Inheritance of Blood Groups

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Lecture 27
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Inheritance of Blood Groups

• Group O fructose
• Group A fructose N-acetyl-galactosamine
• Group B fructose galactose

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Inheritance of Blood Groups

• If an individual inherits alleles that result in
  the production of neither enzyme (no enzyme to
  add N-acetyl-galactosamine no enzyme to add
  galactose) then only fructose will be present
  individual being type O.
• Inheriting an allele for either enzyme will
  result in a terminal sugar being placed thus
  either phenotype A or B is dominant to O.
• Inheriting an allele for each enzyme results in
  some molecular configurations having
  N-acetyl-galactosamine as the terminal sugar
  while others have galactose thus membrane is a
  mosaic with respect to these two terminal sugars
  and the phenotype is AB.
• Alleles A and B we must conclude are co-dominant
  (exhibit incomplete dominance).

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Human Blood Group Genotypes

• IA IA - A
• IA IO - A
• IB IB - B
• IB IO - B
• IA IB - AB
• IO IO - O

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Linkage

• Occurs when genes are on the same chromosome.
• Remember that sex-linked genes are on the X
  chromosome, one of the sex chromosomes.
• If two genes are far apart, the chance of a
  crossover landing between them and producing
  recombinant chromosomes is large.
• If two genes are close together, the chance of a
  crossover between them is small. So the frequency
  of crossing over can be used as a measure of
  distance.
• Recombination Frequency is used to measure the
  frequency of crossing over and calculate
  distances.

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Genetically Inherited Diseases

• Single gene disorders a great deal is known
  about them, and much of our knowledge of human
  genetics is derived from them
• Genetically-determined responses to environmental
  influences, e.g. variation in response to drug
  treatment, adverse drug reactions - underlies the
  growing interest in pharmacogenetics.
• The genetic component in common diseases of adult
  life (e.g. cardiovascular disease, cancer,
  asthma/eczema). Multifactorial Inheritance

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Single Gene Disorders

• Autosomal Recessive
• Autosomal Dominant
• X-linked Recessive
• X-linked Dominant

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Autosomal Recessive

• Homozygous individuals usually born to unaffected
  parents.
• Parents are unaffected carriers.
• Affects either sex.
• Requires inheritance of 2 defective alleles.
• Usually due to loss of gene function.

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Autosomal Recessive Diseases

• Cystic Fibrosis 1/2000 recurrent lung
  infections, infertility in males.
• Phenylketonurea (PKU) 1/2,000-5,000 in Europeans
  mental retardation
• B-thalassemia 1/20,000 in general population
  1/100 in areas where malaria is endemic, severe
  anemia (depletion of rbc).
• Tay-Sachs disease 1/3000 in Ashkenazi Jews,
  neurological degeneration, blindness, paralysis.

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Cystic FibrosisCause

• Northern Europeans and white North Americans - 1
  in 20-25 carriers and 1 in 2000 suffers.
• Africans and Asians 1 in 100 000 births.
• Resistance to cholera.
• Mutation in a gene which encodes the CFTR protein
  (cystic fibrosis transmembrane regulator) on
  chromosome 7. It is 1480 amino acids long
• Allows diffusion of chloride ions in and out of
  the.
• 70 of cases due to deletion of 3 base pairs from
  the gene from codon 508.
• The amino acid phenylalanine (F) is missing.
• Mutation known as F508

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Cystic FibrosisSymptoms and Treatment

• Epithelial cells at mucosal surfaces have the
  function of producing mucus.
• In CF patients this mucus is abnormally thick.
• Build of chloride ions in the cells forces sodium
  ions to enter to balance charge. The high ion
  concentration inside the cell prevents water from
  leaving the cell.
• Lung, pancreas and liver are most affected. The
  thick mucus clogs up airway of lungs and bile
  duct in pancreas.
• Physiotherapy to dislodge mucus from lungs,
  digestive enzymes.
• Gene therapy.

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Phenylketonuria

• Occurs mainly in white Europeans.
• 1 in 10, 000 births, 1 in 80 is a carrier.
• Mutation in the gene that encodes phenylalanine
  hydroxylase which converts phenylalanine into
  tyrosine on chromosome 12.
• Build of phenylalanine leads to formation of
  toxins in the body which affect mental
  development.
• Children normal at birth, excess phenlyalanine
  moves across placenta and is removed by mothers
  liver.
• If not treated in infancy harmful effects noted,
  such a s severe mental retardation.
• Common effects include hyperactive irritable
  behaviour, awkward posture and walk, lighter skin
  (tyrosine used to make melanin), rough dry skin,
  repetitive movement of fingers and hands.

