Lecture 27

Inheritance of Blood Groups

Group O = fructose

Group A = fructose + N-acetyl-galactosamine

Group B = fructose + galactose

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).

Human Blood Group Genotypes

• IA IA - A

• IA IO - A

• IB IB - B

• IB IO - B

• IA IB - AB

• IO IO - O

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.

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

Single Gene Disorders

• Autosomal Recessive

• Autosomal Dominant

• X-linked Recessive

• X-linked Dominant

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.

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.

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

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.

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.

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.

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.

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)

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).

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.

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

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

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

X-linked Dominant Inheritance

• Affected fathers pass disorder to daughters, never to sons.

• Vitamin D-independent rickets

• Quite rare

Multifactorial Inheritance

• Premature coronary heart disease, hypertension and stroke,

• Allergy - eczema/asthma, HLA-related conditions

• Thyroid disorders, insulin-dependent diabetes,

• Mental health problems

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.