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Unformatted text preview: Lecture 23 Transgenes and Gene Targeting in Mice I In the next two lectures I will be telling you about some of the ways in which we can study gene function in higher eukaryotes, more specifically in the laboratory mouse Mus Musculus . I will be doing this by telling you about a remarkable number of manipulations that have been made to the mouse genome in order to generate an experimental mouse model system for human Sickle Cell Disease. The mouse that was developed to explore this human disease turns out to be one of most genetically modified mice on the planet…and so it gives us an interesting framework in which to tell you about making transgenic and knockout mice. To set the scene for genetically modifying mice to mimic human sickle cell disease we need to step back a bit and consider this devastating human disease and some of its features. Human Sickle Cell Disease (a.k.a. sickle cell anemia): Sickle cell disease is a human blood disorder that is caused by a single mutation in a gene that encodes one of the subunits of hemoglobin ( Hb) , namely β-globin. Hemoglobin is a tetrameric protein made up of two α-globin proteins, and two β-globin proteins; ααββ . Each of the 4 globin proteins embrace an iron-containing heme molecule (iron is what makes hemoglobin and Red Blood Cells red) whose function is to bind oxygen in the lungs and release it in all the tissues of the animal. The very simple change of the sixth amino acid in β-globin (glutamine is substituted with a valine) causes devastating consequences. It turns out that Hb containing β-globin subunits with the sickle mutation (known as HbS ) does not directly interfere with the ability of hemoglobin to store or release oxygen, but rather this amino acid change bestows a novel property on the hemoglobin molecule; in its deoxygenated state the HbS molecules aggregate together to form polymeric fibers, and the presence of these fibers grossly distort the shape of Red Blood Cells (RBCs) . Instead of being shaped almost like a doughnut (without the actual hole) and having tremendous flexibility to squeeze through tiny capillaries within tissues, the aggregated HbS fibers cause the RBCs to become curved (like a sickle), rigid, prone to rupture and prone to clumping; rupture causes anemia and clumping clogs small blood vessels, leading to tissue damage. Sickle Cell Disease – An autosomal Recessive disorder of Hemoglobin A single mutation in the sixth amino acid of the β-globin chain (Glutamine -> Valine) causes Sickle Cell Disease • Red blood cells (RBCs) make up 40% of the blood volume • Hemoglobin¡makes¡ up 70% of the proteins in RBCs Sickle Cell Disease – An autosomal Recessive disorder of Hemoglobin A single mutation in the sixth amino acid of the β-globin chain (Glutamine -> Valine) causes Sickle Cell Disease • Red blood cells (RBCs) make up 40% of the blood volume • Hemoglobin¡makes¡ up 70% of the proteins in RBCs Images removed due to copyright reasons....
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This note was uploaded on 09/03/2009 for the course BIOL 7.03 taught by Professor Chriskaiser during the Fall '04 term at MIT.
- Fall '04