Biology 2C03: Genetics What is a Gene?
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1 Biology 2C03: Genetics What is a Gene? September 9 th, 2013 Model Organisms - E. coli - Yeast - Worms - Arabodopsis - Fruitflie - Mouse What is a Gene? - Define, recognize, describe and apply Mendel s first principle - Develop a useful definition for a gene - Distinguish genotype and phenotype - Solve genetic problems relating to monohybrid crosses - Interpret pedigrees - Use the rules of probability to determine genotypic and phenotypic proportions - Distinguish between complete, incomplete and co-dominance - Determine dominance relationships at different phenotypic levels Why Study Genetics? - Genetics plays a critical role in understanding disease Single gene: sickle cell or Huntingtons Complex genes: heart disease, diabetes, multiple genes which increase or decrease the risk of developing disease and is associated with environmental influences - Genetics improves agricultural practices - Genetics used biotechnology industry for drug design, development, and production Bacteria and fungi produce antibiotics Ted Talk % identical - Sequence the entire human genome - Access to genetic information - First attempt at creating a synthetic organism from a genome Fundamental Concepts Review - A gene is the fundamental unit of heredity Unit of information that encodes a genetic characteristic - Genes come in multiple forms called alleles - Genotype confers phenotype
2 Phenotype is manifestation of the genotype - Genetic information is carried in DNA Can also be carried in RNA, for example, influenza - Genes are located on chromosomes - Genetic information is transferred from DNA to RNA to protein Genetic information can also be carried in RNA Basic Principles of Heredity - Gregor Johann Mendel discovered basic principles of heredity - Principle of segregation and independent assortment The Pea Plant Pisium sativum - Easy cultivate Complete generation single growing season - Produce many offspring Enabled calculation meaningful mathematical ratios - Several traits existed 2 easily distinguished forms Multiple phenotypes Shows that it is not specific for only one phenotype Genetic Terminology - Gene: a genetic factor (region of DNA) that helps determine a characteristic - Allele: one of two or more alternative forms of a gene - Locus: specific place on a chromosome occupied by an allele - Genotype: set of alleles possessed by an individual organism - Heterozygote: an individual organism possessing two different alleles at a locus
3 - Homozygote: an individual organism possessing two of the same alleles at a locus - Phenotype or trait: the appearance or manifestation of a character - Character or characteristic: an attribute or feature Case Study: Sickle Cell Disease - Walter Noel: sickle cell proband first individual described to have these symptoms - Symptoms: Severe anemia, debilitating muscle pain, respiratory problems - Admitted hospital 1904 under care of intern Dr. Ernest Irons and supervising physician Dr. James Herrick - Performed blood smear as part of diagnostic attempts - Red bloods cells were pear shaped, flat, and were found in low density s inheritance pattern and physical chemistry of haemoglobin S were understood - Renowned scientist Linus Pauling called sickle cell anemia the first molecular disease - Blood smear under the microscope Normal: round, and numerous Sample from Noel: flat, fewer, and pear-shaped, half-life is shorter therefore there are less RBCs Cellular Phenotype - Abnormal: curved and flat Sickle Cell Anemia or Sickle Cell Disease is Hereditary - Recessive disease
4 Sickle-Cell Disease (SDC) - Clinical condition that results from abnormally low numbers of red blood cells (RBCs) Cannot be treated by change in diet (increase of iron) - RBCs contain haemoglobin that is capable of transporting oxygen from the lungs to the target tissues - SCD is hereditary and is associated with abnormalities in haemoglobin structure - SCD leads to low oxygen in blood causing massive fatigue Physiological Symptoms of SCD - Fatigue and anemia - Pain crises - Swelling and inflammation - Bacterial infections - Splenic sequestration - Lung and heart injury - Leg ulcers - Cellular death throughout body - Loss of RBCs and oxygen deprivation Hemoglobin (Hb) Structure - Hemoglobin is the iron-containing oxygen-transport protein in red blood cells (RBCs) - 90% of proteins in RBCs are haemoglobin - Protein complex; tetramer - 4 proteins: 2 α subunits 2 β subunits
5 - Each subunit associated with one heme = oxygen binding molecule 4 binding sites for oxygen Hemoglobin Structure is the Product of Two Genes - α-globin gene codes for α-globin protein (chromosome 16) - β-globin genes codes for β-globin protein (chromosome 11) - β-globin structure: DNA to mrna Molecular Basis of Sickle Cell Disease - Common form of SCD is caused by a single nucleotide base pair substitution in the β-globin gene sequence - Also known as a single nucleotide polymorphism or SNP - β A : the normal or wildtype allele - HbA protein - Β S : the mutant allele with one nucleotide change - HbS protein variant with one amino acid - Glutamic acid to valine: change to hydrophobic - What is the effect of the valine substitution? Formation of long polymers or aggregates of haemoglobin at low oxygen concentrations Acidic residue changed to a hydrophobic residue Creates a hydrophobic path which interacts with the other hydrophobic patches forming long polymers
6 Aggregation of Hemoglobin - Hydrophobic valnie causes protein aggregates when oxygen is not bound - Linear protein complex changes cell shape - Long polymers causes the sickle cell shape The Sickle Red Cell - Sickled shape prevents the movement of the RBCs through capillaries and limits oxygen transport throughout the body - RBCs normal lifespan is about 120 days, but only days for sickled cells - RBCs are not replaced fast enough fast enough resulting in anemia - Normal red cells maintain their shape as they pass through the capillaries and release oxygen to the peripheral tissues - Haemoglobin polymers form in the sick rell 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
7 Hereditary Anemia :Sickle Cell Anemia Pedigree - Pedigree: pictorial representation of family history for a particular trait - Each generation in pedigree is identified by Roman numeral - Within each generation, individuals identified with Arabic numerals - Filled symbols represent affected individuals - Open symbols represent unaffected individuals Sickle Cell Genotype and Phenotype - Variant sequences of genes are called alleles. Each individual carries two copies of agene or two alleles - Homozygous dominant and heterozygous do not express SCD; therefore, it is a recessive disease - Dominant trait or dominant allele is visible in the heterozygote - Recessive trait or recessive allele is not visible in the heterozygote, but reappears in a cross between two heterozygotes
8 Genotype: Genetic makeup β A β A β A β S β S β S Phenotype: Appearance, trait, effect No sickle cell disease No sickle cell disease Sickle cell disease
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