262
7 Respiratory Pigments
been inactivated not so long ago by the nonsense
mutation 6-GAG( GIu) ~ TAG (stop). Of the two
a genes, a2 is expressed at levels two- to threefold higher than a1 [106].
All the genes mentioned have the two introns
typical of animal globin genes (see Fig. 2.9;
p. 38); the plant haemoglobins contain a third,
centrally located intron [95]. The introns of the
various human globin genes have homologous
positions but very different lengths. Thus,
intron 1 of the a and ~ genes is only 117-130 bp
long, whereas in the ~ gene it is 1265 bp long;
intron 2 has a length of 140-149 bp in the a
genes, 341 bp in the ~ gene, and 850-904 bp in
the ~-like genes [80]. The human globin genes
have clearly attained the character of a model;
much of our knowledge of gene structure, the
control of transcription and expression, and
mRNA processing and translation have been
gained by their study. Regulation of the ~-globin
locus is achieved in the locus control region
(LCR), which is localized in the region 6-20 kb in
front of the E-globin gene and contains four
DNase I hypersensitive sites [66, 105, 124]. The
two changes in gene expression (haemoglobin
switches) during the development from embryonal to foetal haemoglobin and further to the adult
haemoglobins are amongst the most investigated
examples of gene regulation, and, because of the
pathological persistence of Hb F in adults, they
also have medical significance [80]. Gene duplications and deletions have often been observed in
the globin gene clusters. For example, up to 10 %
of the chromosomes in human populations have
only one a gene or have three a genes; duplications have also been reported in the y and ~ genes
[66]. Comparison of neighbouring DNA sequences has shown that conversion between the two
copies of the a and y genes has occurred frequently in the evolution.of the primates, but conversion between the ~ and () genes has been less
frequent [44, 89].
Globin gene mutations in man occur with a frequency of about 0.3 %; more than 400 anomalous haemoglobins are known so far, the study of
which has produced valuable insight into the relationship between haemoglobin structure and
function. Structural variation may involve the
exchange of single amino acids; the most famous
example is Hb S, where exchange of ~A3-Glu for
Val results in the aggregation of haemoglobin
molecules upon deoxygenation and the formation
of anomalous erythrocytes (sickle-cell anaemia).
Other anomalous haemoglobins show shortened
or lengthened chains, deletions or insertions of
single amino acids, or frameshift mutations; the
latter are tolerated only close to the C-terminus.
Gene fusions result, for example, in ()~ hybrids
(Hb Lepore), ~() hybrids (Hb Antilepore) or Ay~
hybrids (haemoglobin b Kenya). Mutations in
transcription and splicing signals, nucleotide
exchange in initiation codons, or the formation of
new termination or splicing signals result in a- or
~-thalassaemia, in which the corresponding
chains are produced in insufficient amounts. The
persistence of foetal haemoglobins in adults also
involved changes in expression control signals
[66, 70].
The location of a- and ~-gene clusters on separate chromosomes is already found in the marsupials [180]. In the mouse, '\jJa-like pseudogenes
are spread over several chromosomes. There is a
large amount of comparative information available on the II cluster of the mammals (Table 7.4).
In addition to man, the gorilla and chimpanzee
also possess a ' \jJ ~ gene between Ay and (). The
pseudogenes of all three species have the ATG
initiator codon mutated to GTG, and 15-TGG to
a stop codon GTA; a frameshift mutation in
codon 20 has resulted in many stop co dons in
exons 2 and 3. In a genealogical tree constructed
by the parsimony method, the primate '\jJ~ and
the goat Ell lie on a line of orthologous genes
which are separate from the E, y, () and ~ genes
and must, therefore, be considered as a different
chain type; this is closer to E and y than to () and
~ and is designated the ' YJ chain. Thus, the original
mammalian ~-gene cluster did not consist of four
genes, as thought earlier, but rather of five (E-y-'YJ()-~) [54]. The separation of the E, y, ' YJ and ~, ()
predecessors occurred 155-200 million years ago.
Consequently, a primitive mammalian species,
like the opossum Didelphis virginiana, possesses
only two ~-like globin loci, one of which is
orthologically homologous to the E, y, and ' YJ
genes of the higher mammals, and the other to
the ~ and () genes [88].
The functional predecessors of the ' YJ genes are
encountered early in mammalian evolution; it
may be, therefore, that there were originally
three haemoglobin switches in mammalian development [54]. The original ~-gene cluster has seen
many changes during mammalian evolution.
Duplication of the y loci occurred only after the
separation of the Old and New World apes
(Catarrhini and Plat yrrhini) , in connection with
the insertion of two type-Kpn transposable elements in the Ely region. An active () gene is found in
the New World apes as well as in man and the
anthropoid apes; () is not expressed in the Old
7 Respiratory Pigments
been inactivated not so long ago by the nonsense
mutation 6-GAG( GIu) ~ TAG (stop). Of the two
a genes, a2 is expressed at levels two- to threefold higher than a1 [106].
