Elekanglgenet2
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: A destiny of gene mutations (alleles) in populations. How common and rare alleles
originate skripta I obr. 3.3
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. 2 Hemoglobin molecule Harrison obr. 10.1 – s textem
Fig. 3 Genetic detemination of human hemoglobins Ayala obr. 21.11 – i s textem
Fig. 4 Disposition of Hb genes along chromosomes Harrison obr. 10.2 – i s textem
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. 5 Tab. ...... Harrison
Neutral
Deleterious: doubtless when heterozygotes are diseased, problematic when heterozygotes are
not manifestly ill (recessive mutations)
Hereditary methemoglobinemias
Fig. 6 moje blána Hemoglobin protection...
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)
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. 7 Some point mutations in the Hb -chain skripta I obr. 3.7
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. 8 zvl. obrázek s mnoha čárkovanými svislicemi
Other polymorphisms: HbC, HbE, HbD, HbK, HbO, HbJ Tongariki – mild problems
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 a gene deletion
Le Pore Hb: mixed chains / and /. Cause: unequal crossing over in meiosis
6.4 Thalassemias
Fig 9 obr. „Overview of thalassemias“ z PowerPointového souboru „Anemia“
Mutations determining the extent to which the polypeptide chains are formed
-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 sequentions GT, AT  shortening of the transcript
- cancelling of splicing sequentions 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
Deficiency of the G6PD  hemolytic crises after ingestion of Vicia fava (bean), antimalarials, sulphonamides etc.
Fig. 10 – Synopsis of thalasemias
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. 11 Genetic architecture of essential hypertension = Fig. 6 z Helath. disease and
normality
3. Molecular physiology of a gene
Molecular organization of an eucaryotic gene (Fig. 3)
A paradigma „one gene  one polypeptide“ is not valid anymore
Different splicing possibilities (Fig. 4)
Isomorphic proteins specific for developmental stages and tissues (Fig. 5)
Alternative promoters – different regulatory sequencies  e.g., different intensity of
production of primary gene product
Exon mutation  intact or defective isoprotein, regulation sequence mutation 
protein may be lacking (not necessarily), Fig. 5