Biology Reference
In-Depth Information
on chromosome 17p11.2, arose during the evolution of the primates but different
lesions have occurred in different phylogenetic branches of the family making
this pseudogene a potentially useful marker in molecular studies (Devor
et al
.,
1998).
Attempts have also been made to estimate the age of pseudogenes (time since
duplication and/or inactivation) by comparing the proportion of silent and
replacement changes in the pseudogene sequence to that exhibited by the active
parent gene. Such estimates assume that following inactivation, pseudogenes will
accumulate mutations at the same rate as silent changes in active genes. However,
what is often ignored is that there is still some selection against silent changes in
functional genes. Moreover, such estimates are extremely sensitive to the con-
founding effects of gene conversion (see Section 6.1.6 and Chapter 9, section 9.6)
whose homogenizing influence serves continually to restart the molecular clock
leading to the underestimation of the age of the pseudogene.
6.1.5 Patterns of mutation in pseudogenes
Pseudogenes represent extremely useful tools for the study of mutation because,
since they lack a biological function and are not subject to selective constraints,
all mutations that occur in pseudogenes are selectively neutral and will become
fixed in the population with equal probability.
Pseudogenes exhibit a very high rate of nucleotide substitution with the CpG
dinucleotide being a hotspot for mutation (Bulmer
et al
., 1986; Gojobori
et al
.,
1982; Li
et al
., 1981; Li
et al
., 1984; Miyata and Hayashida, 1981). By contrast,
deletions occur about once every 40 nucleotide substitutions whilst insertions
occur about once every 100 nucleotide substitutions (Ophir and Graur, 1997). The
age of the pseudogene, however, is not always linearly related to the numbers of
deletions and insertions present (Ophir and Graur, 1997), and this may be due at
least in part to gene conversion (see Section 6.1.6).
The rate of DNA loss through deletion from processed pseudogenes appears to
be considerably higher in rodents than in humans (Graur
et al
., 1989; Ophir and
Graur 1997). Interpretation of such interspecies comparisons can however be con-
founded by possible differences in the frequency of gene conversion between
species.
The mutation rate within processed pseudogenes appears to be higher than in
regions flanking the site of insertion (Casane
et al.
, 1997). This is potentially
explicable if one considers that those sites which are inherently the most mutable
have been maintained by selection within the retrotransposed sequence up until
pseudogene formation whereas such sites have been removed in the flanking
regions which have been unconstrained by the effects of natural selection for
much longer periods of evolutionary time.
6.1.6 Pseudogenes and gene conversion
Gene conversion is the modification of one of two alleles by the other. It involves
the nonreciprocal correction of an 'acceptor' gene or DNA sequence by a 'donor'
sequence which remains physically unchanged. In most known cases, gene
