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Lecture 1 – January 10.docx

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Joe Kim

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BIO 2C03 2013 Lecture 1 – January 10, 2013 Sickle Cell Anemia or Sickle Cell Disease  1904; Walter Noel – severe anemia and debilitating muscle pain (Dr. Ernest Irons and James Herrick)  Blood smear under the microscope: Normal Sample from Noel  Noel had o Fewer red blood cells o Different red blood cell shape o Morphology of plasma membrane is misshapen  Sickle Cell Anemia or Sickle Cell Disease Hereditary o Hb = wild type o Hb = sickle cell allele o Homozygous for sickle cell allele  affected o Heterozygous  sickle cell allele carrier, but not affected o Homozygous for wild type  unaffected; normal hemoglobin  Anemia – clinical condition that results from abnormally low numbers of red blood cells (RBCs)  RBCs contain haemoglobin that is capable of transporting oxygen from the lungs to the target tissues o Hypoxia = Low oxygen = fatigue  Anemia may be temporary due to disease of nutrition (Eg/ low iron levels)  Hereditary anemia is associated with abnormalities in haemoglobin structure  Due to shape disfigurement of sickle shaped red blood cell, transport through capillaries is compromised – get stuck in capillaries  Sickle shaped red blood cells – elongated; can carry oxygen, just can’t be transported  Some areas of the body are completely cut off of oxygen  Many symptoms are due to cells that are dying due to lack of oxygen  Physiological Symptoms o Fatigue and anemia o Pain crises o Swelling and inflammation – red blood cells blocking own transport and white blood cells transport; bacterial infections are not being combatted 1 BIO 2C03 2013 o Bacterial infections – spleen is enlarging and filling with dying red blood cells and building up; stresses normal function of spleen o Splenic sequestration - o Lung and heart injury – areas cut off from oxygen o Leg ulcers – areas cut off from oxygen o Cellular death throughout body  Red blood cells – looking at protein Haemoglobin o 90% of proteins are haemoglobin o Haemoglobin binds to oxygen o HbA = normal o Haemoglobin protein complex; tetramer  α2 2  4 proteins  2 α subunits  2 β subunits  Each tetramer associated with one heme (oxygen binding molecule)  Hemoglobin structure is the produce of two genes o α-globin gene codes for α-globin protein (chromosome 16) o β-globin genes code for β-globin protein (chromosome 11) o β-globin gene structure: DNA to RNA: Graphic view of the β-globin gene; consists of 3 exons and 2 introns, with a total length of 1.6 kb  A common form of SCD is caused by a single nucleotide base pair substitution (single nucleotide polymorphism, SNP) in the β-globin gene sequence o Charged amino acid to hydrophobic amino acid o Changes properties of protein structure A β – the normal or wild type allele  HbA protein S β – the mutant allele with one nucleotide change  HbS protein variant with one amino acid change  Valine substitution o Formation of long polymers (instead of a tetramer) or aggregated of haemoglobin at low oxygen concentrations o Polymers are rigid and inflexible – cells cant bend to get through capillaries o Hydrophobic valine causes protein aggregates when oxygen isnot bound – linear protein complex changes cell shape 2 BIO 2C03 2013 Aggregation of Haemoglobin Tetramers HbA HbS  The sickle shape prevents the movement of the RBCs through capillaries and limits oxygen transport throughout the body  RBCs normal lifespan is ~120 days; only 10-20 days for sickled cells  RBCs are not replaced fast enough  anemia  Capillary flow of Normal Red Cells – normal red cells maintain their shape as they pass through the capillaries and release oxygen to the peripheral tissues  Hemoglobin polymers form in the sickle red cells with oxygen release, causing them to deform; the deformed cells block the flow of cells and interrupt the delivery of oxygen to the tissues  Hereditary Anemia – Sickle Cell Anemia Pedigree o Not every family member or generation is affected o Distinguish individuals – Generation-Number; eg/ 3-7 o 3-5 and 3-6 must be heterozygous  Each individual carries two copies of a gene or two alleles o Alleles – variant sequences of gene Genotype – genetic makeup Phenotype – appearance, trait, effect β β – homozygote No sickle cell disease S S βS S– heterozygote No sickle cell disease Β β – homozygote Sickle cell disease o Dominant trait/allele is visible in the heterozygote o Recessive trait/allele is not visible in the heterozygote; will reappear in a cross between two heterozygotes  Probability of a trait appearing in the offspring – need to know the probability of alleles being distributed to the gametes  Mendel’s Principle of Segregation – the two alleles of an allele pair segregate apart during gamete formation o β β  ½ gametes are β ; ½ gametes are β A S S S o β β  all gametes are β ; alleles still segregate but they are the same Punnett Square: 3 BIO 2C03 2013 Probability Review  Sum Rule = the probability of the occurrence of any of several mutually exclusive events is the sum of the probabilities of the individual events o Probability of rolling a 6 = P(roll a 6) = 1/6 o Probability of rolling an even number = P(roll even) = ½  Product Rule – the probability of two independent events happening simultaneously is the product of their individual probabilities o Probability of rolling two 6’s = P(roll 2 6’s) = 1/36 o Probability of rolling a 4 and a 4 = P(roll 6 and 4) = 1/72 (remember, two different ways) o Probability of rolling two numbers the same = P(roll 2 same) = 1/6  If diploid individuals carry two alleles, we can liken this to a flip of a coin with two sides o A person is diploid (two copies of the genome) S A  Eg/ β β o Probability of flipping a head = P(heads) = ½ o Probability of flipping a tail = P(tails) = ½ o During meiosis, a gamete (haploid) receives just one allele  Probability of a gamete receiving β = P(β ) = 1/2 A A  Probability of a gamete receiving β = P(β ) = 1/2  Coin Flip Simulation – first few flips, probability of head fluctuations, but given enough trials, the probability tends toward P = 0.5 o Due to biological fluctuation, this will be true of inheritance of alleles o Repeat this enough times and you see a normal distribution – 100 flips, most common event would be 50 heads, 50 tails  Do not be surprised to see 49:51 or 52:48 4 BIO 2C03 2013 Towards the left and right, it is much less likely to see these  Probability can be used where one of two alternative outcomes is possible during each of a large number of trials o The probability of having two boys  P = (1/2)(1/2) = 1/4 o The probability of having one boy and one girl must take into account that this can occur in two ways  P = (1/2)(1/2) + (1/2)(1/2) = 1/2 o Probability of having four boys  P = 1/16 o Family ahs four boys; what is the probability that their next child will be a boy?  P = ½  independent events  Redraw as branch diagram Parents – heterozygote or carrier Gametes  Random combination of g
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