Download 5. Common and rare alleles

5. Common and rare alleles
Mutation means 1. the process by which a gene undergoes a
structural change, 2. a modified gene resulting from mutation
Mutations:
-gene mutations
-„point“ mutation – only one nucleotide  qualitative change
-in regulatory sequences  quantitative change
-compound mutations
-chromosomal mutations
-numerical
-structural
Fig. 1: Destiny of gene mutations (alleles) in populations.
How common and rare alleles originate
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Fig.2
2
A fresh allele (point mutation) is subject to changes in its
relative frequency according to the circumstances
(its adaptive value in the environment). A polymorphism may
be totally neutral, slightly different or (rarely) very different.
Rare alleles may produce serious diseases easily
4000 Mendelean conditions, 1/3 of proteins polymorphic,
virtually any locus polymorphic regarding DNA
6. Genic variability of the hemoglobin molecule
6.1 Gene determination and biochemistry
Fig. 3 Hemoglobin molecule
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Fig. 4 Genetic detemination of human hemoglobins
Fig. 5 Disposition of Hb genes along chromosomes
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Different Hb genes resulted from gene duplications. 1 and 2 
the same polypeptide
6.2 Point mutations of Hb molecule
Several hundreds,
the majority of
them rare
Fig. 6
Neutral
Deleterious: doubtless when heterozygotes are diseased, problematic
when heterozygotes are not manifestly ill (recessive mutations)
Hereditary methemoglobinemias
Fig. 7
Several alleles – point mutations in the vicinity
of heme group. Fe3+ bound to the inappropriate AA 
methemoglobin reductase unable to reduce it
(Mutations of methemoglobin reductase 
the same „distant“ phenotype)
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Unstable hemoglobins
Mutation  conformation change  instability of the
molecule  chronic
hemolytic anemia. RBC: Heinz
bodies, stiffness  life span
Changed affinity to oxygen
Enhanced affinity  shift of the dissociation
curve to the left  delivering of oxygen to
tissues  erythrocytosis
Lowered affinity  mild anemia
Small stereochemical changes in a molecule 
drastic changes in function
Fig. 8 Some point mutations in the Hb -chain
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Hb polymorphisms
Sickle cell anemia (HbS)
-chain, position 6, Glu  Val
SCA = homozygosity for HbS - life span, virtually
no descendants
Sickle cell trait heterozygosity for HbS - sickle RBC in
hypoxic conditions
 Oxygen affinity   Hb oxigenation 
gelling of Hb  sickling of RBC and lowered
deformability  obturation of capillaries
 local ischemia etc (Fig. 9
Other polymorphisms: HbC, HbE, HbD, HbK, HbO,
HbJ Tongariki – mild problems
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Adaptive significance of Hb polymorphisms
Dozens of % in (sub)tropical regions, about 5% in the
border localities
Strong directed selection against HbS 
its maintaining cannot be caused by drift
Plasmodium falciparum  stabilizing selection and
balanced polymorphism (resistence in small children,
blocking of penetration through placenta  fertility of
heterozygotic women)
Other polymorphisms – only probability of enhanced resistance
6.3 Other types of Hb mutations
Compound mutations: Hb Harlem
Deletions and additions
Constant Spring Hb: mutation in a stop codon 
additional 31 AA in the -chain
The same effect as gene deletion
Le Pore Hb: mixed chains / and /. Cause: unequal
crossing over in meiosis
6.4 Thalassemias
Fig 10
Mutations
determining
the extent to
which the
polypeptide
chains are
formed
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-thalassemia  interference with -chain production.
Thalassemia major = Cooley´s anemia:
Homozygosity for alleles of -chain gene 
grossly abnormal RBC,
unused -chains precipitate  RBC destruction
Thalassemia minor:
Heterozygotes, many pathological alleles 
heterogeneity of the disease (between homozygotes and norm)
Etiology of -thalassemias:
- intron mutations
- new splicing sequencies GT, AT  shortening of the transcript
- cancelling of splicing sequencies or destruction of the
polyadenylation sequence  prolongation of the transcript
- mutation of a stop codon  chain elongation
- mutation of a starting codon or destruction of a promoter 
complete deletion of the -gene
-thalassemia  interference with -chain production
Etiology: -chain gene deletion, 1 – 4
6.5 A survey of adaptive (health)
significance of Hb mutations
Majority of point mutations are rare, from neutral to
grossly pathologic
In non-malaric regions: a single „normal“ Hb - HbA1
(possibly HbA2 with -chains). These alleles are fixed
and optimal (neutral)
In malaric regions: a whole array of polymorphisms
(balanced polymorphisms) maintained by stabilizing selection
Nearly neutral polymorphisms – a common situation in many
genes. Disadvantageous polymorphic alleles must be
compensated for, typically by heterozygote advantage
6.6 Glucose-6-phosphate dehydrogenase
G6PD polymorphisms
Izoenzymes: in most cases no known functional
explanation of the existence of variants
Pentose shunt pathway  NADPH  reduced
glutathione  protection of Hb against oxidation
Fig.11
Deficiency of the G6PD  hemolytic crises after
ingestion of Vicia fava (bean), anti-malarials,
sulphonamides etc. Fig.12
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B + “normal” G6PD
A - acute
hemolytic
Anemia (AHA)
Favism
Drugs
1
Activity 0.16 T 2
Africa 0.20
2 mutat.
A + asymptom.
Activity 0.84
Africa 0.25
B – (mediter.)
AHA, favism
Act. 0.00 – 0.07 T
Mediter. 0.15 – 0.20
Kurdistan Jews 0.55
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1
2
Gd(A+) – 20% in Africa  slightly reduced activity
Gd(A-) – 20% in Africa  8-20% activity  drug sensitivity
Mediterranean (Gd(B-)) – 15 to 20% in Greece, Sardinia,
Middle East, India  activity less than 7% of norm
In all forms the enzyme is unstable
(e.g., T1/2 = 13 days instead of 62 days)
6.7. Common and rare diseases
Rare diseases
- one major gene and allele
- Mendelean heredity
- severe, in childhood
- rare
- environmental influences weak
Common diseases
- several genes, only slightly deleterious alleles
- only enhanced disposition in families
- chronic, in adults and elderly
- common (mostly „civilization“ diseases)
- environmental conditions decisive
Fig. 13 Genetic architecture of essential hypertension
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