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by: Danial Gorczany

Genetics BIO 328

Danial Gorczany

GPA 3.94


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This 133 page Class Notes was uploaded by Danial Gorczany on Sunday October 25, 2015. The Class Notes belongs to BIO 328 at University of Michigan - Flint taught by Staff in Fall. Since its upload, it has received 14 views. For similar materials see /class/228609/bio-328-university-of-michigan-flint in Biology at University of Michigan - Flint.


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Emzu mmw can Ed Eur ER w iamw I39 339 15 amp WOW w rm mEmEm I 1 39A z p m g m 0960 53829 E Chapter Outline Transposable Elements An Overview Transposable Elements in Bacteria CutandPaste Transposons in Eukaryotes Retroviruses and Retrotransposons Transposable Elements in Humans The Genetic and Evolutionary Significance of Transposable Elements TRANSPOSABLE ELEMENTS Transposable elements transposons are found in the genomes of many kinds of organisms and they are structurally and functionally diverse Types of Transposition CutandPaste transposition An element is cut out of one site in a chromosome and pasted into a new site Replicative transposition An element is replicated and one copy is inserted at a new site Retrotransposition An element is transcribed and the RNA is used as a template to synthesize DNA molecules which are then inserted into new chromosomal sites TABLE 171 Categorization of Transposable Elements by Transposition Mechanism Category Examples Host Organism I Cutandpaste transposons IS elements eg ISSO Bacteria Composite transposons egTnS Bacteria AcDs elements Maize P elements Drosophila hobo elements Drosophila piggyBac moth Sleeping Beauty salmon ll Replicative transposons Tn3 elements Bacteria Ill Retrotransposons A Retroviruslike elements Ty1 Yeast also called long terminal mqu Drosophila repeat or LTR D h retrotransposons gyPSy quotmap I a B Retroposons F G and lelements Drosophila Telomeric retroposons Drosophila LlNEsegL1 Humans SINEs eg Alu Humans CutandPaste Transposons CutandPaste transposition An element is cut out of one site in a chromosome and pasted into a new site Discovered by analyzing genetic instabilities in maize corn Also identified in Drosophia via genetic analyses Ac and D3 Elements in Maize a Discovered by Barbara McCIintock e Aleurone color is affected by the C allele which encodes dominant inhibitor of aleurone coloration o Mosaics with pigmented patches were caused by loss of the C allele Activities of the AcDs Elements The Ac element encodes a transposase that is responsible for excision transposition mutation and chromosome breakage The Ac transposase interacts with sequences at the ends of Ac and D8 elements and catalyzes their movement Deletions or mutations in the Ac gene abolish its catalytic function Hybrid Dysgenesis in Drosophia Crosses between M and P strains produce dysgenic hybrids if the male in the cross is from the P strain The chromosomes of P strains carry genetic factors P elements that are activated in the eggs of M females these factors cause mutations and chromosome breakage Male parent Female parent M P normal normal normal The Structure of P Elements Complete P element all sequences present 2907 np A Transposxase gene I I L gt l 31 np inverted terminal repeats 39 1 Incomplete P elements internal sequences missing 9 2012 John Wiley 8 Sons Inc All rights reserved John Wiley amp Sons Inc TABLE 171 Categorization of Transposable Elements by Transposition Mechanism Category Examples Host Organism I Cutandpaste transposons IS elements eg ISSO Bacteria Composite transposons egTnS Bacteria AcDs elements Maize P elements Drosophila hobo elements Drosophila piggyBac moth Sleeping Beauty salmon ll Replicative transposons Tn3 elements Bacteria Ill Retrotransposons A Retroviruslike elements Ty1 Yeast also called long terminal mqu Drosophila repeat or LTR D h retrotransposons gyPSy quotmap I a B Retroposons F G and lelements Drosophila Telomeric retroposons Drosophila LlNEsegL1 Humans SINEs eg Alu Humans Retroviruses and Retrotransposons An element is transcribed and the RNA is used as a template to synthesize DNA molecules which are then inserted into new chromosomal sites Utilize the enzyme reverse transcriptase to copy RNA into DNA The DNA copies of these entities are subsequently inserted at different positions in genomic DNA Vlralmre 39 quot Reverse inral RNA Th L f transcriptase Viral membrane H 16 gp1ZOCD4 rereptor Cellular membrane Rwy o 45 Reverse transcriptase 9 54 5 L nlv 15 viral protein gp120 and the cellular CD4 receptor protein 4 o The viral and cellular membranes fuse allowing the viral core ll 5T5 to enter the e 5154 o A r 39 mm 5154 r a WMquot DNA 515 the nucleus 0 Cellular 939 39 39 39 Nudeus 54 Cytoplasm mun u L 9154 5154 5 54 0 Progeny virus panicles are free to infect other cells Replication of the HIV Genome tRNA primer 3 PBS Genomic RNA 5 R Aquot 3 U5 PBS gag polenv U3 R a 54 0 DNA synthesis begins using tRNA as primer DNA 3 R US I PBS I m 5 R U5 PBS gag pal env U3 R An 3 5 54 0 RNase H degrades genomic RNA in RNA DNA duplex DNA 3 R us PBS l v 5 PBS gag polenv U3 R Aquot 3 9 PBS R a DNA copy ofrepeated