Môn Sinh học - Chapter 16: The molecular basis of inheritance

When he mixed heat-killed remains of the pathogenic strain with living cells of the harmless strain, some living cells became pathogenic He called this phenomenon transformation, now defined as a change in genotype and phenotype due to assimilation of foreign DNA

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The Molecular Basis of InheritanceChapter 16Overview: Life’s Operating InstructionsIn 1953, James Watson and Francis Crick introduced an elegant double-helical model for the structure of deoxyribonucleic acid, or DNADNA, the substance of inheritance, is the most celebrated molecule of our timeHereditary information is encoded in DNA and reproduced in all cells of the bodyThis DNA program directs the development of biochemical, anatomical, physiological, and (to some extent) behavioral traits© 2011 Pearson Education, Inc.Figure 16.1Concept 16.1: DNA is the genetic materialEarly in the 20th century, the identification of the molecules of inheritance loomed as a major challenge to biologists© 2011 Pearson Education, Inc.The Search for the Genetic Material: Scientific InquiryWhen T. H. Morgan’s group showed that genes are located on chromosomes, the two components of chromosomes—DNA and protein—became candidates for the genetic materialThe key factor in determining the genetic material was choosing appropriate experimental organismsThe role of DNA in heredity was first discovered by studying bacteria and the viruses that infect them© 2011 Pearson Education, Inc.Evidence That DNA Can Transform BacteriaThe discovery of the genetic role of DNA began with research by Frederick Griffith in 1928Griffith worked with two strains of a bacterium, one pathogenic and one harmless© 2011 Pearson Education, Inc.When he mixed heat-killed remains of the pathogenic strain with living cells of the harmless strain, some living cells became pathogenicHe called this phenomenon transformation, now defined as a change in genotype and phenotype due to assimilation of foreign DNA© 2011 Pearson Education, Inc.Living S cells (control)Living R cells (control)Heat-killed S cells (control)Mixture of heat-killed S cells and living R cellsMouse diesMouse diesMouse healthyMouse healthyLiving S cellsEXPERIMENTRESULTSFigure 16.2In 1944, Oswald Avery, Maclyn McCarty, and Colin MacLeod announced that the transforming substance was DNATheir conclusion was based on experimental evidence that only DNA worked in transforming harmless bacteria into pathogenic bacteriaMany biologists remained skeptical, mainly because little was known about DNA© 2011 Pearson Education, Inc.Evidence That Viral DNA Can Program CellsMore evidence for DNA as the genetic material came from studies of viruses that infect bacteriaSuch viruses, called bacteriophages (or phages), are widely used in molecular genetics research© 2011 Pearson Education, Inc.Figure 16.3Phage headTail sheathTail fiberDNABacterial cell100 nmIn 1952, Alfred Hershey and Martha Chase performed experiments showing that DNA is the genetic material of a phage known as T2To determine this, they designed an experiment showing that only one of the two components of T2 (DNA or protein) enters an E. coli cell during infectionThey concluded that the injected DNA of the phage provides the genetic information© 2011 Pearson Education, Inc.Figure 16.4-3Bacterial cellPhageBatch 1: Radioactive sulfur (35S)Radioactive proteinDNABatch 2: Radioactive phosphorus (32P)Radioactive DNAEmpty protein shellPhage DNACentrifugeCentrifugeRadioactivity (phage protein) in liquidPellet (bacterial cells and contents)PelletRadioactivity (phage DNA) in pelletEXPERIMENTAdditional Evidence That DNA Is the Genetic MaterialIt was known that DNA is a polymer of nucleotides, each consisting of a nitrogenous base, a sugar, and a phosphate groupIn 1950, Erwin Chargaff reported that DNA composition varies from one species to the nextThis evidence of diversity made DNA a more credible candidate for the genetic material© 2011 Pearson Education, Inc.Figure 16.UN04Two findings became known as Chargaff’s rulesThe base composition of DNA varies between speciesIn any species the number of A and T bases are equal and the number of G and C bases are equalThe basis for these rules was not understood until the discovery of the double helix© 2011 Pearson Education, Inc.Figure 16.5Sugar–phosphate backboneNitrogenous basesThymine (T)Adenine (A)Cytosine (C)Guanine (G)Nitrogenous basePhosphateDNA nucleotideSugar (deoxyribose)3 end5 endBuilding a Structural Model of DNA: Scientific InquiryAfter DNA was accepted as the genetic material, the challenge was to determine how its structure accounts for its role in heredityMaurice Wilkins and Rosalind Franklin were using a technique called X-ray crystallography to study molecular structureFranklin produced a picture of the DNA molecule using this technique© 2011 Pearson Education, Inc.Figure 16.6(a) Rosalind Franklin(b)Franklin’s X-ray diffraction photograph of DNAFranklin’s X-ray crystallographic images of DNA enabled Watson to deduce that DNA was helical The X-ray images also enabled Watson to deduce the width of the helix and the spacing of the nitrogenous basesThe pattern in the photo suggested that the DNA molecule was made up of two strands, forming a double helix© 2011 Pearson Education, Inc.Figure 16.73.4 nm1 nm0.34 nmHydrogen bond(a)Key features of DNA structureSpace-filling model(c)(b) Partial chemical structure3 end5 end3 end5 endTTAAGGCCCCCCCCCCCGGGGGGGGGTTTTTTAAAAAAWatson and Crick built models of a double helix to conform to the X-rays and chemistry of DNAFranklin had concluded that there were two outer sugar-phosphate backbones, with the nitrogenous bases paired in the molecule’s interiorWatson built a model in which the backbones were antiparallel (their subunits run in opposite directions) © 2011 Pearson Education, Inc.At first, Watson and Crick thought the bases paired like with like (A with A, and so on), but such pairings did not result in a uniform width Instead, pairing a purine with a pyrimidine resulted in a uniform width consistent with the X-ray data© 2011 Pearson Education, Inc.Figure 16.UN01Purine  purine: too widePyrimidine  pyrimidine: too narrowPurine  pyrimidine: width consistent with X-ray dataWatson and Crick reasoned that the pairing was more specific, dictated by the base structuresThey determined that adenine (A) paired only with thymine (T), and guanine (G) paired only with cytosine (C)The Watson-Crick model explains Chargaff’s rules: in any organism the amount of A = T, and the amount of G = C© 2011 Pearson Education, Inc.Figure 16.8SugarSugarSugarSugarAdenine (A)Thymine (T)Guanine (G)Cytosine (C)Concept 16.2: Many proteins work together in DNA replication and repairThe relationship between structure and function is manifest in the double helixWatson and Crick noted that the specific base pairing suggested a possible copying mechanism for genetic material© 2011 Pearson Education, Inc.The Basic Principle: Base Pairing to a Template StrandSince the two strands of DNA are complementary, each strand acts as a template for building a new strand in replicationIn DNA replication, the parent molecule unwinds, and two new daughter strands are built based on base-pairing rules© 2011 Pearson Education, Inc.Figure 16.9-3(a) Parent molecule(b)Separation of strands(c)“Daughter” DNA molecules, each consisting of one parental strand and one new strandAAAAAAAAAAAATTTTTTTTTTTTCCCCCCCCGGGGGGGGWatson and Crick’s semiconservative model of replication predicts that when a double helix replicates, each daughter molecule will have one old strand (derived or “conserved” from the parent molecule) and one newly made strandCompeting models were the conservative model (the two parent strands rejoin) and the dispersive model (each strand is a mix of old and new)© 2011 Pearson Education, Inc.Figure 16.10(a)Conservative model(b)Semiconservative model(c) Dispersive modelParent cellFirst replicationSecond replicationExperiments by Matthew Meselson and Franklin Stahl supported the semiconservative model They labeled the nucleotides of the old strands with a heavy isotope of nitrogen, while any new nucleotides were labeled with a lighter isotope© 2011 Pearson Education, Inc.Figure 16.11Bacteria cultured in medium with 15N (heavy isotope)Bacteria transferred to medium with 14N (lighter isotope)DNA sample centrifuged after first replicationDNA sample centrifuged after second replicationLess denseMore densePredictions:First replicationSecond replicationConservative modelSemiconservative modelDispersive model2134EXPERIMENTRESULTSCONCLUSIONDNA Replication: A Closer LookThe copying of DNA is remarkable in its speed and accuracyMore than a dozen enzymes and other proteins participate in DNA replication© 2011 Pearson Education, Inc.Getting StartedReplication begins at