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 1

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 3

Fig. 4 Genetic detemination of human hemoglobins

Fig. 5 Disposition of Hb genes along chromosomes Different Hb genes resulted from gene duplications.  1 and  2  the same polypeptide 5

Several hundreds, the majority of them rare Fig Point mutations of Hb molecule

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) Neutral Deleterious: doubtless when heterozygotes are diseased, problematic when heterozygotes are not manifestly ill (recessive mutations)

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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

8 Fig. 8 Some point mutations in the Hb  -chain

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

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 6.3 Other types of Hb mutations

6.4 Thalassemias

10 Fig 10 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 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

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 6.5 A survey of adaptive (health) significance of Hb mutations

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 Glucose-6-phosphate dehydrogenase G6PD polymorphisms

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A - acute hemolytic Anemia (AHA) Favism Drugs Activity 0.16 T Africa mutat. A + asymptom. Activity 0.84 Africa 0.25 B – (mediter.) AHA, favism Act – 0.07 T Mediter – 0.20 Kurdistan Jews 0.55 B + “normal” G6PD 12

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)

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 6.7. Common and rare diseases

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