All the genes mentioned have the two introns
typical of animal globin genes (see Fig. 2.9;
p. 38); the plant haemoglobins contain a third,
centrally located intron [95]. The introns of the
various human globin genes have homologous
positions but very different lengths. Thus,
intron 1 of the a and ~ genes is only 117-130 bp
long, whereas in the ~ gene it is 1265 bp long;
intron 2 has a length of 140-149 bp in the a
genes, 341 bp in the ~ gene, and 850-904 bp in
the ~-like genes [80]. The human globin genes
have clearly attained the character of a model;
much of our knowledge of gene structure, the
control of transcription and expression, and
mRNA processing and translation have been
gained by their study. Regulation of the ~-globin
locus is achieved in the locus control region
(LCR), which is localized in the region 6-20 kb in
front of the E-globin gene and contains four
DNase I hypersensitive sites [66, 105, 124]. The
two changes in gene expression (haemoglobin
switches) during the development from embryonal to foetal haemoglobin and further to the adult
haemoglobins are amongst the most investigated
examples of gene regulation, and, because of the
pathological persistence of Hb F in adults, they
also have medical significance [80]. Gene duplications and deletions have often been observed in
the globin gene clusters. For example, up to 10 %
of the chromosomes in human populations have
only one a gene or have three a genes; duplications have also been reported in the y and ~ genes
[66]. Comparison of neighbouring DNA sequences has shown that conversion between the two
copies of the a and y genes has occurred frequently in the evolution.of the primates, but conversion between the ~ and () genes has been less
frequent [44, 89].
Globin gene mutations in man occur with a frequency of about 0.3 %; more than 400 anomalous haemoglobins are known so far, the study of
which has produced valuable insight into the relationship between haemoglobin structure and
function. Structural variation may involve the
exchange of single amino acids; the most famous
example is Hb S, where exchange of ~A3-Glu for
Val results in the aggregation of haemoglobin
molecules upon deoxygenation and the formation
of anomalous erythrocytes (sickle-cell anaemia).
Other anomalous haemoglobins show shortened
or lengthened chains, deletions or insertions of
single amino acids, or frameshift mutations; the
latter are tolerated only close to the C-terminus.
Gene fusions result, for example, in ()~ hybrids
(Hb Lepore), ~() hybrids (Hb Antilepore) or Ay~
hybrids (haemoglobin b Kenya). Mutations in
transcription and splicing signals, nucleotide
exchange in initiation codons, or the formation of
new termination or splicing signals result in a- or
~-thalassaemia, in which the corresponding
chains are produced in insufficient amounts. The
persistence of foetal haemoglobins in adults also
involved changes in expression control signals
[66, 70].
The location of a- and ~-gene clusters on separate chromosomes is already found in the marsupials [180]. In the mouse, '\jJa-like pseudogenes
are spread over several chromosomes. There is a
large amount of comparative information available on the II cluster of the mammals (Table 7.4).
In addition to man, the gorilla and chimpanzee
also possess a ' \jJ ~ gene between Ay and (). The
pseudogenes of all three species have the ATG
initiator codon mutated to GTG, and 15-TGG to
a stop codon GTA; a frameshift mutation in
codon 20 has resulted in many stop co dons in
exons 2 and 3. In a genealogical tree constructed
by the parsimony method, the primate '\jJ~ and
the goat Ell lie on a line of orthologous genes
which are separate from the E, y, () and ~ genes
and must, therefore, be considered as a different
chain type; this is closer to E and y than to () and
~ and is designated the ' YJ chain. Thus, the original
mammalian ~-gene cluster did not consist of four
genes, as thought earlier, but rather of five (E-y-'YJ()-~) [54]. The separation of the E, y, ' YJ and ~, ()
predecessors occurred 155-200 million years ago.
Consequently, a primitive mammalian species,
like the opossum Didelphis virginiana, possesses
only two ~-like globin loci, one of which is
orthologically homologous to the E, y, and ' YJ
genes of the higher mammals, and the other to
the ~ and () genes [88].
The functional predecessors of the ' YJ genes are
encountered early in mammalian evolution; it
may be, therefore, that there were originally
three haemoglobin switches in mammalian development [54]. The original ~-gene cluster has seen
many changes during mammalian evolution.
Duplication of the y loci occurred only after the
separation of the Old and New World apes
(Catarrhini and Plat yrrhini) , in connection with
the insertion of two type-Kpn transposable elements in the Ely region. An active () gene is found in
the New World apes as well as in man and the
anthropoid apes; () is not expressed in the Old