658
CHAPTER 28
Hemoglobin
F I G U R E 2 8 -1 1
Changes in human globin chain concentration during development. [Reproduced with permission from W. G. Wood,
Hemoglobin synthesis during human fetal development.
Br. M ed. B ull.
32, 282 (1976).]
Embryonic hemoglobins normally are not found in the
fetus after the first trimester of pregnancy because synthe-
sis of £ and e chains ceases before the tenth week of gesta-
tion (Figure 28-11). HbF has a higher affinity for oxygen
than does HbA, facilitating oxygen transfer from the ma-
ternal to the fetal circulation, because of the lower affinity
of HbF for 2,3-DPG. Since /3-chain synthesis remains low
relative to y-chain synthesis throughout intrauterine life,
HbF predominates during that period. The mechanisms
that control hemoglobin switching (change in expression
of the globin genes during development) represent an ac-
tive area of research.
Synthesis of the different hemoglobin chains is directed
by different genes, at least one for each chain type. The
chromosomal arrangement of these genes (Figure 28-12)
was determined by restriction endonuclease mapping and
by hybridization with probes (Southern blots) specific for
the different globin genes (Chapter 23). The a-globin gene
complex consists of two
a
genes and one f gene, separated
by a pseudo-aj gene and a pseudo-f gene (previously
designated the
£ {
gene). Pseudogenes have extensive se-
quence homology with the corresponding normal gene but,
because of mutation, do not produce functional polypep-
tides. Pseudogenes are detected by DNA-DNA hybridiza-
tion mapping, making use of their sequence homology
with the probe. Pseudogenes probably arose during evo-
lution by gene duplication and subsequent mutations that
inactivated the gene. The 5-globin gene, which is poorly
expressed, may represent a duplication of the /J-globin
gene that is on its way to becoming a pseudogene. The
a -like Genes
5
'1
HS-40
i
\ \
Ç
yÇ ya a2 al
■ *------Q— a — ■ — ■ ------- 3-
Chromosome 16
5 4 3 2 1
p -like Genes
5'------
1
1
*
1
1
------ W
LCR
e
G
7
Ay y
8
p *
i
-------- ■-------- ■— * -
0
—
■— ■---------3 '
C h ro m o so m e 11
i-----1----- 1_____1__ i_____1__ 1
0
10
20
30
40
50
60 Kilobases
F I G U R E 2 8 - 1 2
Arrangement of the «- and /1-gene complex on human chromosomes 16 and 11 respectively. Functional genes are
indicated by dark boxes; nonfunctional genes or pseudogenes
(f),
which are evolutionary remnants, are shown by open
boxes. The o'-gene complex consists of two pseudogenes,
ft;
and
f a ,
and three functional genes, f ,
a
1
, and «
2
. The
,
8
-gene complex consists of at least one pseudogene
(fP )
and five functional genes,
e, Gy, Ay, S,
and
p.
They are
arranged in the order in which the ,
8
-like genes are expressed during development. Both
a-
and jS-Iike genes contain
essential upstream sequences that can regulate gene expression. In chromosome 11, the locus control region (LCR)
contains five DNase-hypersensitive sites (HS) that are essential for /Mike gene expression. A similar region located in
chromosome 16, designated HS-40, regulates «-like gene expression.
