisher
Some single base-pair substitutions occurring during gene evolution have intro-
duced nonsense mutations into protein coding regions thereby either prema-
turely truncating the protein product (Chapter 8, section 8.7) or abolishing the
expression of that product altogether (Chapter 6, section 6.2). However, other
single base-pair substitutions have introduced missense mutations that have
served to alter the function of specific amino acid residues and these are the topic
of this Section.
Nucleotide substitutions that have occurred and become fixed through
the action of genetic drift are readily apparent in any comparative analysis of
