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Chapter 19: Eukaryotic Genome: Organization, Regulation, and Evolution.

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1 Chapter 19: Eukaryotic Genome: Organization, Regulation, and Evolution

2 Overview: How Eukaryotic Genomes Work and Evolve In eukaryotes, the DNA-protein complex, called chromatin – Is ordered into higher structural levels than the DNA- protein complex in prokaryotes Figure 19.1

3 Both prokaryotes and eukaryotes – Must alter their patterns of gene expression in response to changes in environmental conditions

4 Concept 19.1: Chromatin structure is based on successive levels of DNA packing Eukaryotic DNA – Is precisely combined with a large amount of protein Eukaryotic chromosomes – Contain an enormous amount of DNA relative to their condensed length

5 Nucleosomes, or “Beads on a String” Proteins called histones – Are responsible for the first level of DNA packing in chromatin – Bind tightly to DNA The association of DNA and histones – Seems to remain intact throughout the cell cycle

6 In electron micrographs – Unfolded chromatin has the appearance of beads on a string Each “bead” is a nucleosome – The basic unit of DNA packing Figure 19.2 a 2 nm 10 nm DNA double helix Histone tails His- tones Linker DNA (“string”) Nucleosome (“bad”) Histone H1 (a) Nucleosomes (10-nm fiber)

7 Nucleosome 30 nm (b) 30-nm fiber Higher Levels of DNA Packing The next level of packing – Forms the 30-nm chromatin fiber Figure 19.2 b

8 The 30-nm fiber, in turn – Forms looped domains, making up a 300-nm fiber Figure 19.2 c Protein scaffold 300 nm (c) Looped domains (300-nm fiber) Loops Scaffold

9 In a mitotic chromosome – The looped domains themselves coil and fold forming the characteristic metaphase chromosome Figure 19.2 d 700 nm 1,400 nm (d) Metaphase chromosome

10 In interphase cells – Most chromatin is in the highly extended form called euchromatin

11 Concept 19.2: Gene expression can be regulated at any stage, but the key step is transcription All organisms – Must regulate which genes are expressed at any given time During development of a multicellular organism – Its cells undergo a process of specialization in form and function called cell differentiation

12 Differential Gene Expression Each cell of a multicellular eukaryote – Expresses only a fraction of its genes In each type of differentiated cell – A unique subset of genes is expressed

13 Many key stages of gene expression – Can be regulated in eukaryotic cells Figure 19.3 Signal NUCLEUS Chromatin Chromatin modification: DNA unpacking involving histone acetylation and DNA demethlation Gene DNA Gene available for transcription RNA Exon Transcription Primary transcript RNA processing Transport to cytoplasm Intron Cap mRNA in nucleus Tail CYTOPLASM mRNA in cytoplasm Degradation of mRNA Translation Polypetide Cleavage Chemical modification Transport to cellular destination Active protein Degradation of protein Degraded protein

14 Regulation of Chromatin Structure Genes within highly packed heterochromatin – Are usually not expressed

15 Histone Modification Chemical modification of histone tails – Can affect the configuration of chromatin and thus gene expression Figure 19.4a (a) Histone tails protrude outward from a nucleosome Chromatin changes Transcription RNA processing mRNA degradation Translation Protein processing and degradation DNA double helix Amino acids available for chemical modification Histone tails

16 Histone acetylation – Seems to loosen chromatin structure and thereby enhance transcription Figure 19.4 b (b) Acetylation of histone tails promotes loose chromatin structure that permits transcription Unacetylated histones Acetylated histones

17 DNA Methylation Addition of methyl groups to certain bases in DNA – Is associated with reduced transcription in some species

18 Epigenetic Inheritance Epigenetic inheritance – Is the inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence

19 Regulation of Transcription Initiation Chromatin-modifying enzymes provide initial control of gene expression – By making a region of DNA either more or less able to bind the transcription machinery

20 Organization of a Typical Eukaryotic Gene Associated with most eukaryotic genes are multiple control elements – Segments of noncoding DNA that help regulate transcription by binding certain proteins Figure 19.5 Enhancer (distal control elements) Proximal control elements DNA Upstream Promoter Exon IntronExon Intron Poly-A signal sequence Exon Termination region Transcription Downstream Poly-A signal ExonIntron Exon IntronExon Primary RNA transcript (pre-mRNA) 5 Intron RNA RNA processing: Cap and tail added; introns excised and exons spliced together Coding segment P P P G mRNA 5 Cap 5 UTR (untranslated region) Start codon Stop codon 3 UTR (untranslated region) Poly-A tail Chromatin changes Transcription RNA processing mRNA degradation Translation Protein processing and degradation Cleared 3 end of primary transport