R sequence hybridizes with R Intermediate remaining R sequence of genomic RNA U5 3 R us PBS 5 W 39 Genom39c RNAS PBS gag polenv U3 R 5154 0 DNA strand is extended DNA 3 PBS gag polenv U3 R US PBS I GenomicRNA 539 pB5 l 5 gay pol env U3 R DNA 3 PBS gag panenv U3 R us PBS 539 615 Genomic RNA 539 PBS gag pol env U3 R a RNase H degrades RNA in RNA DNA duplex except for polypurine tract DNA 3 PBS gag polenv U3 R US PBS 9154 Genomic RNA ng 339 quot 5 0 Synthesis of second DNA strand begins using polypurine tract RNA as primer U3 R us PBS 3 DNA 3 PBS gay paneslrv U3 R us PBS 3 DNA 515 PPT 0 RNA primer and tRNA are removed DNA 3 PBS gag polenv U3 R US 5 539 U3 R us PBS 3399 5T5 0quot PBS sequence at 339 end 5 PBS Intermediate hybridizes with PBS at 539 end 9 DNA 3 PBS gag pol env U3 R US 5 539 U3 R us PBS 339 DNA quotquot quot 5150 0 DNA synthesis at 339 ends of both strands completes l HIV DNA genome with LTRs at both ends 3 U3 R US PBS gag polenv U3 R U5 5 539 l l l PBS gag U3 I R us 339 v l 39 v U3 R US pol env LTR LTR Integration of the HIV DoubleStranded DNA into Chromosomal DNA Doublestranded HIV DNA Cleavage site 539 3 3 Cleavage site 9154 Cleavage site lntegrase cleaves HIV DNA near the 339 end of each strand oublestranded DNA of host cell Nucleotides of Cleavage site target DNA sequence 9154 a lntegrase cleaves the target DNA and joins their 539 ends to the 339 ends of the HIV DNA Doublestranded NA of host cell Nucleotides of Cleavage site target DNA sequence Q 2012 John Wiley 8 Suns Inc All rights reserved LED 2012 John Wiley 81 Sons lncAll rights reserved Retroviruslike Elements Found in yeast plants and animals Structure central coding region flanked by long terminal repeats LTRs oriented in the same direction The coding region contains homologues of the gag and pol genes of retroviruses Transposition of the Yeast Ty1 Element Reverse Structural transcriptase protein enzyme t x l I TyA gene TyB gene LTR l A l A I LTR em I o The Ty1 element is I transcribed to I I produce RNA 39 Ty1 RNA L L 45 o The RNA is reverse transcribed into DNA by an enzyme encoded by the TyB gene Ty1 DNA j quot t 1 5150 a The DNA is inserted into a chromosome creating a new copy of the Ty1 element Ti hi e 2012 John Wiley 3 Sons Inc All rights reserved John Wiley amp Sons Inc Retroposons nonLTR Retrotransposons Retrotransposons are a large and widely distributed class of retrotransposons Retroposons move through an RNA molecule that is reverse transcribed into DNA Retroposons have a homologous sequence of AT base pairs at one end that is derived from the polyA tail of retroposon RNA TRANSPOSABLE ELEMENTS IN HUMANS The human genome is populated by a diverse array of transposable elements that collectively account for 44 percent of all human DNA The L1 Element The L1 element is a retroposon belonging to a class of sequences known as the long interspersed nuclear elements LlNEs The human genome contains 30005000 complete L1 elements and more than 500000 truncated L1 elements Complete L1 elements are about 6 kb long have an internal promoter and have two open reading frames that encode a nucleicacid binding protein and a protein with endonuclease and reverse transcriptase activities John Wiley amp Sons Inc L1 element n quot E39 on Cytoplasrn Rihosome l 5quot 54 a I M39 o MA g 7 x gt 3 t 5154 squotOftF1 polypeptide ORFZ polypeptide v AAAAZ39 5T4 i g 5 Chromosomal V 3v DNA 0 The L1 RNA is translated into two polypeptides New insertion Ilt 1Tr39rl 339 Chromosomal 7 sv DNA 9quot o A complete L1 element inserted in a T chromosome is transcribed into L1 RNA 9 s 4 o The L1 RNA is polyadenylated in the nucleus 5T 4 o The polyadenylated L1 RNA moves into the cytoplasm 415 corresponding to each of its 0 sThese a polypeptides remain associated with the L1 RN a The L1 RNA and its associated polypeptides in move into the nucl a AAAAI A39 eus o The ORFZ polypeptide nicks one strand ofa chromosomal DNA molecule and the 339 end of the poyA tail on the L1 RNA is juxtaposed T o the 539 side of the nicked DNA 5 4 0 The ORFZ polypeptide exercises its reverse transcriptase lunction to synthesize a single strand of DNA using the L1 RNA as a template The 339 end of the nicked chromosomal D A sTE serves as the primer for this DNA synthesis The newly synthesized single strand of DNA 39 place between the two sides of the 39 omal DNA Simultaneously the L1 RNA is eliminated and the other strand 0 chromosomal DNA is nicked to allow for synthesis ofa second strand of DNA on line complementary to the L1 sequence in the direction indicated by the thin arrow All the nicks are repaired to linkthe newly inserted L1 element to the chromosomal DNA The retrotransposition cycle TSD targetsite duplication Cordaux and Batzer Nat Rev Gen 2009 lllllllllllllllll lllillllllllllll ll 5quot AA bF m W Wd39mm 539 IIIHHIMIIIMHIMIIIHIIIIIHII transcrlp nnn F 1 Second standdveavage 5 ITITTITIETITIEIIIIWITTIIIITITI IIII h at DNA synthesis 5IllilllllllllIdlllllllllu39k WHA 39I39ITI39T39I39I39I39H39IT 6 MIIIMIIIIIIIIIIMIIE E TED forma an TSD TED I l I 5 ITFIIIIIWWWIIIIIIUIII IIITTITNWWII lllllllll lll llllllll39lllllllllllllSJ L J Ll Short lnterspersed Nuclear Elements SlNEs SINE retroposons are the second most abundant class of transposable elements in the human genome SINE families include the Au MIR and Ther2MIR3 elements SlNEs are usually less than 400 base pairs long and do not encode proteins The reverse transcriptase required for SINE transposition is provided by a LINEtype element LINEs and SINEs Long and hort nterspersed Elements are the most common transposons in the human genome nLTR retratransposons LTR retrotransposons DNA transposons 83 28 Cordaux R and Batzer M Nat Rev Gen 2009 John Wiley amp Sons Inc THE GENETIC AND EVOLUTIONARY SIGNIFICANCE OF TRANSPOSABLE ELEMENTS Transposable elements are used as tools by geneticists In nature they play a role in genome evolution John Wil y 8t inc The Evolutionary Status of Transposable Elements Do transposable elements perform any useful function or are they merely genetic parasites Where did transposable elements come from What mechanisms have evolved to control and limit their movement John ins Transposons and Chromosome Structure Transposable elements have been implicated in the formation of chromosome rearrangements Crossing over may occur between homologous transposons located at different positions on the same chromosome or on different chromosomes These events are referred to as ectopic intrachromosomal exchanges or ectopic interchromosomal exchanges respectively Incomplete P element 39 Complete P element a Mixture of two plasmids vector I t Transposase gene I Foreign DNA ff P element termini Plasmid 5 5 9 54 454 0 Foreign DNA is inserted into 0 A complete P element is o The two plasmids are mixed an incomplete P element in inserted into a different in solution a plasmidThe insert also plasmid contains an eye color gene ry as a marker In ies this gene produces red eyes Chromosome in embryo Chromosome F b 5154 6 54 515 o The plasmid mixture is e In the embryo39s germ line 0 The excised Pelement is microinjected into ary39 mutant 39 I 39 J 39 Fl39 I umn r v e u v L of 39 39 39 rosy eyes from its plasmid Q 2012 John Wiley Er Sons Inc All rights reserved John Wiley amp Sons Inc Intrachromosomal Recombination Between Transposons in the Same Orientation Produces a Deletion loop so that the transposons can pair with each other a G gt i gty A 73 9154 0 The chromosome forms a o Region deleted from T5 thechromosome c Recombination between the D I paired transposons deletes 39 the intervening region E c A B F G i Chromosome with region C D E deleted From Lim J K and Simmons M J 1994 BiaEssays16269 275 Q lCSN Press John Wiley amp Sons Inc Unequal Crossing Over Between Transposons on Sister Chromatids Produces a Gene Duplication Chromosome with two neighboring transposons oriented in the same direction 5T5 l o The chromosome l l gt gt gt replicates to form Chromosome with region duplicated two sister Chromatids 5154 a The sister chromatids pair unequally and i transposonmediated recombination produces Chrowosome w39th one chromosome with reglon dEIeted a deletion and another with a duplication From Lim J K and Simmons MJ1954 BiaEssays 16269 275 ICSN Press John Wileyamp Inc Evolutionary Issues Concerning Transposable Elements Why have transposable elements spread Do they confer a selective advantage or are they genetic parasites How did transposable elements evolve How are retroviruslike elements related to retroviruses The Chromosomal Basis of Mendelism Ronald J Stamper PhD UM Flint 10JuIy2013 Chapter Outline o Chromosomes o The Chromosome Theory of Heredity o SexLinked Genes in Humans o Sex Chromosomes and Sex Determination o Dosage Compensation of XLinked Genes Chromosome Vocabulary Chromatin Haploid n Euchromatin Diploid 2n Heterochromatin Tetraploid 4n Octaploid 8n TA B LE 5 l Chromosome Number in Different Organisms Organism Haploid Chromosome Number Simple Eukaryotes gt Baker s yeast Saccharomyces cerevisiae 1 6 Bread mold Neurospora crassn 7 Unicellular green alga Chlamydomonas reinhardtii 17 Plants Maize Zea mays 10 gt Bread wheat Triticum aestivum 21 Tomato Lycopersicon esculentum 1 2 Broad bean Vicia fabu 6 Giant sequoia Sequoia sempervirens 11 Cruzifer Arubidopsis thaliana 5 Invertebrate Animals Fruit fly Drosophila melonogoster 4 Mosq u ito Anopheles culicifacies 3 Starfish Asterias forbesi 18 Nematode Caenorhubditis elegans Mussel Mytilus edulis 14 Vertebrate Animals gt Human Homo sapiens 23 Chimpanzee Pan troglodytes 24 Cal Felis domesticus 36 Mouse Mus musculus 20 Chicken Gallus domesticus 39 Toad Xenopus Iaevis 17 Fish Esox lucius 25 The Chromosome Theory of Heredity TH Morgan 1909 Studies of eye color in Drosophia Determined to be sexlinked Added evidence to Mendel s principles of independent assortment amp segregation X X X Y Drosophia has p i a 8 XampY sex x w w w Chromosomes Ilke Redeyed female Whiteeyed male humans bot sex determination F doesn t depend on Y X w w W Redeyed female Redeyed male a gene for eye color is located on the X F2 Chromosome Morgan showed that I I w w w w w w Redeyed Red eyed Redeyed Whiteeyed female female male male X X X Y P 8 X Experimental W W w design Redeyed female Whiteeyed male How could you 8 test this theory F1 x w w W Redeyed female Redeyed male 39II N w w w w w w Redeyed Red eyed Redeyed Whiteeyed female female male male Testing the Theory Cross between a