Chapter 22 & 23

Chapter 22 & 23 - Chapter 22 & 23 Developmental...

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Unformatted text preview: Chapter 22 & 23 Developmental Genetics & Cancer Genetics Blind Cave Fish Some populations of Mexican tetras are blind after 10,000 years of living in caves Result of increased expression of two genes sonic hedgehog (shh) and tiggy-winkle hedgehog (twhh) shh was first found in Drosophila and twhh in zebrafish Activates transcription of other genes that leads to apoptosis (cell death) of lens cells Small changes in expression of key genes can have profound effects Developmental Genetics Totipotent - ability to develop into any cell type Every cell in a very early embryo is totipotent Value of embryonic stem cells Plant and fungal cells often remain totipotent Animal cells become committed to development into a specific cell type Process called determination that often occurs after the first few cell divisions of the embryo Cloning of Animals Cloning experiments with frogs date back to the 1950-1960's Cloning of a mammal was not considered possible since highly differentiated cells could not be "reprogrammed" to function as single-celled embryo Dolly the sheep (1997) showed that a terminally differentiated mammalian cell retains all original genetic information Cloning has been achieved with a variety of animals including sheep, goats, mice, rabbits, pigs, horses, mules, cats and dogs Clones are not genetically identical since the cytoplasmic genes (i.e. mitochondria) come from the donor cell and recipient egg Showed that genetic information is not permanently altered or deleted from the genome during development Therefore, development must requires selective expression of genes How is this process regulated in a complex multicellular organism? How Do You Build A Fruit Fly? Drosophila Development THREE LARVAL STAGES - PUPAL - ADULT Initial Stages of Development SYNCYTIUM - RESULTS FROM NINE NUCLEAR DIVISIONS WITHOUT CELL DIVISION ABOUT 6,000 CELLS SURROUND THE OUTER SURFACE OF THE EMBRYO POLE CELLS BECOME THE GERMLINE CELLS Genes For Each Stage of Development EGG POLARITY GENES TRANSCRIPTS FOR EGG POLARITY GENES ARE PRESENT IN THE EGG PRIOR TO FERTILIZATION MATERNAL EFFECT GENES SEGMENTATION GENES Orientation and number of body segments and the identity of each individual segment is established by the time the embryo is 10 hours old HOMEOTIC GENES Development in Drosophila A cascade of genes function to direct the polarity of body formation and the structures associated with individual segment Many code for morphogens, whose concentration gradient affect development of the surrounding regions Establishing Dorsal-Ventral Axis DORSAL PROTEIN IS DISTRIBUTED THROUGHOUT CYTOPLASM IN EGG PRIOR TO FERTILIZATION. AFTER FERTILIZATION, DORSAL PROTEIN IS ABSORBED INTO THE NUCLEI ON VENTRAL SIDE. DORSAL PROTEIN IS A Morphogen THAT FUNCTIONS AS A TRANSCRIPTIONAL ACTIVATOR. HIGH CONCENTRATION OF DORSAL LEADS TO ACTIVATION OF twist GENE LOW CONCENTRATION OF DORAL LEADS TO ACTIVATION OF decapentaplegic GENE DORSAL PROTEIN ABSORBED BY NUCLEI ON VENTRAL SURFACE DORSAL PROTEIN Anterior-Posterior Establishment BICOID mRNA IS IN THE EGG WITH 3' END ANCHORED TO THE ANTERIOR END OF THE EGG. BICOID PROTEIN FORMS A GRADIENT ACROSS THE EMBRYO. HIGH CONCENTRATION OF BICOID PROTEIN ACTIVATES EXPRESSION OF hunchback GENE. HUNCHBACK PROTEIN NEEDED FOR DEVELOPMENT OF HEAD AND THORACIC STRUCTURES. Anterior-Posterior Establishment Nanos mRNA is localized in the posterior end of the egg. After fertilization, nanos mRNA is translated and the nanos protein diffuses toward anterior end Nanos protein represses translation of hunchback mRNA Synthesis of hunchback protein is stimulated at anterior end by bicoid protein and repressed by nanos protein Establishes gradient of hunchback protein from anterior to posterior, which then affects development of other structures Segmentation Genes EXPRESSION OF ~25 SEGMENTATION GENES IS CONTROLLED BY THE CONCENTRATION GRADIENTS FOR THE BICOID AND NANOS PROTEINS FUNCTION TO ESTABLISH THE SEGMENTATI ON PATTERN FUNCTION IN DEVELOPME NT OF PAIRS OF SEGMENTS MUTATIONS IN fushi tarazu GENE CAUSE ABSENCE OF ODDNUMBERED SEGMENTS FUNCTION IN DEVELOPME