What did Herostratus do A He designed the Colossus of Rhodes B He financed the construction of the lighthouse of Alexandria C He burned the temple of Artemis D He decorated the statue of Zeus at Olympia E Dude I don t care what you say Milla Jovovich ROCKS Can t wait for Resident Evil IV the Life of Dick Cheney MCB 140 09 26 07 1 Image courtesy of Prof Jay Hollick MCB Department MCB 140 09 26 07 2 R Alexander Brink 1950 Vicky Chandler Jay Hollick et al MCB 140 09 26 07 3 What is going on 1 The green maize plant is not outcrossing it is selfing 2 The red allele is incompletely penetrant except when in a homozygous state 3 This is actually two locus inheritance and the green locus exhibits full dominant epistasis to the red locus 4 This is actually two locus inheritance and the green locus exhibits full recessive epistasis to the red locus 5 Mmmmm Milla MCB 140 09 26 07 4 What IS going on This is a phenomenon known as paramutation It involves a change in gene behavior that is not associated with a change in the DNA sequence Hence it is strictly speaking not in the realm of genetics Thus it is epigenetic MCB 140 09 26 07 5 Broadly speaking An epigenetic effect on the genome changes the phenotype without changing the genotype The power of the environment and of life history MCB 140 09 26 07 6 Technically A mitotically or meiotically heritable change in gene expression state or genome functional state that is not associated with a change in the primary sequence of DNA MCB 140 09 26 07 7 In other words Genetics Organism or a cell with a phenotype Mutation change in DNA Different phenotype Epigenetics Organism or a cell with a phenotype Something happens but not a change in the DNA Different phenotype MCB 140 09 26 07 8 Cloning hello Dolly and hello again Dolly MCB 140 09 26 07 9 King and Briggs 1956 Serial transplantation of embryonic nuclei Cold Spring Harbor Symp Quant Biol 21 271 289 MCB 140 09 26 07 10 McKinnell R G 1978 Cloning Nuclear Transplantation in Amphibia University of Minnesota Press Minneapolis MCB 140 09 26 07 11 MCB 140 09 26 07 12 How can one explain the fact that cloning works so much better if one use a cell from an early embryo as the donor of the nucleus MCB 140 09 26 07 13 Two explanations 1 Alteration of the actual DNA of the cells as the embryo develops 2 Something else MCB 140 09 26 07 14 MCB 140 09 26 07 15 Reya Clarke and Weissman Nature 2001 MCB 140 09 26 07 16 MCB 140 09 26 07 17 MCB 140 09 26 07 18 MCB 140 09 26 07 19 Of the cells on the previous set of slides which have significant alterations in their DNA sequence relative to that of the original zygote A B C D E The neuron The fibroblast The muscle cell The T cell The macrophage MCB 140 09 26 07 20 King and Briggs 1956 Serial transplantation of embryonic nuclei Cold Spring Harbor Symp Quant Biol 21 271 289 MCB 140 09 26 07 21 MCB 140 09 26 07 22 MCB 140 09 26 07 23 Dolly MCB 140 09 26 07 24 Bill Ritchie Ian Wilmut Dolly MCB 140 09 26 07 25 Semantics 1 Reproductive cloning make new organisms 2 Therapeutic cloning aka somatic cell nuclear transfer no organism made MCB 140 09 26 07 26 Extensive abnormalities in cloned animals Lung failure Liver failure Obesity Etc etc Two problems 1 Cloning is incredibly inefficient 2 Of the animals that are born many have severe defects MCB 140 09 26 07 27 Proof that these abnormalities are entirely epigenetic Dolly s lambs and the offspring of all cloned animals are normal MCB 140 09 26 07 28 Solter and Surani Gynogenetic embryos very small Androgenetic embryos very large MCB 140 09 26 07 29 MCB 140 09 26 07 30 Ah terminology Genes for which you have your Mother s copy turned on Maternally expressed Genes for which you have your Dad s copy turned on Paternally expressed MCB 140 09 26 07 31 What covalent posttranslational modification does genomic DNA undergo during mammalian ontogeny A B C D E Phosphorylation Methylation Acetylation All of the above None of the above MCB 140 09 26 07 32 Spontaneous meCpG deamination colon cancer Should be 4 of all NN in fact is 0 8 Methylation C 5mC CpG 5mCpG 5mCpG TpG TpA deamination MMR CpG UpG CpG no mutation MCB 140 09 26 07 33 Pl is Changed to Pl paramutation MCB 140 09 26 07 34 The Haig hypothesis Imprinting evolved as a manifestation of parental conflict over the allocation of maternal resources to the developing fetus intrauterine tug of war over how big the fetus will be Paternally expressed genes increase embryo size Maternally expressed genes decrease embryo size MCB 140 09 26 07 35 Peromyscus polionotus the monogamous mouse Vrana et al Nature Genetics 20 362 1998 MCB 140 09 26 07 36 Don t clone humans 1 Responsibility for child and his her developmental abnormalities 2 Na ve overestimation of role of DNA in shaping the human being MCB 140 09 26 07 37 Therapeutic cloning somatic cell nuclear transfer MCB 140 09 26 07 38 Embryonic stem cells MCB 140 09 26 07 39 Annu Rev Cell Dev Biol 2001 17 435 462 EMBRYO DERIVED STEM CELLS Of Mice and Men Austin G Smith MCB 140 09 26 07 40 ES cells status quo Limited number of human ES cell lines available for research with federal funds Growth on mouse feeders makes them unsuitable for use as therapeutics The indications being considered are among others cardiovascular and neurological MCB 140 09 26 07 41 Why ES cells and not adult stem cells For the simple reason that ES cells are incomparably easier to grow to large numbers in a dedifferentiated state and then drive them in a controlled fashion to differentiate into a specific cell type Note in this context incomparably means the difference between essentially impossible and feasible MCB 140 09 26 07 42 Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson s disease Ron McKay et al Parkinson s disease is a widespread condition caused by the loss of midbrain neurons that synthesize the neurotransmitter dopamine Cells derived from the fetal midbrain can modify the course of the disease but they are an inadequate source of dopaminesynthesizing neurons because their ability to generate these neurons is unstable In contrast embryonic stem ES cells proliferate extensively and can generate dopamine neurons If ES cells are to become the basis for cell therapies we must develop methods of enriching for the cell of interest and demonstrate that these cells show functions that will assist in treating the disease Here we show that a highly enriched population of midbrain neural stem cells can be derived from
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