heterozygous female and a hemizygous mutant male X X X Y l1 X 8 w w w Redeyed female Whiteeyed male w W w w w w Redeyed Whiteeyed Red eyed Whiteeyed female female male male Cross between a homozygous mutant female and a hemizygous wildtype male Testing the X X X Y Theory quot x w w Whiteeyed female Redeyed male F1 X w w w Redeyed female Whiteeyed male Whiteeyed Redeyed Whiteeyed Redeyed female female male male Follow up Morgan s results confirmed his theory that fruit fly eye color is Xlinked Morgan s student CB Bridges pushed the experiment even farther Whiteeyed female Redeyed male What would you expect in F1 Bridges39 Results After examining the F1 generation Bridges observed mostly redeyed females and whiteeyed males But also observed the occasional whiteeyed females amp redeyed males how The exceptional flies arose by rare nondisjunction events This was proof of the U Normal eggs Nondisjunctional eggs chromosomal theory of heredity W EEO em W XX redeyed XXX metafemale X0 exceptional Sperm fema 2 usually dies redeyed male BO 3 MB 8 XY whiteeyed XXY exceptional YO male whiteeyed female dies SexLinked Genes in Humans X and Y linked genes have been identified and studied in humans 1 Hemophilia Xlinked recessive 2 RG Colorblindness XIinked recessive 3 Retinitis pigmentosa Y Iinked X Y Relatively few YIinked disorders have been described why Termirlal quot regicm VI VII Hemophilia X linked recessive 1 Duke of Kent Victoria of 2 Mary Louisa 4 Augusia of Reuss 1 2 10 11 1 2 3 4 9 39IO 11 12 13 14 15 16 Kaiser Czarina Czar Wilhelm II Alexandra Nicholas II ofGermany sia ofRussia 11 12 13 15 16 17 18 19 20 Russian Imperial Family Spanish Royal Family 1 P zPh39l El b ehquot rlnce Ilp 354135 Mountbatten KEY Hemophilia 1 Prince Charles l Possible hemophilia no de nitive diagnosis Evident carrier 0 Possible carrier Probability of XIinked disorders Probability varies between sexes Probability of Xlinked disorders II III IV 4 HIV4 is color blind 1I2 x12 14 Key V l l f I Color blind 1 PV1 is color blind 12 x12 x12 18 Known carrier Sex Chromosomes and Sex Determination In many organisms the sex chromosomes determine male and female phenotypes but in differing ways Different Sex Determination Systems Humans amp Fruit Flies Males XY heterogametic Females XX homogametic Birds Butterflies some Reptiles Males ZZ homogametic Females ZW heterogametic honeybees Males haploid Females diploid Sex Determination in Human Beings The Presence the Y Chromosome X X X Y SRYgene Zygote l TDF 11 5 o In the absence of 554 a Y chromosome 0 The testisdetermining factor no TDF is produced TDF is produced by a gene I on the Y chromosome 39 i 1 Embryonic gonads 115 Cortex Medulla e The lack ofTDF allows J54 the cortex of the o TDF induces the medulla of embryonic gonads to l the embryonic gonads to develop Into ova need Trgvary Wkestls develop Into testes L v A Differentiated r 1 ds 515A k k F L V a In the absence of Way 9 En testosterone the a The testes produce embryo develops testosterone a hormone that female characteristics initiates development of male l sexual characteristics F l mu 39 39 39 I LL nu l 39 39 201 2 John Wiley amp Sons Inc All rights reserved The SRY gene SRY ex determining Legion X Encodes testisdetermining factor TDF X X SRY gene 0 XX male X Y Missing segment that contains theSRY gene XY female 2 John Wiley 81 Sons Inc All rights reserved Testicular Feminization Testicular development depends on TDF and the testosterone receptor Normal male With the Wi39d39type Tfm gene39 Male with the tfm mutation and testicular feminization Testis Testis SRY datermining gt TEStiS TEStOSterone SRY determining gt Testis gt Testosterone factor I factor Y Y X X I Tfm u Testosterone mug quotquotquotquotquotquotquotquot quotF No testosterone receptor receptor No testosterone TeStOSterone receptor complex receptor complex signals male differentiation No sugnal lMaIe secondary sexual characteristics Female secondary sexual characteristics o 2011 John Wiley amp Sons Inc All rights reserved a 2012 John Wiley a Sons Inc All yigms reserved Sex Determination in Drosophila The Ratio of X Chromosomes to Autosomes TABLE 52 Ratio of X Chromosomes to Autosomes and the Corresponding Phenotype in Drosophila X Chromosomes X and Sets of Autosomes A XA Ratio Phenotype 1 X 2A 05 Male 2X 2A 10 Female 3X 2A 15 Metafemale 4X 3A 133 Metafemale 4X 4A 10 Tetraploid female 3X 3A 10 Triploid female 3X 4A 075 lntersex 2X 3A 067 lntersex 2X 4A 05 Tetraploid male 1X 3A 033 Metamale 2012 John Wiley amp Sans lnAll rights reserved Other Sex Determination Mechanisms The ZW System 99 Birds Butterflies 9 0quot some Reptiles 8 x a 8 Males 22 Z w homogametic z z Females ZW X I heterogametic 8 8 a Z Z 0 Z W 2012ohnWileyampSuns In All n h sreserved Other Sex Determination Systems The Haplo Diplo System Diploid 9 Haploid d eg honeybees Males haploid x Females diploid H eggs develop Unfertilized egg Fertilized egg whether fertilized or not a a a Haploid 0quot Diploid Q 2012 John Wiley 8 Sons Inc All rights reserved Mechanisms of Dosage Compensation Hyperactivation of XIinked genes in male XY s eg Drosophia Inactivation of XIinked genes in female XX s eg mammals Hypoactivation of XIinked genes in female XX s eg C eegans Chapter 19 Regulation of Eukaryotic Gene Expression Dr Ronald J Stamper Bi0328O102 August 5 2013 Outline o Regulation of transcription o mRNA export alternative splicing o RNA Interference o Chromatin Organization amp Gene Expression o Inactivation of Entire Chromosomes Regulating Gene Expression At which points can gene expression be regulated 1 2 3 4 5 Transcription RNA processing RNAstability Translation Posttranslation F t unc Ion W gt 1 gt gt performed by protein DNA RNA transcript mRNA Protein editing complexes splicing folding captail modi cation localization localization Moderate Effect Fast Response Time Large Effect Slow Response Time Levels of mRNA Control 1 Regulated transcription a Transcription factors b En hancersRepressors 2 Alternative Splicing 3 mRNA Export 4 mRNA Stability 1 Normal turnover 2 Targeting by siRNAmiRNA Transcription is controlled by proteins called transcription factors which bind to specific sequences upstream of the basal promoter Octamer GC CAAT GC TATA box box box box box Transcription I I I startpoint l gt ATTTGCAT GGGCGG GGCCAATCT Consensus Consensus Consensus general transcription factors core promoter specialized transcription factors enhancers PDB 1CQT Transcription Factors Specialized transcription factors bind to upstream promoter elements in response to certain stresses eg heatshock hormone signals etc Additional proteins bind at enhancer elements far away from their regulated gene and help hold the RNA polymerase complex at the promoter Enhancer Elements 1 Act over large distances up to several 1000 bp away 2 Act independently of orientation or direction 3 Can be located in any position upstream within the gene or downstream Drosophila yellow gene plus upstream regulatory sequences 77 Kilobases A RNA Exon 1 lntron Exon 2 V v Tissuespeci c Wings Thorax and Larval Bristles tarsal enhancers abdomen body claws and aristae W fies Fig 196 Mediator Complex Enhancer elements in uence transcription through a large complex of proteins called mediator complex mediator lm m l Wm meme Figure 6 19 Molecular Biology of the Cell 4th Edition Heatshock response elementsUHSEs No transcription Res p0 n se Heatshock Heat causes transcription activation of factor HSTF HSTFs which Heatshock 39 Freeinactive bind HSEs and I cause B d I t transcription un ac we V gt Transcription n94 Ilgt hsp70 gene 3 quot RNA polymerase RNA SterOid Response ilii lit ill ie39l lquot Q Elements Steroids can pass through mg A9 ee39Lbeane the cell membrane and protpein amidhmone bind an internal receptor receptowrotein complex The hormonereceptor l Nucleus Cytoplasm complex bInds sterOId mien nuc ear response elements SRE envelope in upstream promoters Mum envelope mRNA eg estrogen androgen 133 o i I 1 New proteins 8 Pe d e H O O n e fptidelr lph n realm Praf 44 complex Target ell Peptides can t pass aaM39 Signalmulezule through the cell membrane so bind a 39 membranebound i i l l Cell receptor quotquot3939 membrane Pa ein The signal is transmitted 2335 cytoplasm internally until a XF binds N I to a response element mum 15 eg Insulin LH FSH Va TSH Newpvoteins39 39l lt H 39 H Promoter Bashing Expmsion TUAI in pollen TUAIUpstream sequences 539UTR GUS 533 1 56 380 I 332 l 271 1 217 l 97 The region between 39 and 97 is critical for expression 1 Levels of mRNA Control 1 Regulated transcription a Transcription factors b En hancersRepressors 2 Alternative Splicing 3 mRNA Export 4 mRNA Stability 1 Normal turnover 2 Targeting by siRNAmiRNA Alternative Splicing allows multiple mRNAs to be created from the same premRNA Exons in rat 39troponin T gene Alternate splicing of exons produces 64 different mRNAs I Exions1 3 9 15 and 18 are present in all mRNAs l Exons 4 8 are present in various combinations in mRNAs j Exons 16 or 1 7 but not both are present in all mRNAs Examples of mRNAs WWW WW WW Control of mRNA Export Requires proper splicing cap amp tail assembly and multiple additional RNAbinding proteins mHNA export Viral Either awn binding proteins 0 nucleopasm cytoplasm Cole 0 Nature Cell Biology 2000 Levels of mRNA Control 1 Regulated transcription a Transcription factors b En hancersRepressors 2 Alternative Splicing 3 mRNA Export 4 mRNA Stability 1 Normal turnover 2 Targeting by siRNAmiRNA mRNA turnover A given mRNA will be degraded in a relatively short time by chemical breakdown or the activity of cellular ribonucleases Halflife varies by RNA from minutes to hours Among 20k mRNAs in mouse ES cells median half life was 71 hours with 1OO mRNAs degrading in lt1hr a Short t12 mRNAs tend to encode regulatory proteins e Long t12 mRNAs tend to encode structural proteins Sharova etal DNA Res 2009 RNA Interference mRNAs stability can be specifically altered by processes called RNA interference Small pieces of RNA 2128bp long serve as targeting sequences to direct proteins that cleave or silence mRNAs siRNA short interfering RNAs cleave target mRNAs miRNA micro RNAs silence target mRNAs Large doublestranded RNA molecule Doublestranded 339 HO 1 39539 539 0H 339 l interfering RNA Ribonucleoprotein particle with double stranded interfering RNA RNAInduced Silencing 5 Complex RISC 339 Ho with singlestranded interfering RNA 9154 o A large double stranded RNA molecule is