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3.1 Essential Questions & Key Terms 1. What is sickle cell disease? 2. Why does the sickling of red blood cells cause health problems? 3. What is sickle cell anemia? 4. How is anemia diagnosed? 5. How does sickle cell disease affect daily life? Key Terms Anemia Blood Plasma Erythrocytes (Red Blood Cells) Hematocrit Leukocytes (White Blood Cells) Sickle Cell Disease Thrombocytes (Platelets) Sickle Cell Disease • Disease passed down through families • Caused by an abnormal type of hemoglobin called hemoglobin S • Affects red blood cells • Red blood cells (normally shaped like a disc) form an abnormal sickle/crescent shape Hemoglobin • Protein • Primary component of red blood cells • Composed of four sub-units • Each carries one oxygen molecule • People with sickle cell have abnormal hemoglobin Sickle Cell Disease • Sickled Red Blood Cells 1. Deliver less oxygen 2. Get stuck more easily in small blood vessels 3. Fragile- break into pieces that can interrupt healthy blood flow • Decrease the amount of oxygen flowing to body tissues even more • …feedback loop? The Affects of SCD • Millions of people throughout the world- major public health concern • 3% of people with SCD die annually- sudden death • More prone to blood clots • Heart attacks • Strokes • Pulmonary embolisms • Increased susceptibility to bacterial and viral infections. Anemia • Blood is deficient in red blood cells, in hemoglobin, or in total volume • SCD often causes anemia • Referred to as Sickle Cell Anemia Activity 3.1.1: Blood Detectives • Anna Garcia’s autopsy report shows she had SCD • You will learn the components and function of blood in order to better understand SCD and it’s impact on the body 1. 2. 3. You will examine Anna’s blood with a microscope You will design an experiment to see how cell shape impacts movement You will complete a hematocrit blood test to determine whether Anna’s SCD was causing other related health problems 3.1.2 Sickle Cell Diaries: @ Home • Almost every patient with SCD experiences painful episodes called crises • The crises can be severe enough to require a hospital stay • Anna’s doctor asked her to keep a diary documenting all of her crises • In this activity you are going to investigate what life is like living with SCD… 3.1.2 Sickle Cell Diaries: @ Home • All docs are online • 2 Tables • One before you collaborate • One after • Collaborate online • Over the phone • 2 Journal Entries • Pick any patient • Pick one career journal • Due Friday January 17th Blood Plasma • The pale yellow fluid portion of whole blood Erythrocytes (Red Blood Cells) • Hemoglobin-containing cells that carry oxygen to tissues and take carbon dioxide back to your lungs to be exhaled • Responsible for the red color of vertebrate blood Leukocytes (White Blood Cells) • Colorless blood cells that lack hemoglobin and contain a nucleus: lymphocytes, monocytes, neutrophils, eosinophils, and basophils • Destroy bacteria • Produce antibodies against bacteria and viruses • Fight malignant diseases Thrombocytes (Platelets) • A minute colorless anucleate (no nucleus) disk-like body of mammalian blood • Main function is to interact with clotting proteins to stop or prevent bleeding Hematocrit • The percent of the volume of whole blood that is composed of red blood cells • Determined by separation of red blood cells from the plasma usually by centrifugation Hematocrit Results Anna’s hematocrit is approximately 30% red blood cell volume. Anything less than 35% for a female is considered a low hematocrit 3.1 The Disease: Review 1. What is sickle cell 2. 3. 4. 5. disease? Why does the sickling of red blood cells cause health problems? What is sickle cell anemia? How is anemia diagnosed? How does sickle cell disease affect daily life? Key Terms Anemia Blood Plasma Erythrocytes (Red Blood Cells) Hematocrit Leukocytes (White Blood Cells) Sickle Cell Disease Thrombocytes (Platelets) 3.2 It’s in the Genes: Essential Questions Key Terms & Key Terms Amino Acid 1. 2. 3. 4. 5. 6. 7. 8. 