21 The Roles of Transcription Factors To initiate transcription – Eukaryotic RNA polymerase requires the assistance of proteins called transcription factors

22 Enhancers and Specific Transcription Factors Proximal control elements – Are located close to the promoter Distal control elements, groups of which are called enhancers – May be far away from a gene or even in an intron

23 Distal control element Activators Enhancer Promoter Gene TATA box General transcription factors DNA-bending protein Group of Mediator proteins RNA Polymerase II RNA Polymerase II RNA synthesis Transcription Initiation complex Chromatin changes Transcription RNA processing mRNA degradation Translation Protein processing and degradation A DNA-bending protein brings the bound activators closer to the promoter. Other transcription factors, mediator proteins, and RNA polymerase are nearby. 2 Activator proteins bind to distal control elements grouped as an enhancer in the DNA. This enhancer has three binding sites. 1 The activators bind to certain general transcription factors and mediator proteins, helping them form an active transcription initiation complex on the promoter. 3 An activator – Is a protein that binds to an enhancer and stimulates transcription of a gene Figure 19.6

24 Some specific transcription factors function as repressors – To inhibit expression of a particular gene Some activators and repressors – Act indirectly by influencing chromatin structure

25 Combinatorial Control of Gene Activation A particular combination of control elements – Will be able to activate transcription only when the appropriate activator proteins are present Figure 19.7a, b Enhancer Promoter Control elements Albumin gene Crystallin gene Liver cell nucleus Lens cell nucleus Available activators Available activators Albumin gene expressed Albumin gene not expressed Crystallin gene not expressed Crystallin gene expressed (a) (b) Liver cell Lens cell

26 Coordinately Controlled Genes Unlike the genes of a prokaryotic operon – Coordinately controlled eukaryotic genes each have a promoter and control elements The same regulatory sequences – Are common to all the genes of a group, enabling recognition by the same specific transcription factors

27 Mechanisms of Post- Transcriptional Regulation An increasing number of examples – Are being found of regulatory mechanisms that operate at various stages after transcription

28 RNA Processing In alternative RNA splicing – Different mRNA molecules are produced from the same primary transcript, depending on which RNA segments are treated as exons and which as introns Figure 19.8 Chromatin changes Transcription RNA processing mRNA degradation Translation Protein processing and degradation Exons DNA Primary RNA transcript mRNA RNA splicing or

29 mRNA Degradation The life span of mRNA molecules in the cytoplasm – Is an important factor in determining the protein synthesis in a cell – Is determined in part by sequences in the leader and trailer regions

30 RNA interference by single-stranded microRNAs (miRNAs) – Can lead to degradation of an mRNA or block its translation Figure 19.9 5 Chromatin changes Transcription RNA processing mRNA degradation Translation Protein processing and degradation Degradation of mRNA OR Blockage of translation Target mRNA miRNA Protein complex Dicer Hydrogen bond The micro- RNA (miRNA) precursor folds back on itself, held together by hydrogen bonds. 1 2 An enzyme called Dicer moves along the double- stranded RNA, cutting it into shorter segments. 2 One strand of each short double- stranded RNA is degraded; the other strand (miRNA) then associates with a complex of proteins. 3 The bound miRNA can base-pair with any target mRNA that contains the complementary sequence. 4 The miRNA-protein complex prevents gene expression either by degrading the target mRNA or by blocking its translation. 5

31 Initiation of Translation The initiation of translation of selected mRNAs – Can be blocked by regulatory proteins that bind to specific sequences or structures of the mRNA Alternatively, translation of all the mRNAs in a cell – May be regulated simultaneously

32 Protein Processing and Degradation After translation – Various types of protein processing, including cleavage and the addition of chemical groups, are subject to control

33 Proteasomes – Are giant protein complexes that bind protein molecules and degrade them Figure 19.10 Chromatin changes Transcription RNA processing mRNA degradation Translation Protein processing and degradation Ubiquitin Protein to be degraded Ubiquinated protein Proteasome and ubiquitin to be recycled Protein fragments (peptides) Protein entering a proteasome Multiple ubiquitin mol- ecules are attached to a protein by enzymes in the cytosol. 1 The ubiquitin-tagged protein is recognized by a proteasome, which unfolds the protein and sequesters it within a central cavity. 2 Enzymatic components of the proteasome cut the protein into small peptides, which can be further degraded by other enzymes in the cytosol. 3

34 Concept 19.3: Cancer results from genetic changes that affect cell cycle control The gene regulation systems that go wrong during cancer – Turn out to be the very same systems that play important roles in embryonic development

35 Types of Genes Associated with Cancer The genes that normally regulate cell growth and division during the cell cycle – Include genes for growth factors, their receptors, and the intracellular molecules of signaling pathways

