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Overview: How Eukaryotic Genomes Work and Evolve • Two features of eukaryotic genomes are a major information-processing challenge: – First, the typical eukaryotic genome is much larger than that of a prokaryotic cell – Second, cell specialization limits the expression of many genes to specific cells • The DNA-protein complex, called chromatin, is ordered into higher structural levels than the DNAprotein complex in prokaryotes Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Nucleosomes, or “Beads on a String” • Proteins called histones are responsible for the first level of DNA packing in chromatin • The association of DNA and histones seems to remain intact throughout the cell cycle • In electron micrographs, unfolded chromatin has the appearance of beads on a string • Each “bead” is a nucleosome, the basic unit of DNA packing Animation: DNA Packing Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-2a 2 nm DNA double helix Histones Histone tails Histone H1 Linker DNA (“string”) Nucleosome (“bead”) Nucleosomes (10-nm fiber) 10 nm Higher Levels of DNA Packing • The next level of packing forms the 30-nm chromatin fiber Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-2b 30 nm Nucleosome 30-nm fiber • In turn, the 30-nm fiber forms looped domains, making up a 300-nm fiber Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-2c Protein scaffold Loops 300 nm Looped domains (300-nm fiber) Scaffold • In a mitotic chromosome, the looped domains coil and fold, forming the metaphase chromosome Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-2d 700 nm 1,400 nm Metaphase chromosome • Interphase chromatin is usually much less condensed than that of mitotic chromosomes • Much of the interphase chromatin is present as a 10-nm fiber, and some is 30-nm fiber, which in some regions is folded into looped domains • Interphase chromosomes have highly condensed areas, called heterochromatin, and less compacted areas, called euchromatin Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 • A multicellular organism’s cells undergo cell differentiation, specialization in form and function Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Differential Gene Expression • Differences between cell types result from differential gene expression, the expression of different genes by cells within the same genome • In each type of differentiated cell, a unique subset of genes is expressed • Many key stages of gene expression can be regulated in eukaryotic cells Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-3 Signal NUCLEUS Chromatin DNA Gene available for transcription Gene Transcription RNA Exon Primary transcript Intro RNA processing Tail Cap mRNA in nucleus Transport to cytoplasm CYTOPLASM mRNA in cytoplasm Degradation of mRNA Translation Polypeptide Cleavage Chemical modification Transport to cellular destination Active protein Degradation of protein Degraded protein DNA Methylation • DNA methylation, the addition of methyl groups to certain bases in DNA, is associated with reduced transcription in some species • In some species, DNA methylation causes longterm inactivation of genes in cellular differentiation • In genomic imprinting, methylation turns off either the maternal or paternal alleles of certain genes at the start of development Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Epigenetic Inheritance • Although the chromatin modifications just discussed do not alter DNA sequence, they may be passed to future generations of cells • The inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence is called epigenetic inheritance Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Roles of Transcription Factors • To initiate transcription, eukaryotic RNA polymerase requires the assistance of proteins called transcription factors • General transcription factors are essential for the transcription of all protein-coding genes • In eukaryotes, high levels of transcription of particular genes depend on control elements interacting with specific transcription factors Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 • An activator is a protein that binds to an enhancer and stimulates transcription of a gene Animation: Initiation of Transcription Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-6 Distal control element Activators Promoter Gene DNA TATA box Enhancer General transcription factors DNA-bending protein Group of mediator proteins RNA polymerase II RNA polymerase II Transcription Initiation complex RNA synthesis • Some transcription factors function as repressors, inhibiting expression of a particular gene • Some activators and repressors act indirectly by influencing chromatin structure Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Mechanisms of Post-Transcriptional Regulation • Transcription alone does not account for gene expression • More and more examples are being found of regulatory mechanisms that operate at various stages after transcription • Such mechanisms allow a cell to fine-tune gene expression rapidly in response to environmental changes Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 Animation: RNA Processing Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-8 Exons DNA Primary RNA transcript RNA splicing mRNA or mRNA Degradation • The life span of mRNA molecules in the cytoplasm is a key to determining the protein synthesis • The mRNA life span is determined in part by sequences in the leader and trailer regions Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Initiation of Translation • The initiation of translation of selected mRNAs can be blocked by regulatory proteins that bind to sequences or structures of the mRNA • Alternatively, translation of all mRNAs in a cell may be regulated simultaneously Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Protein Processing and Degradation • After translation, various types of protein processing, including cleavage and the addition of chemical groups, are subject to control • Proteasomes are giant protein complexes that bind protein molecules and degrade them Animation: Protein Processing Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Animation: Protein Degradation LE 19-10 Proteasome and ubiquitin to be recycled Ubiquitin Proteasome Protein to be degraded Ubiquitinated protein Protein entering a proteasome Protein fragments (peptides) Concept 19.3: Cancer results from genetic changes that affect cell cycle control • The gene regulation systems that go wrong during cancer are very same systems that play important