Page 63 - Genetics_From_Genes_to_Genomes_6th_FULL_Part3

10.4 A Comprehensive Example: The Hemoglobin Genes 357

fundamental insights into the mechanisms that change Figure 10.20 Effects of deletions in the β-globin gene
globin expression during normal development from cluster. (a) Normal situation. The locus control region (LCR)
embryonic to fetal to adult forms. Furthermore, the DNA sequentially turns on the transcription of the ε gene in embryos: the
sequence of these clusters reveals how various mutations two γ genes during fetal development, and the β and δ genes in
adults. (b) Loci with a deletion of the β and δ genes cannot switch
give rise to a range of globin-related disorders. Hemoglo- gene expression at birth, so the γ fetal polypeptides are still
bin disorders are the most common genetic diseases in the produced in adults. This hereditary persistence of fetal hemoglobin
world and include sickle-cell anemia, which arises from an is benign. (c) Deletion of the LCR prevents the expression of all
altered β chain, and thalassemia, which results from genes in the cluster, causing severe β-thalassemia.
decreases in the amount of either α or β chain production. (a) Normal cluster

LCR G A 1
The Order of the Hemoglobin Genes in
the α and β Clusters Reflects the Timing
of Their Expression (b) Hereditary persistence of fetal hemoglobin
X
For the α-like chains, the temporal order of protein LCR G A 1
expression is ζ-globin during the first five weeks of em-
bryonic life, followed by α-globin (encoded by both the
α1 and α2 genes) during fetal and adult life. For the β-like - deletion- deletion
chains, the order of protein production is ε-globin during
the first five weeks of embryonic life; then γ-globin (c) Severe -thalassemia
(encoded by the Aγ and Gγ genes) during fetal life; and Loss of gene expression
finally, within a few months of birth, mostly β but also G A 1
some δ chains (see Fig. 10.19c).
If you compare Figs. 10.11 and 10.19c, you will note LCR
that within each cluster, the order of globin genes on the Deletion
chromosomes parallels the order of their expression during
development. Furthermore, all the genes in the α-globin
locus are oriented in the same direction relative to chromo- have certain deletions extending across the β and δ genes
some 16; that is, they all use the same strand of DNA as the (compare Fig. 10.20a and b). Because of these specific
template for transcription. The genes in the β-globin locus deletions, the LCR can’t switch, as it normally would near
are also all oriented in the same direction, here relative to the time of birth, from γ-globin production to β- and
chromosome 11. The organization of these globin-gene- δ-globin production. People with this rare condition,
containing regions contrasts with most regions of the called hereditary persistence of fetal hemoglobin, continue
genome, where adjacent genes appear to be oriented ran- to produce large enough amounts of fetal γ-globin through-
domly. These facts taken together suggest that whatever out adulthood to maintain near-normal health.
mechanism turns the globin genes on and off during differ-
ent stages of development takes advantage of their relative
positions and orientations. Globin-Related Diseases Result from a
We now understand what that mechanism is: Each of
the two globin loci contains a locus control region (or Variety of Mutations
LCR) at one end that controls sequential gene expression By comparing DNA sequences from affected individuals
from that locus (Fig. 10.11). The LCR at each locus is a col- with those from healthy individuals, researchers have
lection of regulatory elements called enhancers that are dis- learned that two general classes of disorders arise from
cussed in detail in Chapter 17. Through their interactions alterations in the hemoglobin genes.
with proteins called transcription factors, the enhancers In one class, mutations change the amino acid sequence
activate transcription of each gene in the right cells at the and thus the three-dimensional structure of the α- or
appropriate time. β-globin chain. These structural changes result in an altered
One interesting consequence of the β-globin locus’s protein whose malfunction causes the destruction of red
organization and its control through the LCR is seen in a blood cells. Diseases of this type are known as hemolytic
rare medical condition with a surprising prognosis. In anemias. An example is sickle-cell anemia, caused by an
some adults, the red blood cell precursors express neither A-to-T substitution in the sixth codon of the β-globin chain.
the β nor the δ genes. Although this should be a lethal situ- This simple change in DNA sequence alters the sixth amino
ation, these adults remain healthy. Sequence analysis of acid in the chain from glutamic acid to valine. Red blood
the β-globin locus from affected adults shows that they cells carrying these altered molecules often have abnormal