36 Oncogenes and Proto-Oncogenes Oncogenes – Are cancer-causing genes Proto-oncogenes – Are normal cellular genes that code for proteins that stimulate normal cell growth and division

37 A DNA change that makes a proto-oncogene excessively active – Converts it to an oncogene, which may promote excessive cell division and cancer Figure 19.11 Proto-oncogene DNA Translocation or transposition: gene moved to new locus, under new controls Gene amplification: multiple copies of the gene Point mutation within a control element Point mutation within the gene Oncogene Normal growth-stimulating protein in excess Hyperactive or degradation- resistant protein Normal growth-stimulating protein in excess Normal growth-stimulating protein in excess New promoter

38 Tumor-Suppressor Genes Tumor-suppressor genes – Encode proteins that inhibit abnormal cell division

39 Interference with Normal Cell- Signaling Pathways Many proto-oncogenes and tumor suppressor genes – Encode components of growth-stimulating and growth-inhibiting pathways, respectively

40 Figure 19.12a (a) Cell cycle–stimulating pathway. This pathway is triggered by a growth factor that binds to its receptor in the plasma membrane. The signal is relayed to a G protein called Ras. Like all G proteins, Ras is active when GTP is bound to it. Ras passes the signal to a series of protein kinases. The last kinase activates a transcription activator that turns on one or more genes for proteins that stimulate the cell cycle. If a mutation makes Ras or any other pathway component abnormally active, excessive cell division and cancer may result. 1 2 4 3 5 GTP Ras GTP Hyperactive Ras protein (product of oncogene) issues signals on its own NUCLEUS Gene expression Protein that stimulates the cell cycle P P P P MUTATION P DNA P The Ras protein, encoded by the ras gene – Is a G protein that relays a signal from a growth factor receptor on the plasma membrane to a cascade of protein kinases 2 Receptor Transcription factor (activator) 5 G protein 3 Protein kinases (phosphorylation cascade) 4 1 Growth factor

41 The p53 gene encodes a tumor-suppressor protein – That is a specific transcription factor that promotes the synthesis of cell cycle–inhibiting proteins Figure 19.12b UV light DNA Defective or missing transcription factor, such as p53, cannot activate transcription MUTATION Protein that inhibits the cell cycle pathway, DNA damage is an intracellular signal that is passed via protein kinases and leads to activation of p53. Activated p53 promotes transcription of the gene for a protein that inhibits the cell cycle. The resulting suppression of cell division ensures that the damaged DNA is not replicated. Mutations causing deficiencies in any pathway component can contribute to the development of cancer. (b) Cell cycle–inhibiting pathway. In this 1 3 2 Protein kinases 2 3 Active form of p53 DNA damage in genome 1

42 Mutations that knock out the p53 gene – Can lead to excessive cell growth and cancer Figure 19.12c EFFECTS OF MUTATIONS Protein overexpressed Cell cycle overstimulated Increased cell division Cell cycle not inhibited Protein absent Effects of mutations. Increased cell division, possibly leading to cancer, can result if the cell cycle is overstimulated, as in (a), or not inhibited when it normally would be, as in (b). (c)

43 The Multistep Model of Cancer Development Normal cells are converted to cancer cells – By the accumulation of multiple mutations affecting proto-oncogenes and tumor-suppressor genes

44 A multistep model for the development of colorectal cancer Figure 19.13 Colon Colon wall Normal colon epithelial cells Small benign growth (polyp) Larger benign growth (adenoma) Malignant tumor (carcinoma) 2 Activation of ras oncogene 3 Loss of tumor- suppressor gene DCC 4 Loss of tumor-suppressor gene p53 5 Additional mutations 1 Loss of tumor- suppressor gene APC (or other)

45 Certain viruses – Promote cancer by integration of viral DNA into a cell’s genome

46 Inherited Predisposition to Cancer Individuals who inherit a mutant oncogene or tumor-suppressor allele – Have an increased risk of developing certain types of cancer

47 Concept 19.4: Eukaryotic genomes can have many noncoding DNA sequences in addition to genes The bulk of most eukaryotic genomes – Consists of noncoding DNA sequences, often described in the past as “junk DNA” However, much evidence is accumulating – That noncoding DNA plays important roles in the cell

48 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Relationship Between Genomic Composition and Organismal Complexity Compared with prokaryotic genomes, the genomes of eukaryotes – Generally are larger – Have longer genes – Contain a much greater amount of noncoding DNA both associated with genes and between genes