particular sites called origins of replication, where the two DNA strands are separated, opening up a replication “bubble”A eukaryotic chromosome may have hundreds or even thousands of origins of replicationReplication proceeds in both directions from each origin, until the entire molecule is copied© 2011 Pearson Education, Inc.Figure 16.12a(a) Origin of replication in an E. coli cellOrigin of replicationParental (template) strandDouble- stranded DNA moleculeDaughter (new) strandReplication forkReplication bubbleTwo daughter DNA molecules0.5 mFigure 16.12b(b) Origins of replication in a eukaryotic cellOrigin of replicationDouble-stranded DNA moleculeParental (template) strandDaughter (new) strandBubbleReplication forkTwo daughter DNA molecules0.25 mAt the end of each replication bubble is a replication fork, a Y-shaped region where new DNA strands are elongatingHelicases are enzymes that untwist the double helix at the replication forksSingle-strand binding proteins bind to and stabilize single-stranded DNATopoisomerase corrects “overwinding” ahead of replication forks by breaking, swiveling, and rejoining DNA strands© 2011 Pearson Education, Inc.Figure 16.13TopoisomerasePrimaseRNA primerHelicaseSingle-strand binding proteins535533DNA polymerases cannot initiate synthesis of a polynucleotide; they can only add nucleotides to the 3 endThe initial nucleotide strand is a short RNA primer© 2011 Pearson Education, Inc.An enzyme called primase can start an RNA chain from scratch and adds RNA nucleotides one at a time using the parental DNA as a templateThe primer is short (5–10 nucleotides long), and the 3 end serves as the starting point for the new DNA strand© 2011 Pearson Education, Inc.Synthesizing a New DNA StrandEnzymes called DNA polymerases catalyze the elongation of new DNA at a replication forkMost DNA polymerases require a primer and a DNA template strandThe rate of elongation is about 500 nucleotides per second in bacteria and 50 per second in human cells© 2011 Pearson Education, Inc.Each nucleotide that is added to a growing DNA strand is a nucleoside triphosphatedATP supplies adenine to DNA and is similar to the ATP of energy metabolismThe difference is in their sugars: dATP has deoxyribose while ATP has riboseAs each monomer of dATP joins the DNA strand, it loses two phosphate groups as a molecule of pyrophosphate© 2011 Pearson Education, Inc.Figure 16.14New strandTemplate strandSugarPhosphateBaseNucleoside triphosphateDNA polymerasePyrophosphate55553333OHOHOHPP i2 P iPPPAAAATTTTCCCCCCGGGGAntiparallel ElongationThe antiparallel structure of the double helix affects replicationDNA polymerases add nucleotides only to the free 3end of a growing strand; therefore, a new DNA strand can elongate only in the 5to3direction© 2011 Pearson Education, Inc.Along one template strand of DNA, the DNA polymerase synthesizes a leading strand continuously, moving toward the replication fork© 2011 Pearson Education, Inc.Figure 16.15Leading strandLagging strandOverviewOrigin of replicationLagging strandLeading strandPrimerOverall directions of replicationOrigin of replicationRNA primerSliding clampDNA pol IIIParental DNA355335353535To elongate the other new strand, called the lagging strand, DNA polymerase must work in the direction away from the replication forkThe lagging strand is synthesized as a series of segments called Okazaki fragments, which are joined together by DNA ligase© 2011 Pearson Education, Inc.Figure 16.16b-6Template strandRNA primer for fragment 1Okazaki fragment 1RNA primer for fragment 2Okazaki fragment 2Overall direction of replication33333333333355555555555522211111Figure 16.17OverviewLeading strandOrigin of replicationLagging strandLeading strandLagging strandOverall directions of replicationLeading strandDNA pol IIIDNA pol IIILagging strandDNA pol IDNA ligasePrimerPrimaseParental DNA55555333333214The DNA Replication ComplexThe proteins that participate in DNA replication form a large complex, a “DNA replication machine”The DNA replication machine may be stationary during the replication processRecent studies support a model in which DNA polymerase molecules “reel in” parental DNA and “extrude” newly made daughter DNA molecules© 2011 Pearson Education, Inc.Figure 16.18Parental DNADNA pol IIILeading strandConnecting proteinHelicaseLagging strandDNA pol IIILagging strand template555555333333Proofreading and Repairing DNADNA polymerases proofread newly made