roles in embryonic development • Thus, research into the molecular basis of cancer has benefited from and informed many other fields of biology Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Types of Genes Associated with Cancer • Genes that normally regulate cell growth and division during the cell cycle include: – Genes for growth factors – Their receptors – Intracellular molecules of signaling pathways • Mutations altering any of these genes in somatic cells can lead to cancer Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 • A DNA change that makes a proto-oncogene excessively active converts it to an oncogene, which may promote excessive cell division and cancer Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-11 Proto-oncogene DNA Translocation or transposition: gene moved to new locus, under new controls Gene amplification: multiple copies of the gene New promoter Normal growth-stimulating protein in excess Point mutation within a control element Oncogene Normal growth-stimulating protein in excess Normal growth-stimulating protein in excess Point mutation within the gene Oncogene Hyperactive or degradationresistant protein Tumor-Suppressor Genes • Tumor-suppressor genes encode proteins that inhibit abnormal cell division • Any decrease in the normal activity of a tumorsuppressor protein may contribute to cancer Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Multistep Model of Cancer Development • More than one somatic mutation is generally needed to produce a full-fledged cancer cell • About a half dozen DNA changes must occur for a cell to become fully cancerous • These changes usually include at least one active oncogene and mutation or loss of several tumorsuppressor genes • Colorectal cancer, with 135,000 new cases and 60,000 deaths in the United States each year, illustrates a multistep cancer path Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-13 Colon Normal colon epithelial cells Loss of tumorsuppressor gene p53 Activation of ras oncogene Loss of tumorsuppressor Colon wall gene APC (or other) Small benign growth (polyp) Loss of tumorsuppressor gene DCC Additional mutations Larger benign growth (adenoma) Malignant tumor (carcinoma) • Certain viruses promote cancer by integration of viral DNA into a cell’s genome • By this process, a retrovirus may donate an oncogene to the cell • Viruses seem to play a role in about 15% of human cancer cases worldwide Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Inherited Predisposition to Cancer • The fact that multiple genetic changes are required to produce a cancer cell helps explain the predispositions to cancer that run in some families • Individuals who inherit a mutant oncogene or tumor-suppressor allele have an increased risk of developing certain types of cancer Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 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 much more noncoding DNA Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • The sequencing of the human genome reveals what makes up most of the 98.5% of the genome that does not code for proteins, rRNAs, or tRNAs • Most intergenic DNA is repetitive DNA, present in multiple copies in the genome • About three-fourths of repetitive DNA is made up of transposable elements and sequences related to them Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-14 Exons (regions of genes coding for protein, rRNA, or tRNA) (1.5%) Repetitive DNA that includes transposable elements and related sequences (44%) Introns and regulatory sequences (24%) Repetitive DNA unrelated to transposable elements (about 15%) Unique noncoding DNA (15%) Alu elements (10%) Simple sequence DNA (3%) Large-segment duplications (5–6%) Transposable Elements and Related Sequences • The first evidence for wandering DNA segments came from geneticist Barbara McClintock’s breeding experiments with Indian corn • McClintock identified changes in the color of corn kernels that made sense only by postulating that some genetic elements move from other genome locations into the genes for kernel color Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • The classic examples of multigene families of nonidentical genes are two related families of genes that encode globins • Globin gene family clusters also include pseudogenes, nonfunctional nucleotide sequences that are similar to the functional genes Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 19.5: Duplications, rearrangements, and mutations of DNA contribute to genome evolution • The basis of change at the genomic level is mutation, underlying much of genome evolution • The earliest forms of life likely had a minimal number of genes, including only those necessary for survival and reproduction • The size of genomes has increased over evolutionary time, with the extra genetic material providing raw material for gene diversification Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Duplication of Chromosome Sets • Accidents in meiosis can lead to one or more extra sets of chromosomes, a condition known as polyploidy • The genes in one or more of the extra sets can diverge by accumulating mutations; these variations may persist if the organism carrying them survives and reproduces Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 region Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-18 Transposable element Gene Nonsister chromatids Crossover Incorrect pairing of two homologues during meiosis and 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 • After the duplication events, differences between the genes in the globin family arose from mutations that accumulated in the gene copies over many generations Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-19 Ancestral globin gene Duplication of ancestral gene Mutation in both copies Transposition to different chromosomes Further duplications and mutations 1 2 1 -Globin gene family on chromosome 16 A -Globin gene family on chromosome 11 • Subsequent duplications of these genes and random mutations gave rise to the present globin genes, which code for oxygen-binding proteins Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • The similarity in the amino acid sequences of the various globin proteins supports this model of gene duplication and mutation Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Evolution of Genes with Novel Functions • The copies of some duplicated genes have diverged so much in evolution that the functions of their encoded proteins are now very different Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings