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Genetics, the Human Genome Project, and SARS June 2, 2003 Learning objectives Understand what causes SARS and the life cycle of the coronavirus. Understand classical genetics, Mendel’s contributions Understand the Human Genome Project The History The technology How is it useful? The ethical questions Workshop-Work in groups to give a presentation on assigned viruses Homework-see last slide, due June 9. SARS-Severe Acute Respiratory Syndrome Symptoms Fever Dry cough Shortness of breath Headache Hypoxaemia-low blood oxygen concentration Reference: wwwmicro.msb.le.ac.uk/3035/Coronaviruses .html SARS-Typical Clinical Course Clinical course Viral pneumonia After a few days one feels the symptoms. Then there is gradual improvement the first week. This is followed by worsening in the second week. This worsening is directly related to the patient’s immune response—not viral replication. Death results from progressive respiratory failure due to alveolar damage SARS Mean incubation period-6.4 days Fatality rate is 13.2% for patients<60 Fatality rate is 43.3% for patients>60 Caused by coronavirus Pathogenesis Coronaviruses infect mammals and birds First isolated in chickens in 1937. In 1965, Tyrrell and Bynoe found that coronaviruses can cause the common cold. The other major virus that does this is the rhinovirus. Transmitted by respiratory secretions and fecal-oral route Morphology of Coronavirus Virus particles are irregularly shaped viruses. Contain clubs on surface composed on sugar-modified proteins S-Spike protein, receptor binding, cell fusion, major antigen HE-Envelope protein M-Membrane protein, for budding and envelope formation N-phosphoprotein, associates with RNA genome Coronavirus genome Type IV (+) sense RNA viruses Non-segmented, single strand, 27-31 kilobases long. Genome has a 5’ methylated cap and 3’ poly-A and functions directly as a mRNA Keywords: Polymerase Full length (+) sense, (-) sense Nested transcripts 5’ non-translated leader sequence 3’ polyadenylated Each mRNA is monocistronic, only one gene can be translated. Each gene is separated by UCUAAAC. This intergenic sequence interacts with polymerase plus cellular proteins to place a leader sequence onto the start of each ORF. The HCoV that causes SARS is a new type of coronavirus previously unknown It seems to have originated in the Guangdong province of China. Civet Tests for coronavirus in humans 1) Serological. Detection by enzymelinked immunosorbent assay (ELISA). Within 14 days of illness onset for positive. Negative result-must wait for 21 days post-onset 2) RT-PCR-can detect within first 10 days after illness onset. In-class exercise 1) Working in pairs choose one virus and obtain this information: A) Picture of virus B) Whether it is an RNA or DNA virus C) The virus life cycle D) The symptoms of humans that contract the virus E) What are the tests for viral detection? F) What is the route of viral transmission? G) What is the best treatment for patients with infection? H) When and where was the last outbreak of the virus? List of viruses: Ebola, Human papilloma Virus, Human Immunodeficiency Virus-1, Epstein-Barr Virus Gregor Mendel (1822-1884) Monk Gardener High School Teacher Mathematician Scientist Father of Classical Genetics Parental generation (P) First filial (F1) Second filial (F2) Key findings of monohybrid cross Genotype dictates phenotype. Dominant trait Recessive trait A gene can have more than one allele Principle of segregation. The F1 generation contained two alleles that segregated in F2. Homozygous vs. heterozygous Punnett square is used to determine probabilities Key findings of dihybrid cross Principle of independent assortmentwhen genes are located on separate chromosomes alleles will distribute according to predicted 0.25 probability. Requires genes to be located on separate chromosomes Workshop View Punnett squares of monohybrid and dihybrid Crosses. Then take test. http://www.an.psu.edu/jxm57/irp/mendel.html Three alleles for a single gene. Two are co-dominant, one is recessive Linked genes Genes carried on the same chromosome. X-linked genes Queen Victoria (1819-1901) Queen Victoria of England was a carrier of the gene for hemophilia. She passed the harmful allele for this X-linked trait on to one of her four sons and at least two of her five daughters. Her son Leopold had the disease and died at age 30, while her daughters were only carriers. As a result of marrying into other European royal families, the princesses Alice and Beatrice spread hemophilia to Russia, Germany, and Spain. By the early 20th century, ten of Victoria's descendents had hemophilia. All of them were men. A Pedigree of Hemophilia in the Royal Families of Europe Crossing over Homologous chromosomes during early stages of meiosis. Results in recombination Nondisjunction Chromosomes fail to separate during meiosis. Sequencing DNA What is the approach used to sequence genomes? Divide and conquer Split the genome into fragments Clone into vectors that can accept large fragments: yeast artificial chromosomes (YAC Library) Landmarks within the genome can be obtained using Sequence Tagged Sites (STS) Sequences of YAC clones are matched with each other. Sequences that overlap form contigs. History of the Human Genome Project 1953 Watson, Crick DNA structure 1972 Berg, 1st recombinant DNA 1977 Maxam, Gilbert, Sanger sequence DNA 1980 1982 1984 1985 1986 Botstein, Sinsheimer DOE begins Wada MRC Davis, genome proposes to publishes hosts Skolnick build first large meeting to studies with White discuss HGP $5.3 million automated genome propose to sequencing Epstein-Barrat UCSanta map human robots virus (170 Cruz; genome with Kary Mullis kb) RFLPs develops PCR 1987 Gilbert announces plans to start company to sequence and copyright DNA; Burke, Olson, Carle develop YACs; DonisKeller publish first map (403 markers) History of the Human Genome Project (continued) 1987 (cont) 1988 1989 Hood produces first automated sequencer; Dupont devolops fluorescent dideoxynucleotides Proposal Venter Simon Hood, to sequence announces develops Olson, 20 Mb in strategy to BACs; US Botstein model sequence and French Cantor propose organism by ESTs. He teams 2005; plans to publish first using Lipman, patent physical STS’s to map Myers partial maps of the human chromosome genome publish the cDNAs; BLAST Uberbacher s; first algorithm develops genetic maps GRAIL, a of mouse and gene finding human program genome published NIH supports the HGP; Watson heads the project and allocates part of the budget to study social and ethical issues 1990 1991 1992 1993 Collins is named director of NCHGR; revise plan to complete seq of human genome by 2005 1995 Venter publishes first sequence of free-living organism: H. influenzae (1.8 Mb); Brown publishes on DNA arrays 1996 Yeast genome is sequenced (S. cerevisiae) History of the Human Genome Project (continued) 1997 Blattner, Plunket complete E. coli sequence; a capillary sequencing machine is introduced. 1998 SNP project is initiated; rice genome project is started; Venter creates new company called Celera and proposes to sequence HG within 3 years; C. elegans genome completed 1999 2000 NIH proposes to sequence mouse genome in 3 years; first sequence of chromosome 22 is announced Celera and others publish Drosphila sequence (180 Mb); human chromosome 21 is completely sequenced; proposal to sequence puffer fish; Arabadopsis sequence is completed 2001 Celera publishes human sequence in Science; the HGP consortium publishes the human sequence in Nature 2003 Completed genomes: 112 Microbial 18 Eukaryotes 1275 Viruses How much of the genome is defined? Unknown Function Homework Due June 9 p. 351, problems 1,4 p. 358 1-5 p. 366 Reviewing Ideas: 1, 5-7; Using Concepts: 1-3 p. 367 Synthesis: 1; Extensions: 1 p. 415 Reviewing Ideas: 7-10, 14; Using Concepts: 1-3; Synthesis: 1-2; Extensions: 1 Reading for next week: pp.557-569