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Molecular Genetics of Sickle Cell Disease.docx

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Bhagwati Gupta

September 12 , 2013 Biology 2C03: Genetics Molecular Genetics of Sickle Cell Disease Let’s Review What we Learned Last Class with an Example - P generation: perform a cross between two black-furred rabbits. In the F1 generation you get 6 black-furred offspring and two white-furred offspring.  What is the pattern of inheritance?  Recessive  What is the genotypic ratio in the black-furred offspring?  1 B/B:2B/b genotypic ration among the black F1 progeny  What if you wanted to breed white-furred rabbits, but white-furred rabbits have reduced fertility, what would you do next?  Breed heterozygous parents - F1 generation: perform a cross between two black-furred rabbits from the F1 progeny. What is the probability of white-furred offspring in the F2?  To get a white rabbit, both rabbits must be B/b in genotype and a b/b offspring must be produced by these parents  We need to calculate two probabilities: 1) Probability the parents are heterozygous  There will be a 1/3 chance that the F1 black rabbit is B/B and a 2/3 chance that the black rabbit is B/b 2) Probability heterozygous parents will produce b/b offspring  The chance of two B/b parents giving offspring is ¼  P (white offspring) = P(both F1 rabbits are B/b) x P(b/b offspring) – (2/3 x 2/3) x (1/4) = 1/9 Sickle Cell Disease is an Autosomal Recessive Disorder - Clues to look for in a pedigree for autosomal recessive inheritance: 1) Usually appears in both sexes with equal frequency 2) Tends to skip generations 3) Affected offspring usually born unaffected parents 4) When both parents are heterozygous, approximately ¼ children affected (if there is more than ¼, suggest that it may be dominant) - Other patterns of inheritance  Autosomal dominant traits  X-chromosome linked inheritance Molecular Basis of Inheritance of SCD - Sickle cell anemia is a hereditary disorder inherited in an autosomal recessive manner - What is the molecular basis of inheritance? - James Neel (1949) examined the parents of children with SCD - Hypothesized if SCD was produced by an autosomal recessive allele, the parents of SCD are heterozygous carriers Neel’s Hypothesis - Neel predicted that since parents are heterozygotes they may have some sickled cells - After examination, all 42 parents had sickled cells in their blood  Not completely autosomal recessive - This is sometimes referred to as Sickle Cell Trait and these individuals are heterozygous carriers of the sickle cell allele Hereditary Variation can be Studied at the Molecular Level - 1949 Pauling published study in Science entitled “Sickle Cell Anemia, a Molecular Disease” - Showed haemoglobin from patients with SCD has a different electrical charge than haemoglobin from healthy individuals - First time “abnormal” protein was linked to a disease and that genes determined protein structure  Found that DNA within the cell determines protein structure - Fifty years later still discussed in medical and biology textbooks (and genetics lectures Molecular Identification of SCD - Hemoglobin variants were identified - Homozygous: 1 band - Heterozygous: two bands = two hemoglobim variants that have two charges - Homozygous: more negative charge - This is consistent with a small difference in the charge of the protein - The amount of a protein in a band on the gel can be quantified using densitometry - Each peak represents a band on the electrophoretic gel  Two peaks for heterozygous  Mixing mutant and wildtype would result in the two peaks observed in a heterozygous individual - Pauling performed two-dimensional paper chromatography of normal haemoglobin A and sickle cell haemoglobin S - Separated based on size and charge which is how they identified which amino acid was responsible - All the spots were the same except for one spot - Vernon Ingram (father of molecular medicine) analyzed peptide one amino acid at a time: glutamic to a valine - Showed sickle cell haemoglobin differs by a single amino acid, the number 6 position, in the β chain of hemoglobin Molecular Genetics - The importance of Pauling’s work: 1) Identified laboratory methods for the detection of distinct forms of haemo
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