49 Now that the complete sequence of the human genome is available – We know what makes up most of the 98.5% that does not code for proteins, rRNAs, or tRNAs Figure 19.14 Exons (regions of genes coding for protein, rRNA, tRNA) (1.5%) Repetitive DNA that includes transposable elements and related sequences (44%) Introns and regulatory sequences (24%) Unique noncoding DNA (15%) Repetitive DNA unrelated to transposable elements (about 15%) Alu elements (10%) Simple sequence DNA (3%) Large-segment duplications (5-6%)

50 Transposable Elements and Related Sequences The first evidence for wandering DNA segments – Came from geneticist Barbara McClintock’s breeding experiments with Indian corn Figure 19.15

51 Transposon New copy of transposon Transposon is copied DNA of genome Insertion Mobile transposon (a) Transposon movement (“copy-and-paste” mechanism) Retrotransposon New copy of retrotransposon DNA of genome RNA Reverse transcriptase (b) Retrotransposon movement Insertion Movement of Transposons and Retrotransposons Eukaryotic transposable elements are of two types – Transposons, which move within a genome by means of a DNA intermediate – Retrotransposons, which move by means of an RNA intermediate Figure 19.16a, b

52 Sequences Related to Transposable Elements Multiple copies of transposable elements and sequences related to them – Are scattered throughout the eukaryotic genome In humans and other primates – A large portion of transposable element–related DNA consists of a family of similar sequences called Alu elements

53 Other Repetitive DNA, Including Simple Sequence DNA Simple sequence DNA – Contains many copies of tandemly repeated short sequences – Is common in centromeres and telomeres, where it probably plays structural roles in the chromosome

54 Genes and Multigene Families Most eukaryotic genes – Are present in one copy per haploid set of chromosomes The rest of the genome – Occurs in multigene families, collections of identical or very similar genes

55 DNA RNA transcripts Non-transcribed spacer Transcription unit DNA 18S5.8S28S rRNA 5.8S 28S 18S Some multigene families – Consist of identical DNA sequences, usually clustered tandemly, such as those that code for RNA products Figure 19.17a Part of the ribosomal RNA gene family

56 The classic examples of multigene families of nonidentical genes – Are two related families of genes that encode globins Figure 19.17b The human  -globin and  -globin gene families  -Globin Heme Hemoglobin  -Globin  -Globin gene family  -Globin gene family Chromosome 16Chromosome 11 Embryo Fetus and adult Embryo FetusAdult  GG AA        22  11 22 11 

57 Concept 19.5: Duplications, rearrangements, and mutations of DNA contribute to genome evolution The basis of change at the genomic level is mutation – Which underlies much of genome evolution

58 Duplication of Chromosome Sets Accidents in cell division – Can lead to extra copies of all or part of a genome, which may then diverge if one set accumulates sequence changes

59 Duplication and Divergence of DNA Segments Unequal crossing over during prophase I of meiosis – Can result in one chromosome with a deletion and another with a duplication of a particular gene Figure 19.18 Nonsister chromatids Transposable element Gene Incorrect pairing of two homologues during meiosis Crossover and

60 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Evolution of Genes with Related Functions: The Human Globin Genes The genes encoding the various globin proteins – Evolved from one common ancestral globin gene, which duplicated and diverged Figure 19.19 Ancestral globin gene          22  11 22 11   GG AA    -Globin gene family on chromosome 16  -Globin gene family on chromosome 11   Evolutionary time Duplication of ancestral gene Mutation in both copies Transposition to different chromosomes Further duplications and mutations

61 Subsequent duplications of these genes and random mutations – Gave rise to the present globin genes, all of which code for oxygen-binding proteins

62 The similarity in the amino acid sequences of the various globin proteins – Supports this model of gene duplication and mutation Table 19.1

63 Evolution of Genes with Novel Functions The copies of some duplicated genes – Have diverged so much during evolutionary time that the functions of their encoded proteins are now substantially different

64 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Rearrangements of Parts of Genes: Exon Duplication and Exon Shuffling A particular exon within a gene – Could be duplicated on one chromosome and deleted from the homologous chromosome

65 In exon shuffling – Errors in meiotic recombination lead to the occasional mixing and matching of different exons either within a gene or between two nonallelic genes Figure 19.20 EGF Epidermal growth factor gene with multiple EGF exons (green) F FF F Fibronectin gene with multiple “finger” exons (orange) Exon shuffling Exon duplication Exon shuffling K FEGFK K Plasminogen gene with a “kfingle” exon (blue) Portions of ancestral genesTPA gene as it exists today

66 How Transposable Elements Contribute to Genome Evolution Movement of transposable elements or recombination between copies of the same element – Occasionally generates new sequence combinations that are beneficial to the organism Some mechanisms – Can alter the functions of genes or their patterns of expression and regulation

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