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

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

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

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

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

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

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
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 Enhancer (distal control elements) Proximal control elements DNA Upstream Promoter Exon Intron Poly-A signal sequence Termination region Transcription Downstream Poly-A signal Primary RNA transcript (pre-mRNA) 5 Intron RNA RNA processing: Cap and tail added; introns excised and exons spliced together Coding segment P G mRNA 5 Cap 5 UTR (untranslated region) Start codon Stop 3 UTR tail Chromatin changes RNA processing degradation Translation Protein processing and degradation Cleared 3 end of primary transport Figure 19.5

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 An activator Is a protein that binds to an enhancer and stimulates transcription of a gene Distal control element Activators Enhancer Promoter Gene TATA box General transcription factors DNA-bending protein Group of Mediator proteins RNA Polymerase II RNA synthesis Transcription Initiation complex Chromatin changes 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 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 Enhancer Promoter Control elements Albumin gene Crystallin Liver cell nucleus Lens cell Available activators expressed gene not Crystallin gene not expressed (a) (b) Figure 19.7a, b

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 Chromatin changes Transcription RNA processing mRNA degradation Translation Protein processing and degradation Exons DNA Primary RNA transcript RNA splicing or Figure 19.8

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 Blockage of translation
RNA interference by single-stranded microRNAs (miRNAs) Can lead to degradation of an mRNA or block its translation 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. 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 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 Figure 19.9

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 Enzymatic components of the proteasome cut the protein into small peptides, which can be further degraded by other enzymes in the cytosol. 3 The ubiquitin-tagged protein is recognized by a proteasome, which unfolds the protein and sequesters it within a central cavity. 2 Multiple ubiquitin mol- ecules are attached to a protein by enzymes in the cytosol. 1 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 Figure 19.10

34 The gene regulation systems that go wrong during cancer
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
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 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 within the gene Oncogene Normal growth-stimulating protein in excess Hyperactive or degradation- resistant protein New promoter Figure 19.11

38 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 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 1 Growth factor 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 Hyperactive Ras protein (product of oncogene) issues signals on its own NUCLEUS Gene expression Protein that stimulates the cell cycle P MUTATION DNA G protein 3 Protein kinases (phosphorylation cascade) 4 2 Receptor Transcription factor (activator) 5

41 (b) Cell cycle–inhibiting pathway. In this
The p53 gene encodes a tumor-suppressor protein That is a specific transcription factor that promotes the synthesis of cell cycle–inhibiting proteins UV light DNA Defective or missing transcription factor, such as p53, cannot activate 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 Figure 19.12b

42 Mutations that knock out the p53 gene
Can lead to excessive cell growth and cancer (c) 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). EFFECTS OF MUTATIONS Protein overexpressed Protein absent Cell cycle overstimulated Increased cell division Cell cycle not inhibited Figure 19.12c

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

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 The bulk of most eukaryotic genomes
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 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 Exons (regions of genes coding for protein, rRNA, tRNA) (1.5%) Repetitive DNA that includes transposable elements and related sequences (44%) Introns and regulatory (24%) Unique noncoding DNA (15%) DNA unrelated to (about 15%) Alu elements (10%) Simple sequence DNA (3%) Large-segment duplications (5-6%) Figure 19.14

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 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 Transposon New copy of transposon is copied DNA of genome Insertion Mobile transposon (a) Transposon movement (“copy-and-paste” mechanism) Retrotransposon retrotransposon RNA Reverse transcriptase (b) Retrotransposon movement 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
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 Some multigene families
Consist of identical DNA sequences, usually clustered tandemly, such as those that code for RNA products DNA RNA transcripts Non-transcribed spacer Transcription unit 18S 5.8S 28S rRNA 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 -Globin Heme Hemoglobin -Globin -Globin gene family -Globin gene family Chromosome 16 Chromosome 11 Embryo Fetus and adult Adult G A    2 1  Figure 19.17b The human -globin and -globin gene families

57 The basis of change at the genomic level is mutation
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 Nonsister chromatids Transposable element Gene Incorrect pairing of two homologues during meiosis Crossover and Figure 19.18

60 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 Ancestral globin gene  2 1  G 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 Figure 19.19

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 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 EGF Epidermal growth factor gene with multiple EGF exons (green) F Fibronectin gene with multiple “finger” exons (orange) Exon shuffling duplication K Plasminogen gene with a “kfingle” exon (blue) Portions of ancestral genes TPA gene as it exists today Figure 19.20

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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