diced into small doublestranded interfering RNAs 21 28 base pairs long 5154 o The small interfering RNAs and proteins assemble into ribonucleoprotein particles 397ng o The small interfering RNA in a ribonucleoprotein particle is unwound to produce an RNAInduced Silencing Complex RISC Fig 198 RNAInduced Silencing 5 Complex RISC 339 Ho with singlestranded interfering RNA 7154 o The RISC targets a sequence Messenger RNA in a messenger RNA that is with sequence complementary to the ywm 339 complementary to interfering RNA interfering RNA 6154 o The RlSC39s interfering RNA basepairs with its target 539 0H 3 in the messenger RNA 339 HO 1 539 154 9 54 a If imperfectly basepaired If perfecuy39 base39pa39red39 translation of the mRNA is arrested the RNA 395 dePVEd and polypeptide synthesis from the and the mRNA Is degraded mRNA is repressed siRNA W mIRNA 539 5 0H 339 0N1 g WOH 339 Fig 198 Sources of siRNA and miRNA 1 Exogenous dsRNA eg viruses transposon etc 2 Transcription of inverted repeat sequences in genomic DNA G U A G U u u 3 c quot c C C A GGG cucu GG GU CACACU If u ccc GAGA CC CA GUGUGA A I 5 u U U A I G U l 1 U C G A Celegans miRNA gene lin4 39 U I Fig 199 a Silencing of lin14 mRNA The lin14 mRNA is silenced when the lin4 miRNARISC complex binds l U C I c A ll 39 lin4 miRNA I C A l 5 u u G I UCCCUGAGA GUG A339 AGGGACUCU CAC U 1 lin14 mRNA Chromatin Organization The activity of a given region of DNA depends on local chromatin organization nucleosome packing can make DNA more or less accessible Nucleosomes Nucleosome core Linker DNA 146 nucleotide pairs varying in length of DNA wrapped as from 8 to 114 134 turns around nucleotide pairs b an octamer of histones Fig 917 Chromatin Organization Accessible open DNA is called euchromatin lnaccessible closed DNA is called heterochromatin 77 If a chromosome rearrangement occurs that moves a gene from heterochromatin to euchromatin or vice versa the gene s expression will be altered Called Positioneffect variegation An example of epigenetic regulation gene expression controlled by something other than DNA sequence factors Temporal Expression By changing chromatin structure at different stages of development different forms of a gene can be expressed V Gt B t The Bglobin gene cluster Key Tlme Of express39on Locus Control Region El Embryo Fetus I Infant and Adult I Pseudogene Chromatin Remodeling Nucleosome positions can be altered in several ways by protein complexes 1 histone acetyl transferases HATs increased expr 2 histone methyl transferases HMTs decreased expr 3 SWISNF complex opens promoter area El acetylltiun methylalion ubiquinntiun El sumoylalion El phaspharylation Dr Zheng GA State DNA Methylation Cytosine bases in DNA can be methylated usually in CpG dinucleotides NHZ 5 of these are methylated I In the human genome N f C CH3 CpG islands exist near many I 3 5 transcription start sites C 2 1 6 C 12kb long CpGrich 0 N H 30000 in human genome I function somewhat unclear H 5methyl cytosine Fig 1912 Imprinting In some few cases expression of a gene depends on its parental origin eg the mouse lgf2 gene is only expressed from the paternal chromosome eg the mouse H19 gene is only expressed from the maternal chromosome Imprinting results from differential DNA methylation in the germ line eg lgf2 is CpG methylated in eggs but not in sperm cells Chromosome InActivation Entire chromosomes can be hyperactivated or hypoactivated eg dosage compensation on the Xchromosome e Mammalian females XX inactivate one copy of the Xchromosome a Drosophia males XO hyperactivate their single X chromosome 9 C elegans hermaphrodites XX hypoactivate both Xchromosomes Cellular Reproduction Ronald J Stamper PhD Bi0328O102 O1JuIy 2013 Chapter Outline Cloning o Cells and Chromosomes Cellular environment 0 Prokaryotic and Eukaryotic cells 0 Chromosomes amp gene locations 0 Cell division o Mitosis o Meiosis o Model Organism Life Cycles Questions about the chapter 7 anyone anyoneu Animal cell Nuclear pure WNUCIEEV Envatupa quot Nucteus aj Tr Nuclaulus Frag ribusumes Mrtochondrmn Gulgx appalams u 1 Et Rcmgh endnpbasmic rEthLHUI39IT 39 quot Mimmbulas tquot Is Credit J Craig Venter Institute wwwjcvi com The Cell Cycle Mitosis IQ Duplication of chromosomes in Sphase to yield associated pairs of identical sister chromatids Duplication of microtubule organizing centers MTOCs in mammals centrosomes comprised of two centrioles each Condensation of chromosomes prophase 20 um Mitosis 4 Alignment of chromosomes at cell center amp attachment to microtubules metaphase 5 Separation of sister chromatids and migration to opposite poles anaphase I u u u u u u u u I 0 o quot u 0 early 1 t metaphasc anaphase prophase prophase gt I action of condensation separin cohesin complex mzuj l znm Tngetneruntii sepann dn uspartquot Natceii simian MItOSIs 6 Decondensation of chromosomes and reformation of nuclear membranes telophase 1 Cell membrane growth and separation of daughter cells cytokinesis Cleavage luvmw m lmag x 3m anlnlnulheck Alklnl Ahaul urn are man u Mitosis Pay attention to the terms quotchromosomequot versus chromatid Capwlgm e 2w by quotnewquot Inc An n39gm mama eg humans have 46 chromosomes 92sister39 quot39in Iquot I39 2 x 46 chromosomes