9. What is the DNA code? What is the connection between genes and proteins? How are proteins produced in a cell? How does the sequence of nucleotides in DNA determine the sequence of amino acids in a protein? What is a mutation? What determines the shape of a protein? Is the shape of a protein affected by its surrounding environment? How does a change in the DNA code affect the shape of a protein? Can changing just one nucleotide in a gene change the shape of a protein? Anticodon Codon Hydrophilic Hydrophobic Messenger RNA (mRNA) Mutation Nucleotide Protein Protein Synthesis Ribonucleic Acid (RNA) Ribosome Transcription Transfer RNA (tRNA) Translation Proteins • What we know… • DNA codes for proteins • Proteins produced all our genetic traits • Responsible for just about everything our bodies do • Amazingly… • All the proteins we need are manufactured based on a code of four letters: A,T, C and G • The arrangement of these nucleotides dictates everything we are genetically and runs our whole bodies, because they dictate what proteins our bodies produce 3.2.1 Protein Synthesis 1. The information on DNA is copied onto an mRNA strand 2. As, Cs, Gs and Us (in place of Ts) 3. 4. 5. 6. 7. mRNA leaves the nucleus and moves into the cytoplasm A ribosome attaches to the mRNA tRNA molecules bring amino acids (there are 20) into the ribosome The amino acid sequences match up with mRNA sequences- 3 at a time (codons) The ribosome assembles the amino acids into the specific protein originally coded for by the gene on the DNA Transcription & Translation WATCH VIDEO From DNA to mRNA to Amino Acid: A= U A= U C= G G= C A= U T= A A= U C= G C= G Structure of Proteins • Polymers of amino acids • Joined by peptide bonds Activity 3.2.1 Protein Synthesis • You will explore how the body uses DNA to produce proteins More on translation… More on transcription… What’s Due? • Friday- Activity 3.2.2 Decoding- Presenting at end of class, conclusion questions due • Tuesday- Activity 3.1.2 SC Diaries (all work and conclusion questions), answer conclusion questions on separate sheet, and pick one CJ Activity 3.2.2: The Genetic Code • Decode messages • Transcription and translation • Effect of mutations on protein production • Genetic mutation that causes SCD • Chose 1 to illustrate with any supplies you chose • Decode the others in your lab book Activity 3.1.1: Blood Detectives • Anna Garcia’s autopsy report shows she had SCD • You will learn the components and function of blood in order to better understand SCD and it’s impact on the body Complete Microscopy- Part 1 Experiment- Part 2 1. 2. 1. 3. Determine the tipping point of sickle cell disease. What percentage of red blood cells must have a sickled-shape to impede blood flow? Design your own experiment using materials provided. Record design and results in your manual and put results on board. Hematocrit- Part 3 Hematocrit • The percent of the volume of whole blood that is composed of red blood cells • Determined by separation of red blood cells from the plasma usually by centrifugation Hematocrit Results Anna’s hematocrit is approximately 30% red blood cell volume. Anything less than 35% for a female is considered a low hematocrit Activity 3.2.3: Does Changing One Nucleotide Make a Big Difference? Nova Documentary The sickle form of the hemoglobin gene: 1. A is changed to a T 2. 6th amino acid in the b-globin protein from GAG to GUG 3. 6th amino acid in the protein to become valine instead of glutamic acid That single amino acid replacement 1. Alters the shape and the chemistry of the hemoglobin molecule 2. Causing it to polymerize 3. Distort the red blood cell into the sickle shape Genetic mutation to hemoglobin, causing sickle cell disease Activity 3.2.3: Does Changing One Nucleotide Make a Big Difference? Glutamic Acid: Hydrophilic or hydrophobic? ____Hydrophilic______ Positive, negative or neutral? ___Negative_______ Valine: Hydrophilic or hydrophobic? _____Hydrophobic_______ Positive, negative or neutral? ____Neutral____________ Protein shape dictates function! What dictates shape? 1. • • 2. 3. • • Amino acids present Charge- positive vs. negative amino acids Hydrophobic vs. hydrophilic The order of amino acids Surrounding Environment Oil Water 3.2 It’s in the Genes: Review 1. 2. 3. 