7.1.5 The Gene Families of Vertebrate Haemoglobins
263
World apes or lemurs [173]. Inactivation of this
gene in Lemur fulvus is the result of hybridization
with the ~ gene [60]. Conversions between 6 and
~ have occurred frequently in mammalian evolution and have led not uncommonly to the formation of hybrid genes, e.g. rabbit 'l/J~2, mouse bh2
and bh3, and goat 'l/JW and 'l/JW [54]. Thus, the
rabbit ~-gene cluster (Table 7.4) consists of two
embryonal active genes, ~4 and ~3, which are
comparable to E and y, and a foetal/adult gene ~1,
which corresponds to the ~ gene of other mammals [114].
Haemoglobin evolution in the rodents apparently led initially to three adult ~ genes. At any
rate, three active ~ genes (b1, b2 and b3) are
found in Peromyscus maniculatus, and several rat
lines also express three adult ~ genes. The ~-gene
cluster of the mouse, on the other hand, has only
two active adult genes (Table 7.4) [129, 147].
During the evolution of the ruminants, an ancestral gene cluster with the form E, E, 'l/J, ~ was
duplicated (cattle) or even triplicated (goat,
sheep) (Table 7.4). Sequence comparisons between the goat and sheep show that the rate of
evolution of the haemoglobins after the two
duplication steps was about threefold higher compared with that in man and the mouse. The goat
produces three consecutive non-embryonal ~
types; the foetal chain ~F (earlier y) is followed by
the juvenile form ~c for up to 3 months after
birth, when it is replaced by the adult type ~A.
This third switch is reversible; ~c is again produced after extensive loss of blood [144]. Sheep
of the haplotype A have the same 12 genes at the
~ locus as have the goat, and also produce ~c during anaemic stress. Haplotype B sheep lack four
genes, including ~c [47]. The third gene block
with the juvenile/stress haemoglobin chain ~c is
also missing from the bovine genome (Table 7.4).
Furthermore, one of the bovine pseudogenes is
duplicated, and in relation to this remarkable
phenomenon it should be recalled that pseudogenes may serve as gene reservoirs [144]. The haemoglobin system of the domestic pig also has
some special features: there is only one adult haemoglobin, a2~2' but four embryonal haemoglobins with the compositions ~2E2' azEz, ~z8z and
a z8 z. This 8-chain, which should not be confused
with the product of the 8 gene recently found in
the a cluster, so far appears unique to the pig [11].
There are, as yet, no such detailed concepts of
the evolution of the mammalian a-gene cluster
(Table 7.4). It occurs at a significantly faster rate
than that of the ~ cluster [58]. Two ~ genes are
found in man and the chimpanzee. The ~1 gene,
which in man has become a pseudogene, appears
to be active in the chimpanzee [185]. Duplicated
a loci are found in many mammals, e.g. dogs,
rodents, horses, cattle and primates, and appear
to be subject to frequent gene conversion [34].
Genes in homologous positions in different species may be active or non-functional, depending
upon whether or not they have been recently corrected through conversion with a functional a
gene [58]. The sensational discovery of the 81
gene of the orangoutan as the first representative
of a new a subfamily will certainly stimulate further research into the evolution of the a-gene
cluster. Genes of the 8 family have been detected
in various primates, the rabbit and probably also
the horse. In contrast to the genes of the rabbit
and the primitive primate Galago, the genes of
the higher primates Papio anubis and Pongo pygmaeus (orang-utan) are intact and probably functional. Transcripts of the 81 globin gene have
been found in embryonal erythroidal cells and in
a human erythroleukaemia cell line [68, 102]. The
81 genes of Pongo and Papio have only 27 substitutions, of which 22 are synonymous. The amino
acid sequences of 81 and a1 differ in only
55 positions, from which it can be concluded that
a duplication a/8 occurred about 260 million
years ago. There is more than one 8 copy in
Papio, Pongo and man [146]. The ~-globin locus
of the rabbit consists of three active genes and
one pseudo gene , whereas the a locus has five
embryonal ~ genes in addition to one a and two 8
genes (Table 7.4); in this case, ~1, ~2 and ~3 have
suffered deletions and the substitution of critical
amino acids, and they no longer produce functional globin chains [32, 114].
Post-translationally altered haemoglobins are
widely found in the mammals. The proportion of
'glycosylated haemoglobins, however, appears to
be dependent upon their rate of formation, which
itself is determined by the glucose permeability of
the erythrocyte membrane [137]. Allelic variants
of the haemoglobins are actually no less common
in other vertebrates than in man, but they have
been less intensively investigated [123]. As well as
in man, the sickle-cell phenomenon has been
observed in numerous deer species, in sheep,
goat, genets, the mongoose and even lizards;
only in man and the deer has a mutation of the ~
chain been shown to be causal [149].