DNA, replacing any incorrect nucleotidesIn mismatch repair of DNA, repair enzymes correct errors in base pairingDNA can be damaged by exposure to harmful chemical or physical agents such as cigarette smoke and X-rays; it can also undergo spontaneous changesIn nucleotide excision repair, a nuclease cuts out and replaces damaged stretches of DNA© 2011 Pearson Education, Inc.Figure 16.19NucleaseDNA polymeraseDNA ligase5555555533333333Evolutionary Significance of Altered DNA NucleotidesError rate after proofreading repair is low but not zeroSequence changes may become permanent and can be passed on to the next generationThese changes (mutations) are the source of the genetic variation upon which natural selection operates© 2011 Pearson Education, Inc.Replicating the Ends of DNA MoleculesLimitations of DNA polymerase create problems for the linear DNA of eukaryotic chromosomesThe usual replication machinery provides no way to complete the 5 ends, so repeated rounds of replication produce shorter DNA molecules with uneven endsThis is not a problem for prokaryotes, most of which have circular chromosomes© 2011 Pearson Education, Inc.Figure 16.20Ends of parental DNA strandsLeading strandLagging strandLast fragmentNext-to-last fragmentLagging strandRNA primerParental strandRemoval of primers and replacement with DNA where a 3 end is availableSecond round of replicationFurther rounds of replicationNew leading strandNew lagging strandShorter and shorter daughter molecules3333355555Eukaryotic chromosomal DNA molecules have special nucleotide sequences at their ends called telomeresTelomeres do not prevent the shortening of DNA molecules, but they do postpone the erosion of genes near the ends of DNA moleculesIt has been proposed that the shortening of telomeres is connected to aging© 2011 Pearson Education, Inc.Figure 16.211 mIf chromosomes of germ cells became shorter in every cell cycle, essential genes would eventually be missing from the gametes they produceAn enzyme called telomerase catalyzes the lengthening of telomeres in germ cells© 2011 Pearson Education, Inc.The shortening of telomeres might protect cells from cancerous growth by limiting the number of cell divisionsThere is evidence of telomerase activity in cancer cells, which may allow cancer cells to persist© 2011 Pearson Education, Inc.Concept 16.3 A chromosome consists of a DNA molecule packed together with proteinsThe bacterial chromosome is a double-stranded, circular DNA molecule associated with a small amount of proteinEukaryotic chromosomes have linear DNA molecules associated with a large amount of proteinIn a bacterium, the DNA is “supercoiled” and found in a region of the cell called the nucleoid© 2011 Pearson Education, Inc.Chromatin, a complex of DNA and protein, is found in the nucleus of eukaryotic cellsChromosomes fit into the nucleus through an elaborate, multilevel system of packing© 2011 Pearson Education, Inc.Figure 16.22aDNA double helix (2 nm in diameter)DNA, the double helixNucleosome (10 nm in diameter)HistonesHistonesHistone tailH1Nucleosomes, or “beads on a string” (10-nm fiber)Figure 16.22b30-nm fiber30-nm fiberLoopsScaffold300-nm fiberChromatid (700 nm)Replicated chromosome (1,400 nm)Looped domains (300-nm fiber)Metaphase chromosomeChromatin undergoes changes in packing during the cell cycleAt interphase, some chromatin is organized into a 10-nm fiber, but much is compacted into a 30-nm fiber, through folding and loopingThough interphase chromosomes are not highly condensed, they still occupy specific restricted regions in the nucleus© 2011 Pearson Education, Inc.Most chromatin is loosely packed in the nucleus during interphase and condenses prior to mitosisLoosely packed chromatin is called euchromatinDuring interphase a few regions of chromatin (centromeres and telomeres) are highly condensed into heterochromatinDense packing of the heterochromatin makes it difficult for the cell to express genetic information coded in these regions© 2011 Pearson Education, Inc.Figure 16.UN03DNA pol III synthesizes leading strand continuouslyParental DNADNA pol III starts DNA synthesis at 3 end of primer, continues in 5  3 directionOrigin of replicationHelicasePrimase synthesizes a short RNA primerDNA pol I replaces the RNA primer with DNA nucleotides3335555Lagging strand synthesized in short Okazaki fragments, later joined by DNA ligaseFigure 16.UN06

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