Page 93 - Genetics_From_Genes_to_Genomes_6th_FULL_Part2

252 Chapter 7 Anatomy and Function of a Gene: Dissection Through Mutation

Figure 7.29 The molecular basis of sickle-cell and other anemias. (a) Substitution of glutamic acid by valine at the sixth amino
acid from the N terminus affects the three-dimensional structure of the β chain of hemoglobin. Hemoglobins incorporating the mutant β chain
form aggregates that cause red blood cells to sickle. (b) Red blood cell sickling has many phenotypic effects. (c) Other mutations in the
β chain gene also cause anemias.
(a) From mutation to phenotype (b) Sickle-cell anemia is pleiotropic

Normal individual Sickle-cell individual
Sickling of red blood cells
N ••• N •••
Rapid destruction Clumping of cells; Accumulation
of sickle cells interference with of red blood cells
circulation in spleen
Valine
Valine
Valine
Proline
Proline
Leucine
Leucine
Histidine
Histidine
Threonine
Threonine
Anemia Local failures Enlargement and
Glutamic acid
Glutamic acid
Glutamic acid
Glutamic acid
1. The polypeptide: in blood supply damage to spleen
the chain of
hemoglobin
Fatigue, heart damage, Damage to
overactivity of heart, kidney,
bone marrow muscle/joints,
Glutamic acid Valine brain, lung,
gastrointestinal tract
2. The protein:
(made of two
and two (c) chain substitutions/variants
chains) Amino acid position
…
1 2 3 … 6 7 … 26 … 63 … 67 125 … 146
Free Long fibers
proteins Normal (HbA) Val His Leu Glu Glu Glu His Val Glu His
HbS Val His Leu Val Glu Glu His Val Glu His
3. Red blood HbC Val His Leu Lys Glu Glu His Val Glu His
cell making HbG San Jose Val His Leu Glu Gly Glu His Val Glu His
thousands
of hemoglobin HbE Val His Leu Glu Glu Lys His Val Glu His
molecules HbM Saskatoon Val His Leu Glu Glu Glu Tyr Val Glu His
Hb Zurich Val His Leu Glu Glu Glu Arg Val Glu His
HbM Milwaukee 1 Val His Leu Glu Glu Glu His Glu Glu His
Disk-shaped Sickle-shaped HbD Punjab Val His Leu Glu Glu Glu His Val Gln His
between the wild-type and mutant proteins (Fig. 7.29a). different amino acids, but occasionally, two independent
Hemoglobin consists of two types of polypeptides: a so- mutations result in different substitutions for the same
called α (alpha) chain and a β (beta) chain. The sixth amino acid. Geneticists use the term missense mutation to
amino acid from the N terminus of the β chain was describe a genetic alteration that causes the substitution of
glutamic acid in normal individuals but valine in sickle- one amino acid for another.
cell patients.
Ingram thus established that a mutation substituting
one amino acid for another had the power to change the A Protein’s Amino Acid Sequence Dictates
structure and function of hemoglobin and thereby alter the Its Three-Dimensional Structure
phenotype from normal to sickle-cell anemia (Fig. 7.29b). Despite the uniform nature of protein construction—a
We now know that the glutamic acid-to-valine change af- string of amino acids joined by peptide bonds—each poly-
fects the solubility of hemoglobin within the red blood cell. peptide folds into a unique three-dimensional shape. Bio-
At low concentrations of oxygen, the less soluble sickle- chemists often distinguish between four levels of protein
cell form of hemoglobin aggregates into long chains that structure: primary, secondary, tertiary, and quaternary.
deform the red blood cell (Fig. 7.29a). The first three of these apply to any one polypeptide chain,
Because people suffering from a variety of inherited
anemias also have defective hemoglobin molecules, In- while the quaternary level describes associations between
multiple polypeptides within a protein complex.
gram and other geneticists were able to determine how a
large number of different mutations affect the amino acid
sequence of hemoglobin (Fig. 7.29c). Most of the altered Primary, secondary, and tertiary protein structures
hemoglobins have a change in only one amino acid. In The linear sequence of amino acids within a polypeptide is
various patients with anemia, the alteration is generally in its primary structure. Each unique primary structure