Pseudogenes and their formation - Human Gene Evolution - page 277

introns (Bergstrom et al ., 1998). Some gene conversion events can neverthe-
less involve rather longer stretches of DNA, for example over the entire rhe-
sus monkey

2 globin genes (Slightom et al ., 1988) and over the entire
hominoid immunoglobulin C

1 and

genes (Kawamura et al ., 1992). The interpre-
tational problem in such studies lies in the fact that it is difficult to distin-
guish a single large gene conversion event from multiple overlapping short
gene conversions.
(iv) The age of the pseudogenes . The degree of sequence homology to the functional
gene will decay with time and this could serve to reduce the frequency of gene
conversion as well as the length of sequence involved. Further, the number of
inactivating mutations acquired by the pseudogene will increase with time
and this would have the effect of reducing the likelihood of a functionally
productive gene conversion event.

At the present time, definitive evidence for pseudogene-mediated gene conver-
sion is fairly sparse. Since by its very nature, gene conversion tends to cover its
own traces, such evidence may prove hard to obtain. Further, although the donor
sequence might be a pseudogene in an extant genome, this does not mean that it
was necessarily a pseudogene at the time of the gene conversion event. The
demonstration that the sequence in question has been accumulating mutations
over a considerable period of time would provide evidence in favor of an ancient
inactivating event. Again, however, gene conversion could confound estimates of
the length of evolutionary time elapsed. The above notwithstanding, one possible
example of pseudogene-mediated gene conversion involves a human
immunoglobulin V H pseudogene (V4-55P) which may have served as a donor
sequence in the conversion of two functional V H ( IGHV ; 14q32) genes, V4-4b and
V4-28 (Haino et al ., 1994). Similarly, a human pseudogene in the human growth
hormone gene cluster may have templated sequence changes in a functional
source gene: the growth hormone 1 ( GH1 ; 17q22-q24) gene promoter region con-
tains five single base polymorphic alleles (at -57, -1, +3, +16, and +26) which are
identical to the bases present at the homologous locations in the promoter of the
closely linked and evolutionarily related pseudogene ( CSHL1 ) but are different to
those present in the more distal CSH1 , GH2 and CSH2 genes (Giordano et al .,
1997). A gorilla HLA-A gene has been shown to be similar to an HLA-AR pseudo-
gene only in exon 2 with the remainder of the gene being closely related to other
primate A locus genes (Watkins et al ., 1991). Finally, immunoglobulin V gene
diversity in chickens is known to be increased by gene conversion during B-cell
development; the germline pool of donor sequence information for somatic gene
conversion is found in the families of V pseudogenes located 5

to the single func-

tional V gene at each locus (McCormack et al ., 1993).

6.1.7 Pseudogene reactivation

Pseudogenes may be by definition inactive but this does not mean that they can
never regain their activity. Indeed, Marshall et al. (1994) calculated that the resur-
rection of pseudogenes is probabilistically feasible within about 6 Myrs of forma-
tion but that it is unlikely after more than 10 Myrs have elapsed owing to the
accumulation of multiple inactivating mutations.