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(Toder
et al
., 1995). Similarly, the human pseudoautosomal genes
CSF2RA
(Xp22.32/Yp11.3),
SHOX
(Xp22/Yp11.3) and
IL3RA
(Xp22.3/Yp11.3), are auto-
somal in the mouse (Ellis, 1996). Further evidence for the process of attrition may
come from the finding that whereas the
Fxy
gene spans the PAR on the murine X
chromosome, its human counterpart (
FXY
; Xp22.3) lies proximal to the human
PAR (Perry
et al
., 1998).
The 'X-driven' hypothesis of Graves (1995; 1998) essentially proposes that the
rapid evolutionary spreading of X inactivation preceded the decay of Y chromo-
somal genes and even drove its initial steps. This hypothesis predicts that inacti-
vated X-linked genes with functionally comparable Y-linked homologues should
exist as evolutionary intermediates, but as yet no such gene has been found in any
mammalian species. Indeed, a considerable number of human X-linked genes
escape X-inactivation but have no detectable Y-borne counterpart.
An alternative 'Y-driven' pathway of X-Y gene evolution has been proposed by
Jegalian and Page (1998). Briefly, these authors suggested that many extant genes
represent intermediates on a general pathway by which X-Y genes or gene clus-
ters evolved from autosomal genes (
Figure 2.9
). Autosomal genes would have
entered the pathway either by virtue of their presence on the emergent sex chro-
mosomes or via translocation of an autosomal gene. This would have been fol-
lowed by suppression of X-Y recombination. These steps occurred either at the
chromosomal or sub-chromosomal level and gave rise to functionally equivalent
X-linked (but not inactivated) genes and Y-linked genes. Subsequently, three dif-
ferent processes (Y gene decay, upregulation of X-linked gene expression, and X-
inactivation) interacted resulting in an inactivated X-linked gene accompanied by
the loss of the Y gene. Expression of the X-linked gene then increased as an adap-
tation to the reduced or restricted expression of its Y-linked counterpart. This
compensated for the loss of Y gene function and restored optimal expression lev-
els in males. X-inactivation, on the other hand, may be viewed as a counter-
response which restored optimal expression levels in females. This explanation
could in principle account for most X-linked and X-Y homologous genes in extant
mammals, many of which exist at intermediate steps in the pathway. Jegalian and
Page (1998) pointed out that only one gene cannot be accommodated in their
pathway schema: the human pseudoautosomal gene,
SYBL1
, which is X-inacti-
vated and transcriptionally silenced on the Y chromosome. A model for the evo-
lution of the mammalian sex chromosomes summarizing the above processes is
presented in
Figure 2.10.
2.3.5 Evolution of the mitochondrial genome
The 16 569 bp of the human mitochondrial genome encodes 13 polypeptides, all
subunits of the enzyme complexes of the pathway of oxidative phosphorylation,
and a total of 22 tRNAs. The mitochondrial genome is characterized by its high
proportion of coding DNA, the paucity of repetitive DNA sequence, the absence
of introns within its genes and its own genetic code distinct from that of the
nuclear genome (Kurland, 1992). Mitochondrial genes experience a mutation rate
that has been estimated to be up to 17 times higher than the corresponding rate
for nuclear genes (Wallace
et al
., 1987). This is thought to be due to the fact that