4. 5. 6. 7. 8. 9. What is the DNA code? What is the connection between genes and proteins? How are proteins produced in a cell? How does the sequence of nucleotides in DNA determine the sequence of amino acids in a protein? What is a mutation? What determines the shape of a protein? Is the shape of a protein affected by its surrounding environment? How does a change in the DNA code affect the shape of a protein? Can changing just one nucleotide in a gene change the shape of a protein? Key Terms Amino Acid Anticodon Codon Hydrophilic Hydrophobic Messenger RNA (mRNA) Mutation Nucleotide Protein Protein Synthesis Ribonucleic Acid (RNA) Ribosome Transcription Transfer RNA (tRNA) Translation 3.3 Chromosomes 1. 2. 3. 4. Key Terms Allele Autosome How is DNA passed to new Chromosome Dominant trait cells during cell division? Gene What is a chromosome? Genetic Material How are traits passed Genotype Heredity through the generations? Homologous Should a person have rights Chromosomes to their organs and tissues? Karyotype (Optional) Meiosis Mitosis Mutation Pedigree Phenotype Recessive Trait How do you get Sickle Cell Disease? • Caused by an abnormal gene • Inherited Disease • E.g., Tay Sachs, hemophilia, cystic fibrosis, and Huntington’s disease • Vs. Infectious (like…) • How are mutations in DNA passed down from one generation to the next? Activity 3.3.1: How is DNA Passed Through the Generations? • Chromosomes contain the codes for how to make specific proteins • Determine the organism’s traits • Chromosome Compaction • Specific instructions for a protein are on sections of the chromosome called genes Chromosomes • DNA is stored in a • • • • • compact form called chromosomes 46 chromosomes in somatic (body) cells 23 chromosomes in sex cells Egg cell from the mother fuses with the sperm cell from the father (zygote) = 46 chromosomes, 23 pairs One from mother and one from father in each pair Early Zygote Nuclei from egg and sperm fusing Chromosomes and Sickle Cell • Chromosome 11 carries the instructions (genes) to make the hemoglobin protein • There are different versions of these genes: • Normal – healthy • Mutated or changed – Sickle cell or other hemoglobin disorder Mitosis (video) 1. The chromosomes coil up 2. A mitotic spindle moves them to the 3. 4. 5. 6. middle of the cell The sister chromatids then separate Move to opposite poles of the cell Two nuclei form (1 at each pole) Cytokinesis, in which the cell divides in two LM 250 INTERPHASE Centrosomes (with centriole pairs) Chromatin PROPHASE Early mitotic spindle Centrosome PROMETAPHASE Fragments of nuclear envelope Kinetochore Nucleolus Nuclear envelope Chromosome, consisting Plasma membrane of two sister chromatids Centromere Spindle microtubules ANAPHASE METAPHASE Metaphase plate Spindle Daughter chromosomes TELOPHASE&CYTOKINESIS Cleavage furrow Nuclear envelope forming Nucleolus forming Under the scope… Meiosis (video) ◦ Meiosis, like mitosis, is preceded by chromosome ◦ ◦ ◦ ◦ duplication But in MEIOSIS: The cell divides twice to form four daughter cells Four DIFFERENT CELLS with HALF the genetic information Half the number of chromosomes ◦ The first division, meiosis I Starts coping (sisters chromatids) and with synapsis- the pairing of homologous chromosomes ◦ In crossing over Homologous chromosomes exchange corresponding segments ◦ Meiosis I separates each homologous pair produce two daughter cells, each with one set of chromosomes ◦ Meiosis II is essentially the same as mitosis The sister chromatids of each chromosome separate The result is a total of four haploid cells Meiosis MEIOSIS I: Homologous chromosomes separate INTERPHASE Centrosomes (with centriole pairs) Nuclear envelope PROPHASE I METAPHASE I Sites of crossing over Spindle Chromatin Sister chromatids Tetrad Microtubules Metaphase attached to plate kinetochore Centromere (with kinetochore) ANAPHASE I Sister chromatids remain attached Homologous chromosomes separate Prophase l of Meiosis Sites of crossing over Spindle Sister chromatids Homologous Chromosomes Tetrad: via synapsis Tetrad Chiasma Centromere Meiosis Continued… MEIOSIS II: Sister chromatids separate TELOPHASE I AND