NT OF EACH INDIVIDUAL SEGMENT Homeotic Genes MUTATIONS IN HOMEOTIC GENES LEAD TO DEVELOPMENT OF STRUCTURES IN THE WRONG SEGMENT! MUTATIONS IN Biotharx GENES LEAD TO FORMATION OF A SECOND PAIR OF WINGS, WHICH ARE USUALLY NONFUNCTIONAL MUTATIONS IN Antennapedia GENES LEAD TO FORMATION LEGS WHERE THE ANTENNAE SHOULD DEVELOP Expression of the homeotic genes is controlled by the concentration gradients of the gap, pairrule and segment-polarity genes Example - Ultrabithorax (Ubx) gene expression is activated when the Hunchback protein concentration is within a specific range Normally, the proper concentration is only in the middle portion of the embryo, which is where UBx should be expressed Homeobox Homeotic genes function to define structures within individual segments Each gene contained a conserved sequence called the homeobox 180 nt sequence that encodes for 60 amino acids Forms a helix-turn-helix domain, common in DNA binding proteins Used to look for analogous genes in other animals HOX Genes Found conserved sequences in all animals that have been examined Including nematodes, beetles, sea urchins, frogs, birds, mammals Even found in plants and fungi Transcription factors Suggest that HOX genes arose early in the evolution of eukaryotes Homology Between Homeotic Genes and Mammalian HOX Genes MAMMALIAN HOX GENE HOMOLOGS OCCUR IN THE SAME ORDER ALONG THE CHROMOSOME AS DROSOPHILA HOMEOTIC GENES Apoptosis Programmed cell death Most cells have a genetic program for cell death A series of proteins called caspases cleave other proteins at specific sites. Eventually, cleavage of an inactive DNAse leads to activation and degradation of the nuclear genome followed by cell death Apoptosis can also be triggered in cells infected by a virus, DNA damage or mitochondrial damage Apoptosis in Development and Disease Some stages in development require the removal of excess cells by apoptosis Drosophila embryos with mutations genes that trigger capsases and therefore do not have apoptosis die during embryogenesis Some diseases are affected by excessive or absence of apoptosis Example - neurodegenerative diseases can be affected by a loss of neurons by apoptosis Eyeless Gene in Drosophila Discovered in 1915 Recessive mutation causing formation of a small eye 1993 - Walter Gehring showed that the eyeless gene encodes a transcription factor Engineered a transgene to be expressed in tissue where the gene is normal off Shared Developmental Pathways "Evo-Devo" - the study of evolution through developmental pathways Eyeless gene has counterparts in both the mouse and humans In mouse, the gene is called Small eye In humans, it is the Aniridia gene Once thought that the eyes of insects and mammals evolved independently Similarities in these three genes more strongly suggest a common pathway that diverged to form the eye in flies, Antibody Diversity Immune system can respond to nearly any antigen encountered Estimate that mammalian immune system can produce ~1015 different antibodies How is this achieved with no more than 25,000 or so genes in the entire human genome? Somatic Recombination GENE ENCODING THE INDIVIDUAL CHAINS OF THE ANTIBODY IS COMPOSED OF SEGMENTS CODING THE VARIABLE(V), JOINING (J) AND CONSTANT (C) PORTIONS Somatic Recombination PRE-mRNA HAS 1 V REGION, SEVERAL J REGIONS AND 1 C REGION PROCESSING LEADS TO EACH B-CELL PRODUCING AN UNIQUE KAPPA LIGHT CHAIN Chapter 23 Cancer Genetics Cancer Genetics Basically a genetic disease that is not inherited Most, if not all cancers, result from DNA mutations Many DNA damaging agents are also carcinogens Certain cancers are consistently associated with a particular chromosomal abnormality Some cancers clearly occur at higher than expected frequencies in certain families Cancers are "multiple hit" events Cancer is the result of a process involving two or more genetic mutations Individual may inherit one of the mutations, thus making them more susceptible since fewer additional events are required This is why certain cancers appear to plague certain families Most Cancers Arise From Spontaneous Mutations Cancer affects most individuals later in life since it usually results from random mutations accumulated over a lifetime Exposure to environmental