The only avian haemoglobin system to have
been extensively investigated is that of the
chicken. Some illuminating changes in the course
of embryo development have received particular
attention. There are four embryonal haemoglo-
263
World apes or lemurs [173]. Inactivation of this
gene in Lemur fulvus is the result of hybridization
with the ~ gene [60]. Conversions between 6 and
~ have occurred frequently in mammalian evolution and have led not uncommonly to the formation of hybrid genes, e.g. rabbit 'l/J~2, mouse bh2
and bh3, and goat 'l/JW and 'l/JW [54]. Thus, the
rabbit ~-gene cluster (Table 7.4) consists of two
embryonal active genes, ~4 and ~3, which are
comparable to E and y, and a foetal/adult gene ~1,
which corresponds to the ~ gene of other mammals [114].
Haemoglobin evolution in the rodents apparently led initially to three adult ~ genes. At any
rate, three active ~ genes (b1, b2 and b3) are
found in Peromyscus maniculatus, and several rat
lines also express three adult ~ genes. The ~-gene
cluster of the mouse, on the other hand, has only
two active adult genes (Table 7.4) [129, 147].
During the evolution of the ruminants, an ancestral gene cluster with the form E, E, 'l/J, ~ was
duplicated (cattle) or even triplicated (goat,
sheep) (Table 7.4). Sequence comparisons between the goat and sheep show that the rate of
evolution of the haemoglobins after the two
duplication steps was about threefold higher compared with that in man and the mouse. The goat
produces three consecutive non-embryonal ~
types; the foetal chain ~F (earlier y) is followed by
the juvenile form ~c for up to 3 months after
birth, when it is replaced by the adult type ~A.
This third switch is reversible; ~c is again produced after extensive loss of blood [144]. Sheep
of the haplotype A have the same 12 genes at the
~ locus as have the goat, and also produce ~c during anaemic stress. Haplotype B sheep lack four
genes, including ~c [47]. The third gene block
with the juvenile/stress haemoglobin chain ~c is
also missing from the bovine genome (Table 7.4).
Furthermore, one of the bovine pseudogenes is
duplicated, and in relation to this remarkable
phenomenon it should be recalled that pseudogenes may serve as gene reservoirs [144]. The haemoglobin system of the domestic pig also has
some special features: there is only one adult haemoglobin, a2~2' but four embryonal haemoglobins with the compositions ~2E2' azEz, ~z8z and
a z8 z. This 8-chain, which should not be confused
with the product of the 8 gene recently found in
the a cluster, so far appears unique to the pig [11].
There are, as yet, no such detailed concepts of
the evolution of the mammalian a-gene cluster
(Table 7.4). It occurs at a significantly faster rate
than that of the ~ cluster [58]. Two ~ genes are
found in man and the chimpanzee. The ~1 gene,
which in man has become a pseudogene, appears
to be active in the chimpanzee [185]. Duplicated
a loci are found in many mammals, e.g. dogs,
rodents, horses, cattle and primates, and appear
to be subject to frequent gene conversion [34].
Genes in homologous positions in different species may be active or non-functional, depending
upon whether or not they have been recently corrected through conversion with a functional a
gene [58]. The sensational discovery of the 81
gene of the orangoutan as the first representative
of a new a subfamily will certainly stimulate further research into the evolution of the a-gene
cluster. Genes of the 8 family have been detected
in various primates, the rabbit and probably also
the horse. In contrast to the genes of the rabbit
and the primitive primate Galago, the genes of
the higher primates Papio anubis and Pongo pygmaeus (orang-utan) are intact and probably functional. Transcripts of the 81 globin gene have
been found in embryonal erythroidal cells and in
a human erythroleukaemia cell line [68, 102]. The
81 genes of Pongo and Papio have only 27 substitutions, of which 22 are synonymous. The amino
acid sequences of 81 and a1 differ in only
55 positions, from which it can be concluded that
a duplication a/8 occurred about 260 million
years ago. There is more than one 8 copy in
Papio, Pongo and man [146]. The ~-globin locus
of the rabbit consists of three active genes and
one pseudo gene , whereas the a locus has five
embryonal ~ genes in addition to one a and two 8
genes (Table 7.4); in this case, ~1, ~2 and ~3 have
suffered deletions and the substitution of critical
amino acids, and they no longer produce functional globin chains [32, 114].
Post-translationally altered haemoglobins are
widely found in the mammals. The proportion of
'glycosylated haemoglobins, however, appears to
be dependent upon their rate of formation, which
itself is determined by the glucose permeability of
the erythrocyte membrane [137]. Allelic variants
of the haemoglobins are actually no less common
in other vertebrates than in man, but they have
been less intensively investigated [123]. As well as
in man, the sickle-cell phenomenon has been
observed in numerous deer species, in sheep,
goat, genets, the mongoose and even lizards;
only in man and the deer has a mutation of the ~
chain been shown to be causal [149].
The only avian haemoglobin system to have
been extensively investigated is that of the
chicken. Some illuminating changes in the course
of embryo development have received particular
attention. There are four embryonal haemoglo-