CYTOKINESIS PROPHASE II METAPHASE II ANAPHASE II TELOPHASE II AND CYTOKINESIS Cleavage furrow Sister chromatids separate Haploid daughter cells forming Possibility 1 Possibility 2 Two equally probable arrangements of chromosomes at metaphase I Metaphase II Gametes Mitosis Meiosis Parent cell (before chromosome replication) Meiosis i Prophase I Prophase Duplicated chromosome (two sister chromatids) Metaphase Anaphase Telophase Tetrad formed by synapsis of homologous chromosomes Chromosome replication Chromosome replication 2n = 4 Chromosomes align at the metaphase plate Sister chromatids separate during anaphase 2n Daughter cells of mitosis 2n Tetrads align at the metaphase plate Metaphase I Homologous chromosomes separate during anaphase I; sister chromatids remain together No further chromosomal replication; sister chromatids separate during anaphase II Anaphase I Telophase I Haploid n=2 Daughter cells of meiosis I Meiosis ii n n n n Daughter cells of meiosis II What happens to chromosomes throughout? It’s all in the name… • Start as chromatin • Duplicate • Thicken and clump into chromosomes • Consist of two sister chromatids- replicates • In meiosis… • Chromosomes (sister chromatid duplicates) find their other half (maternal and paternal) • They make homologous pairs, forming an tetrad • One chromosome carrying info from the mother, the other carrying info from the father Mutations are the original source of genetic variation Raw material for natural selection 1. Synapsis and crossing over during prophase 2. Independent assortment (orientation) of homologous chromosome pairs along the metaphase plate (during metaphase) 3. Random Fertilization of eggs by sperm 3.3 Chromosomes Review 1. How is DNA passed to new cells during cell division? 2. What is a chromosome? 3. How are traits passed through the generations? 4. Should a person have rights to their organs and tissues? (Optional) Key Terms Allele Autosome Chromosome Dominant trait Gene Genetic Material Genotype Heredity Homologous Chromosomes Karyotype Meiosis Mitosis Mutation Pedigree Phenotype Recessive Trait 3.4 Inheritance 1. Why does sickle cell disease run in families, yet is not present in every generation? 2. How can doctors and genetic counselors calculate the probability of a child inheriting a disease? 3. How does the presence of malaria in a region affect the frequencies of normal versus sickle cell alleles? Key Terms Allele Chromosome Dominant Trait Gene Genotype Heredity Pedigree Phenotype Punnett Square Recessive Trait How do we know all this stuff? • Experimental genetics began in an abbey garden • Father of modern genetics • Gregor Mendel’s quantitative experiments • Parents pass on to their offspring discrete heritable factors, which maintain individuality • 7 years after Darwin’s Origins in 1859 • Pea plants The Humble Pea • Easy to grow, came in many varieties, easy to ensure self or cross fertilization • Crossed plants that differed in certain characteristics • Traced traits from generation to generation • P(parental generation) • F1 generation • F2 generation Different alleles of 7 genes Flower color Flower position Purple Axial Seed color Yellow Seed shape Round Pod shape Pod color Inflated Green White Terminal Green Wrinkled Constricted Yellow Stem length Tall Dwarf P generation (true-breeding parents) F1 generation Purple flowers White flowers All plants have purple flowers Fertilization among F1 plants(F1 F1) F2 generation 3 4 of plants have purple flowers 1 4 of plants have white flowers Mendel found for each characteristic… • An organism inherits two alleles, one from each parent • If the two alleles of an inherited pair differ • Then one determines the organism’s appearance and is called the dominant allele • The other allele as no noticeable effect on the organism’s appearance and is called the recessive allele Genetic makeup (alleles) pp PP P plants Gametes All p All P F1 plants (hybrids) All Pp 1 2P Gametes 1 2p Sperm P F2 plants Phenotypic ratio 3 purple : 1 white p P PP Pp p Pp pp Eggs Genotypic ratio 1 PP : 2 Pp: 1 pp • Homologous chromosomes bear the two alleles for each characteristic • Alternative forms of a gene