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finding is consistent with the hypothesis that these segments were duplicated prior
to the divergence of zebrafish and mammals. The presence of more than two copies
of each paralogous chromosomal segment, is suggestive of at least two rounds of
duplication which would have occurred after the divergence of the cephalochor-
dates and cranial chordates, but before the divergence of the ray-finned and lobe-
finned fishes, which is thought to have occurred about 420 Myrs ago.
Several extensive regions of paralogy have been identified in the human genome
which have been claimed to result from ancient tetraploidization events. The 13
groups of paralogous genes found on chromosomes 4 and 5 (
Table 2.1
) provide one
example (Lundin, 1993). Lundin (1993) identified several other possible examples
of paralogous pairs or groups of genes on different human chromosomes: (i) parts
of chromosomes 2, 7, 12, 14, and 17, (ii) parts of chromosomes 8, 10, and 16, and
(iii) parts of chromosomes 1, 11, 12, 15, and 19 (
Table 2.2
). Although the extensive
paralogy noted between chromosomes 11 and 12 is explicable by a model of chro-
mosome duplication resulting from tetraploidization, there are some discrepancies
in the locations of genes on these chromosomes. These can however be accounted
for by the occurrence of a pericentric inversion on chromosome 12.
Paralogy may be explained by mechanisms other than tetraploidization. Indeed,
some paralogous gene loci are explicable by regional duplication (see Chapter 9, sec-
tion 9.5);
Table 2.3
lists those identified on human chromosome 1. The relative
importance of regional duplication/translocation as compared to tetraploidization is
unclear and ambiguity even extends to individual cases. Thus, the relative locations
of the tyrosine hydroxylase (
TH
; 11p15.5), tryptophan hydroxylase (
TPH
; 11p14.3-
p15.1) and phenylalanine hydroxylase (
PAH
; 12q22-q24) genes have been explained
in terms of both mechanisms (Craig
et al
., 1986; Ledley
et al
., 1987; Lundin, 1993).
The two highly related regions on the proximal and distal long arms of human
chromosome 21 (21q22.1 and 21q11.2) appear to have arisen as a result of an intra-
chromosomal duplication of >200 kb (Dutriaux
et al
., 1994). This duplication is
thought to have arisen between 15 and 30 Myrs ago after the separation of the
orangutan from the other great apes (Orti
et al
., 1998). By contrast, the origin of the
paralogous 2-20 Mb segments on human chromosomes 1, 6, and 9 (Banyer
et al
.,
1998; Endo
et al
., 1998; Katsanis
et al
., 1996) is unclear. Regardless of the mecha-
nism, at least two intra-chromosomal duplications must have occurred resulting in
the triplication of a series of genes, for example the retinoid X receptor genes
RXRG
(1q22-q23),
RXRB
(6p21.3) and
RXRA
(9q34.31), the pre-B cell leukemia
transcription factor genes
PBX1
(1q23),
PBX2
(6p21.3), and
PBX3
(9q34), and the
tenascin genes
TNR
(1q25-q31),
TNXA
(6p21.3), and
HXB
(9q32-q34) (Katsanis
et
al
., 1996). Interestingly,
Alu-
and LINE-dense clusters flank the boundaries of the
6p21.3 segment, a finding which may be significant in view of the recombinogenic
potential of these sequence elements. In this context, it may be significant that a
sequence related to the pseudoautosomal boundary of the human sex chromo-
somes (see Section 2.3.4) has also been noted at the centromeric boundary of the
6p21.3 segment (Fukagawa
et al
., 1996).
2.1.2 Consequences of genome duplications for gene evolution
In principle, the genetic redundancy created by a genome duplication would have