following cytokinesis Hammngue Hpmmmgupi lnllvpnlu if mmm empaum 6 mm in mmm ms mm o man WWW Pmllhl tannins 1D i 8 m anvnsn m n ms nu DIMEI augmm EMS kmsd am an n mmmnsum a mu dm mmd quotmm m we 2mm mane ansm mm 2 EM and m m 9 mm manhrin am am Meiosis one duplication event followed by two division events mill Mail DE 7 opium mother anquot fl lTlEl39DCjE 5 um Eyn tasis Note These diagrams refer to digaid cells e g humans r 39Dimsiunl o o o o o 00 identical ciplnid 42m daughter cells Neridentiizal hanluid in tells Meiosis 1 stages MEOSIS l Pmphase I Leptmema Pruphase I Zygunema Pmphasel Pachynarna Pmphase I Diplonema L I a Chromosomes each cnnsis n Homologous chmmasomes Hammogous chromusomes Hnmnlnguus hmmnsomas of two sistr chmma ds begin ta begin ta pair are fully paired 5213313124 except at chiasmata v Ch msma I 39 gt Q 4quot J Twa ch msmatz Racnmhmant Tam mmmands Meiosis 1 stages Pmpnase I Dmkinasis rquot Melanhasa I Maphusal a v Pam cmnmnsomzs mndanse Med hmmnsames am un lumarand hemmzamnhedtn 39 snmdla hm mm and mm m awash pales of ma cu wmplmd an m mm begin m mm Meiosis II stages Anaphase u Telnplluse MEmsls Memphis u a v quotr L t um daughter 39 Chmmr umas dacan anse T quot39 r 7 an m sepavam by Lylnplasmi memmnas Slsizr nhmmah ds main Chmmnsnmas em mnsrs ng Chmmammes augn an the In each cell anuense and hamme attachad m smndla bers Meiosis in humans 2n cell 46 chromosomes 2 each of 23 chromosomes 9 Sphase 92 sister chromatids in 46 pairs eg 1a 1a 1b1b 2a2a 2b2b 3a 3a etc 9 homologous chromosomes pair giving 23 tetrads eg 1a 1a 1b1b 2a2a2b2b 3a 3a 3b3b etc 9 crossing over occurs between homologous pairs 9 tetrads dissociate and segregate gives 2 x 23 pairs eg 1a 1a 1b1b 2a2a 2b2b 3a 3a etc 9 sister chromatids separate gives 4 x 23 chromosomes eg 1a 1a 1b 1b 2a 2a 2b 2b 3a 3a etc Model Organisms What makes a good genetic model organism TABLE 21 Some Important Model Genetic Organisms Hapluid Chromosome Genome Size in Gene Urganism Number millions of base pairs Number 53 ccharomycea Eerewgrae Iyeastl 15 12 45258 Arabidopsa s thairana owering plan 5 57 277 Caanorhabrtis elega n5 warm 5 700 21733 Dmsopbr ia meianagaster yl it 70 T7030 Damn redo zebra sh 25 LEIGH 2352 Mug muscuiLJE mouse ED 2900 253 Model Organisms yeast Haplmd n calls saCCharomyces nfuppnsite Emily y maungtypes cereVISIae Q 16 a ml Mm hapo1d or deIOId f genome 12Mb Q genes 6k DxplomZn K zygote totally sequenced O Mews Spormanun A us with four haplmd n ascosuures Model Organisms A thaliana 4 Q Magmang 5 mm mm mmumwzn rm Wm a u PEA mam 3 km o Magnum a ngarumgmas y A mm mm Mm no Magnum quotmy 1 gt gt 4quot an Emmy F g Q mm 5 533 Ww amm m I m mm egmw m mum w m sum Sm 9mm an as gum mm man a 5 34m Snug nmzjmslb l mm39r hm 339 3 Wm WM Mm mm mum 5mm b Daranus Mm mhrgt muggy as unmaryuuuunn o W M Lin 6mm mm Madam w mm m Mr B m ru Model organisms Mus musculus Note difference between female and male gametes Much longer generation time Small litter sizes Much higher maintenance costs Chapter 21 Cancer Genetics Ronald J Stamper PhD Bi0328O102 August 8 2013 ProtoOncogene Oncogene Tumor Suppressor Gene Dominant activators eg myc ras Only one mutation is needed Cell Division Tumor Suppressor Genes antioncogenes function to keep cellular division processes in check only one copy is required for function so both alleles must be mutated for lossof function 7 the twohit hypothesis TwoHit Hypothesis Developed by following rare cancers that followed a pattern of family inheritance eg retinoblastoma a tumor of the eye results from mutation of both alleles of the RB gene stjudeorgretinoblastoma Sporadic Retinoblastoma Sporadic Retinoblastoma Parents X RB RB RBquot RB children Child inherits two RB alleles RB RB Fig 216 Somatic mutation TWO sepa rate creates one RB spontaneous mutations 1 my allele RB th39t must occurto develop 395 39 retinoblastoma l Somatic mutation creates another RB39 allele R3 5 second hit rare cancer Fig 216 Inherited I n Retinoblastoma Retinoblastoma E i x i i One mutated allele is W RF 35 W inherited family predisposition Child inherits one children RB allele rst hit Rs 1 R5 LOSSOfI Only one spontaneous heterong psny mutation has to occur to develop the disease Somatlc mutatlon 39 t th more common than In the 11373 w RB39 RB39 overall population Emmi h Fig 216 TA B IL E 21 2 Inherited Cancer Syndromes Syndrome Familial retinoblastoma polyposis FAP y colorectal cancer HNPCC Neurofibromatosis type 1 Ir Wilms39tumor Familial breast cancer 1 Familial breast cancer 2 von HippelLindau disease Familial melanoma Ataxia telangiectasia Bloom39s syndrome a 16427 quot Primary Mmor Retinoblastoma ltnnma L r I I Neurofibromas meningiomas Renal cancer Melanoma Lymphoma Solid tumors 13q143 17p131 5q21 17q112 22q122 11p13 17q21 13q12 3p25 15q261 1ncnl regulati Transcription factor Regulation of Scatenin Cell cycle nd transcriptional on DNA mismatch repair Regulation of Rasmediated Transcriptional repressor DNA repair DNA repair Regulation oftranscriptional elongation Inhibitor of CDK5 DNA helicase many inherited cancer syndromes are caused by mutation of tumorsuppressor genes EarlyG1 What does RB do CD H pREI EZF The RB gene encodes v the pRB protein which helps regulate entry into CyclinECDKZ l the cell cycle complex START checkpoint Cyclin DCDK4 complex I a Phosphoryliated pRB lt l 39 lt m N n Active W Lgt DNA IVV Cell ycle Late G1 protein Fig 217 RNA p53 p53 is another tumorsuppressor protein encoded by the TP53 gene upregulated during stress conditions p53 acts as a transcription factor in two main ways 1 activates transcription of p21 which inhibits CDKs to prevent cell cycle progression 2 activates transcription of BAX which ultimately triggers apoptosis cdyated Lya39nes 39l 4 62 92 95 295 325 33953 364 393 Nterminus Cnre dama39n Ciiennims Missiaise Nenaenae Silent Ether To 131 I l 35 9113 95 6 Cancer Cases with p53 Many clinically relevant Type mutations mutations have been Lung 70 identified in TP53 Colon 60 Ovary 60 Lymphoma 30 Breast 20 Dr Xin Lu Leukemia 10 pAPC is another tumorsuppressor protein that regulates division of intestinal epithelial cells loss of fxn colon cancer 117 cells are shed from the human intestine every day Ganz 2 Nat Immunology pAPC function a cum 9 lt g As cells get slgna i a 39 further from the o Plaima crypts membrane Bcalenin is synthesized in responselnasignaling a Pathwav A LEW pm dIVIdIng em TCF i K 9 a mains 139 i Bcaienin forms a cnmplex B Ca eniquot forms a WMPIEquot r39 B39camn39 wkh pAPC in due cytoplasm Z i ff fyifs m x pAPC degrades 3 W W 3 Bcatenin to The Btatenintranscription The B39GmnimPAPC OMPIEX factor omplex migrates to the 332M gigizieirher degradation of a i nutieus to activate the 39 gamma 9 growth pathways products promote cell division 6 o O 0 o 9 W DNA m L m Fig 219 BRCA I amp BRCAZ Tumor suppressor genes implicated in hereditary breast and ovarian cancers Large proteins in the nucleus of cells Contain transcriptional activation domains and protein interaction domains a known interaction with RAD51 a DNA repair factor Mutations account for 710 of breastovary cancers in USA Carriers of mutation are 510x higher risk than normal1 1 National Cancer Institute 2012 ProtoOncogene Oncogene Tumor Suppressor Gene Dominant eg RB p53 activators BRCA12 eg myc ras APC Only one Two mutation is mutations are needed needed Cell DIVISIOh inherited spontaneous Typical Cancer Progression Pathway to metastatic coioreclai cancer iria tivation Activation of AFC tumor of items suppressar gene oncogene Normal intestinal Dygplastlc WI gt Early epithelium adennma epithelium 39 inactivation of Inactivation inattivatiun of tumor suppressor of TP53 tumnr other tunmr gene on laq suppressor gene suppressnr genes M974 1 Mn jdils1fptn am in From Kinzler K W and Vagelste ln B 39l 996 Cir391 871 591 70 upwith Cell Press Tm mum Cnup ad regawr Nu nae Exc smn repau DNA Warstvanu Emsern rem Ease EAHS N Epa Bush I z 1 xv 4 I NTH 39 mm ram r535 nDNAdamage NFED nnsE Q4 4 MRN Lampxa Wsmatm repa r Nnnrnnmnmgnus Ig enmmmng rEL aH NHEJ macyan m nWsEerDa r H lmuh remmmnannna repah hep ier 8 The Genetics of Bacteria and Their Viruses Medica RFPhotutake Chapter Outline 3 Viruses and Bacteria in Genetics o The Genetics of Viruses a The Genetics of Bacteria o Mechanisms of Genetic Exchange in Bacteria s The Evolutionary Significance of Genetic Exchange in Bacteria ST 54 T 0 min A T4 bacteriophage attaches to an Ecoli cell and injects its DNA The host bacterium is lysed releasing about 300 progeny phage 6quot T 2 min Synthesis of phagespeci c mRNAs begins 914 T 1 7 min The rst intact phage T6 min particles are assembled Replica on of Phage DNA begins host Key DNA has been T4 DNA degraded by phage encoded nucleases E coli DNA m T4 mRNA attached T 14 min DNA lled heads tails lacking 0 ho quotbosomes tail bers and assembled tail 0 Phagespeci c proteins bers rst appear Assembled tail ber Normal E coli replication takes about 20 min 9 2012 John Wiley amp Sons Inc All rights reserved Bacteriophage 7t Doublestranded DNA genome o Genome contains 48502 base pairs and about 50 genes 9 May be ytic or lysogenic DNA packaged in head a 50 nm b nunst F Howatsom quotam ne Exym nn Vol 3 Jahnwlley lasans 1971 Bacteriophage 7t lytic pathway lysogenic pathway mp rquot Linear ylnkiged cu oilhela bdachrumosom Cluularinlracellullrform onha lambda chrumnmme X Sitrsneci c mumblnaxion ll 1 mediated by x magma Circullr E cull chmmusuma 45 0 Integration Circular chromosome of a lysogenlc a call cell e 45 showing the locations ula kw genes 0 Menu Lambda E coli cell phage Lambda DNA in head E E coli chromosome l Circular form of lambda chromosome Many viral I Lytic pathway ll Lysogenic pathway chromosomes Sitespeci c recombination Lambda prophage l Viral assembly S John Wiley 5 Sons Inc Bacterial colonies Serratia marcescens l Transformation uptake of free DNA E Bacterium Bacterial chromosome Donor Recipient cell cell Lysed bacterium Recipient bacterium 201 2 John Wiley amp Sons Inc All rights reserved Streptococcus pneumoniae Transformation What happened in this sample Living Type IIIS bacteria recovered Live mouse 3 Dead mouse Living Type IIIS Heatkilled Type IIIS Live mouse 35 Live mouse Living Type quotR Live mouse 997 egg No capsu39e Live mouse Living Type IIIS Heatkilled Type Ills bacteria recovered Living TypellR Live mouse 23gt Dead mouse 393 2012 John Wiley amp Sons Inc All rights reserved


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