reside at the same locus on homologous chromosomes 1. Homozygous recessive 2. Homozygous dominant 3. Heterozygous Dominant allele Gene loci a B P a b PP Homozygous for the dominant allele aa Homozygous for the recessive allele Bb Heterozygous P Genotype: Recessive allele Back to…How do you get SCD? • It is an inherited blood disorder • Both parents have to have it to pass on the abnormal gene • If you inherit the problem gene from one parent and a normal gene from the other • ‘Sickle cell trait' or be a Carrier • Doesn't usually cause any symptoms • Can be passed on to the next generation. Chromosomes and Sickle Cell • Chromosome 11 carries the instructions (genes) to make the hemoglobin protein. • There are different versions of these genes: • Normal--healthy • Mutated or changed-Sickle cell or other hemoglobin disorder. 3.4.1: Family Inheritance • Pedigrees show the occurrence of a particular trait from one generation to the next • P, F1 and F2 generations • Males are represented by squares • Females are represented by circles • Relationships are represented with lines • Make it easier to visualize relationships within families • Used to determine the mode of inheritance (dominant versus recessive) of genetic diseases • Pedigrees illustrate what is or has been • Vs. Punnett Squares & probability (next) With two carriers= 25% Chance SCD • For every pregnancy when both parents have sickle trait, there is a 1in 4 chance that their offspring will have sickle cell anemia. 3.4.1: Family Inheritance & Pedigrees • How does analyzing pedigrees help doctors, epidemiologists, researchers, and other scientists understand how diseases are inherited? • How are pedigrees used to track diseases? • Why does sickle cell disease run in families, yet is not present in every generation? Mendel’s Laws Law of Dominance • In a cross of parents that are pure for contrasting traits, only one form of the trait will appear in the next generation. Offspring that are hybrid for a trait will have only the dominant trait in the phenotype. • Dominant vs. recessive traits Law of Segregation • During the formation of gametes (eggs or sperm), the two alleles responsible for a trait separate from each other. Alleles for a trait are then "recombined" at fertilization, producing the genotype for the traits of the offspring. • Which of the two alleles ends up in which gamete (monohybrid cross in Punnett square) Law of Independent Assortment • The different traits do not influence the inheritance of each other. They are inherited INDEPENDENTLY. • When looking at multiple traits, alleles segregate separately (dihybrid cross in Punnett square) Punnett Squares Reginald Punnett A DIHYBRID CROSS! • Something a bit more challenging • Uses Mendel's 3rd Law as well 3.4.2 What’s the Probability? • How can doctors and genetic counselors calculate the probability of a child inheriting a disease? 3.4.2 What’s the Probability? Punnett Squares • Create your own handout for this activity • Write four word problems that require Punnett squares • Be creative! • Set up one question with chromosomes • Use a pedigree for at least one • Always ask for the genotypic and phenotypic ratio • Always ask a “what’s the percent chance that..” question • Be sure to have an answer key • Work in 1s or 2s, but you’ll need to type and print one handout each • TRADE- Due Monday! • Let’s complete some examples Example with chromosomes • Complete a Punnett square for these parents. Determine the genotypic and phenotypic ratios. Determine the percent chance a child has of having sickle cell anemia from this reproductive pairing Example with pedigree • Anna’s mother passed away three years ago, so she was unavailable for genetic testing. Based upon Anna’s family pedigree that you created in the previous activity, determine her mother’s possible genotypes and phenotypes related to sickle cell anemia. Explain your reasoning and describe the information you used to make your prediction. Example word problem • Juan’s family has a history of sickle cell disease. His father died of sickle cell disease complications when Juan was six years old. He remembers his father being in great