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Sickle Cell Anaemia

• 100, 000 deaths per year.
• 1 in 400 sufferers and 1 in 10 carriers.
• Common in Africa, Pakistan and India.
• Pakistan 1 prevalence rate of defective gene (1
  in 100 carriers).
• Defect in haemoglobin, 2 alpha chains (141 amino
  acids long) and 2 beta chains (146 amino acids
  long) on chromosome 11.
• Fault in the 6th amino acid on the beta chains.
• HbA has a glutamic acid (negative/polar) and HbS
  has valine (non polar/hydrophobic).
• Substitution mutation CTC is now CAC
• The presence of valine makes deoxygenated
  haemoglobin less soluble. So come out of solution
  and form rigid rod-like fibres.
• Heterozygous carriers have a selective advantage
  over normal individuals.

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Beta-Thalassaemia

• Common around the Mediterranean, India, Pakistan
  and South East Asia.
• In Pakistan approx 4000 new births per year.
• 7 carriage rate in Pakistan.
• Different types of mutations in the beta chain.
• Five common mutations in Pakistan IVS1-5(G-C)
  37.3, Fr8-9(G) 25.9, del619 7.0, Fr41-42
  (TTCT) 6.7 and IVS1-1 (G-T) 5.4.
• Ethnic distribution IVS1-5 (G-C) common in
  Punjabis and Sindhi Fr 8-9 common in Pathans.
• Result is the formation of an abnormal
  haemoglobin molecule, normal life span is 90 days
  however when mutated gene present cells die
  within a few weeks.

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Autosomal Dominant Inheritance

• Affected person has an affected parent
• Transmitted by either sex
• Affected person has 50 chance of passing on
  disease to offspring
• Usually due to gain of function or novel function
  of gene (neomorphic mutation)

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Autosomal Dominant Diseases

• Huntington Disease 1/10,000 - involuntary
  movements, dementia.
• Myotonic Dystrophy 1/8,500 - prolonged muscle
  contraction (myotonia), muscle atrophy,
  cataracts. myotonic dystrophy gene, found on
  chromosome 19, codes for a protein kinase that is
  found in skeletal muscle.
• Neurofibramomatosis, type I (Nf1) and type II
  (Nf2) 1/4,000-5,000 - Nf1 tumours on the
  peripheral nerves of the head, neck and body
  pigmented café-au-lait spots (6 or more).

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Huntington's Chorea (Disease)

• HD is a hereditary brain disorder affecting the
  central nervous system.
• It causes progressive deterioration of both
  physical and congnitive abilities.
• Caused by the loss of cells in a part of the
  brain called the basal ganglia. This cell damage
  affects the cognitive ability (thinking,
  judgement, memory), movement and emotional
  control.
• The symptoms appear gradually, usually in
  midlife, between the ages of 30 and 50. However,
  the disease has been known to strike young
  children as well as the elderly.
• Mutation occurs in HD gene on chromosome 4-
  nucleotide repeats.

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X-linked Recessive Inheritance

• Affects mainly males
• Often find affected uncles and nephews
• Males are usually born to carrier mothers
• Never get male to male transmission

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X-linked Recessive Diseases

• Duchenne Muscular Dystrophy - males 1/3,500 -
  early onset, progressive muscle weakness, severe
  skeletal muscle degeneration.
• Haemophilia A - males 1/5,000 - deficiency of
  clotting factor VIII, excessive bleeding from
  minor traumas, internal bleeding.
• Fragile X syndrome - males 1/1,500, females
  1/2,500 - mental retardation - mildly affects 1/3
  of female carriers- appears partially dominant

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Haemophilia A

• The gene for Factor VIII is carried on the
  non-homologous part of the X chromosome.
• Two allelic forms dominant (H) and recessive (h).
• Genotype XHXH normal female
• Genotype XHXh carrier female
• Genotype XHY normal male
• Genotype XhY haemophiliac male

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X-linked Dominant Inheritance

• Affected fathers pass disorder to daughters,
  never to sons.
• Vitamin D-independent rickets
• Quite rare

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Multifactorial Inheritance

• Premature coronary heart disease, hypertension
  and stroke,
• Allergy - eczema/asthma, HLA-related conditions
• Thyroid disorders, insulin-dependent diabetes,
• Mental health problems

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Genetic Screening

• Carrier recognition.
• Prenatal Diagnosis (Fetal testing)
• 1) Amniocentesis at 15-16 weeks.
• 2) Chorionic villi sampling at 8-12 weeks.
• 3) Ultrasound.
• New born screening.