carcinogens increases the frequency of those random mutations Increases the probability that the gene, when mutated can lead to cancer, will be "hit" Clonal Evolution of Tumors A single cell undergoes a mutation that allows abnormal rates of cell division Over time, cells develop additional mutations that allows them to be even more aggressive and proliferative Defects in DNA repair pathways may exacerbate this effect Many cancer cells are aneuploid due to defects in chromosome segregation during mitosis Oncogenes Cell division is controlled by regulatory processes that both stimulate cell division as well as ones that inhibit it Dominant mutations that stimulate cell divisions are called oncogenes Proto-oncogenes are the normal cellular counterparts Tumor-Suppresor Genes Recessive mutations that inactivate genes that inhibit cell division are called tumorsuppressor genes Rb-1 is a tumor suppressor gene The Rb-1 protein function to prevent cells from progressing through the cell cycle if conditions are not appropriate Mutation of the Rb-1 gene can lead to cells with uncontrolled cell growth cancer Retinoblastoma is a rare childhood disease that is inherited as an autosomal dominant trait Cells from retinoblastoma patients always show both RB-1 alleles are mutated Recessive mutation at the molecular level The retina contains ~108 cells If you inherit a mutation in the Rb-1 gene, there is a 100% chance that you will develop retinoblastoma Yet, the tumor cells are always homologous recessive with two mutant copies of the Rb-1 gene Why does retinoblastoma appear to be inherited as an autosomal dominant mutation, yet at the cellular level it is clearly recessive? Retina has ~ 108 cells Effectively a 100% chance that you have a spontaneous mutation in the Rb-1 gene in at least one retinal cell If you inherit a mutated Rb-1 gene, you will have one retinal cell with two mutant alleles The single cell expands to form the tumor Other Contributors to Cancer Defects in DNA repair genes increase the overall rate of genetic mutations Mutations affecting chromosome segregation Mutations affecting DNA methylation, which influences gene expression Mutations affecting expression of telomerase Affects on vascularization and metastasis MicroRNAs and Cancer MicroRNAs regulate gene expression by degrading specific mRNAs or interfering with their translation Many tumors show a wide range of inhibition of microRNA activity May allow oncogenes to be expressed at even higher levels Chromosomal Mutations Some cancers are associated with specific chromosome mutations Chronic myelogenous leukemia often involves a reciprocal translocation between chromosomes 22 and 9 Fuses the BCR gene from chromosome 22 to portion of c-ABL Fusion protein is more active in stimulating cell proliferation and eventually leads to leukemia AML DUE TO OVER-EXPRESSION OF C-ABL BURKITT LYMPHOMA DUE TO OVER-EXPRESSION OF C-MYC Viruses Associated With Some Cancers Viruses are clearly associated with a fairly small number of human cancers (Table 23.5) Viruses can mutate and rearrange protooncogenes to create oncogenes Viruses can also expression of host genes since viral genes often have strong promoters Epigenetic Changes in Cancer Finding changes in DNA methylation and chromatin structure associated with many cancer types Methylation affects gene expression and cancer cells often have abnormal methylation patterns Hypermethylation may repress expression of tumorsupressor genes Hypomethylation has been shown to be associated with chromosome stability A new and robust area of cancer research Colorectal Cancer Arises Through A Series of Mutations in Specific Genes QuickTimeTM and a decompressor are needed to see this picture. Spring 2012 Courses Genes and Development on TR from 3:00-4:20PM. Instructor is Dr. Nambu. CMBB Research Seminar on W from 4:005:00PM. Counts as a DIS credit (S/U grade) Practical Cell Neuroscience on M from 10:0011:30AM. Lab on M or T from 1:00-3:50PM. Instructor is Dr. Dawson-Scully ...
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This note was uploaded on 02/13/2012 for the course BIO GENETIC taught by Professor Binnanger during the Spring '11 term at FAU.

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