pain. Juan marries Gina. Gina’s maternal grandmother and paternal grandfather had sickle cell disease, but neither of her parents has the disease. Juan does not want to have children because he is convinced they will have sickle cell disease. Gina is not so sure. They have come to you for advice about having whether or not to have children. Based on your calculations of the probability of their child getting sickle cell disease, what is your advice? Show your calculations and explain your reasoning for your response. It may be helpful for you to draw pedigrees and possible Punnett squares for both Juan’s and Gina’s families. Read Survival of the Sickest • Read- Introduction, Ironing It Out and Hey, Bud, Can You Do Me a Fava? • This is a book about mysteries and miracles. About medicine and myth. About cold iron, red blood, and neverending ice. It’s a book about survival and creation. It’s a book that wonders why, and a book that asks why not. It’s a book in love with order and a book that craves a little chaos. Most of all, it’s a book about life—yours, ours, and that of every little living thing under the sun. About how we all got here, where we’re all going, and what we can do about it. Welcome to our magical medical mystery tour. Genetic Basis for Sickle Cell Disease • PBS Sickle Cell Link (Video) • A bit on evolution…. What were Darwin’s Main ideas anyway??? 1. Species change over time 2. Living species have arisen from earlier life forms (descending from a common ancestor) Close ties between organisms and their environments* Can be traced back to the ancient Greeks Evolution is the greatest unifying theme in biology, and The Origin of Species fueled an explosion in biological research and knowledge that continues today. Evolutionary theory continues to expand beyond Darwin’s basic ideas. Nonetheless, few contributions in all of science have explained so much, withstood as much repeated testing over the years, and stimulated as much other research as those of Darwin. • Natural Selection 1. Produce more offspring than the environment can support 2. Individuals of a population vary in their characteristics 3. Many characteristics can be inherited 4. Beneficial characteristics are preferentially passed down • • Darwin found convincing evidence for his ideas in the results of artificial selection With humans playing the role of the environment Hundreds to thousands of years of breeding (artificial selection) Ancestral dog (wolf) Throughout Human Evolution • The best genes survive from one generation to next • Why do we still have some deleterious genetic mutations? • Various mutations have provided a benefit • Extra Iron • Sickle Cell • We continue to see these mutations in modern day humanity even when the benefit no longer exists (leftover) The Immortal Story of Henrietta Lacks • The first cell line, cultured more than 60 years ago • The HeLa Cell-Line has been reproducing independently, fueling biological research • Bioethics- The study of controversial ethics brought about by advances in biological or medical research The Great Debate • Two sides of the argument • Henerietta’s • Dr. Gey’s • Prep time • Design opening and closing statement • Make THREE KEY arguments • Plan a defense against your opponent • H: Opening statement (1 minutes) • • G: Opening statement (1 minutes) • H: Key Point 1(one minute) • G: rebuttal • • H: rebuttal • G: Key Point 1(one minute) • H: rebuttal • • G: rebuttal • • H: Key Point 2 (one minute) • G: rebuttal • H: rebuttal • G: Key Point 2 (one minute) • H: rebuttal • G: rebuttal H: Key Point 3 (one minute) • G: rebuttal • H: rebuttal G: Key Point 3 (one minute) • H: rebuttal • G: rebuttal H: Closing (one minute) G: Closing (one minute) 3.4 Inheritance Review 1. Why does sickle cell disease run in families, yet is not present in every generation? 2. How can doctors and genetic counselors calculate the probability of a child inheriting a disease? 3. How does the presence of malaria in a region affect the frequencies of normal versus sickle cell alleles? Key Terms Allele Chromosome Dominant Trait Gene Genotype Heredity Pedigree Phenotype Punnett Square Recessive Trait