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Chapter 19 The Organization and Control of Eukaryotic Genomes Human Genome 3 billion base pairs. 30,000 to 50,000 genes. 3%-5% active at any moment. Questions? With so much DNA in a cell, how is it organized or packaged? How is the expression of the DNA controlled? Movie – DNA Packaging Microscopic Levels 1. 2. 3. 4. Nucleosomes 30-nm Chromatin Fibers Looped Domains Chromosomes Nucleosomes "Beads on a String”. DNA wound on a protein core. Packaging for DNA. Controls transcription. Protein Core Two molecules of four types of Histone proteins. H1- 5th type of Histone protein attaches the DNA to the outside of the core. 30 - nm Chromatin Fibers A cylinder of tightly coiled nucleosomes 30 - nm in diameter. Looped Domains Loops of 30 - nm chromatin. Protein Scaffold Chromosomes Large units of DNA. Similar to "Chapters" in the Book of Life. Chromosome Regions 1. Heterochromatin - highly condensed chromatin; areas that are not transcribed. 2. Euchromatin - less condensed chromatin; areas of active transcription. Molecular Level Organization 1. Repetitive Sequences 2. Satellite DNA 3. Interspersed Repetitive DNA 4. Multigene Families Repetitive Sequences Tandemly repeating units of 1-10 nucleotides. 10% to 15% of total DNA. Satellite DNA Repetitive areas of DNA found at the: Tips of chromosomes. Centromere regions. Structural DNA. Result Give regions of the DNA different densities. Linked to some genetic disorders. Ex. - Fragile X Syndrome Huntington’s disease Interspersed Repetitive DNA 25 - 40% of DNA Copies of repetitive units that are scattered among genes. Often transcribed, but function not clear. Multigene Families A collection of identical or very similar genes. From a common ancestral gene. May be clustered or dispersed in the genome. Identical Families Identical genes for the same protein. Ex: Ribosomal Protein and rRNA. Result - Many copies of ribosomes possible. Most common gene in DNA. Identical Genes Nonidentical Families Related clusters of genes that are nearly identical in their base sequences. Ex: Globin Genes Globin Gene Evolution a - Globin Family Found on chromosome 16. Contains two copies of a globin, one fetal globin and four pseudogenes. b - Globin Family Found on chromosome 11. Contains two copies of b globin, one embryo, two fetal and one pseudogene. Pseudogene Gene with sequences very similar to real genes, but lack promoter sites. Are not transcribed into proteins. Possible proof of transpositions ? Genome Plasticity Changes in the ways a gene can be expressed. Seen only in somatic cells. Have major effects on gene expression within particular cells and tissues. Types 1. Gene Amplification 2. Selective Gene Loss 3. Genomic Rearrangements Gene Amplification The selective replication of certain genes. Ex: rRNA genes in eggs Result - many copies of rRNA for making ribosomes. Selective Gene Loss Loss of genes or chromosomes in some tissues during development. Result - DNA (genes) lost and not expressed. Genomic Rearrangements Shuffling of DNA areas (not from Meiosis). Ex: Transposons retrotransposons antibody genes. Transposons - Example Result Genes moved structurally within the genome. Transcription control changed. Control of Gene Expression Complicated Process. Many levels of control are possible. Main Control Levels 1. Nucleus - those inside the nuclear membrane. 2. Cytoplasm - those that occur in the cytoplasm. Nucleus Level 1. 2. 3. 4. Extra-Cellular Signals Chromatin Modifications Transcriptional Control Posttranscriptional Control Extra-Cellular Signal Signal from outside the cells (usually a hormone). Review specifics from Chapter 11. Result - regions of DNA activated for transcription. Chromatin Modifications DNA Methylation. Histone Acetylation. Gene rearrangements. Gene amplification. DNA Methylation Addition of methyl groups (-CH3) to DNA bases. Result - long-term shut-down of DNA transcription. Ex: Barr bodies genomic imprinting Histone Acetylation Attachment of acetyl groups (-COCH3) to AAs in histones. Result - DNA held less tightly to the nucleosomes, more accessible for transcription. Transcriptional Control Ex: Enhancers, DNA-Binding Domains regulatory RNA. Result - genes are more (or less) available for transcription. Factors that affect the transcription of genes. Movie – Turning on a Gene Enhancers Areas of DNA that increase transcription. May be widely separated from the gene (usually upstream). DNA-Binding Domains Proteins that bind to DNA and regulate transcription. Ex: Helix-turn-Helix Zinc-Finger Leucine Zipper DNA – Binding Domains Regulatory RNA Small RNA molecules that are not translated Interact with DNA Whole new area in gene regulation Posttranscriptional Control 1. RNA Processing Ex - introns and exons. 2. RNA Transport - moving the mRNA into the cytoplasm. 3. RNA Degradation - breaking down old mRNA. Transcription Control Movie – RNA processing Cytoplasm Level of Control 1. Translation 2. Polypeptide Changes Movie – Translation control Translation Control Regulated by the availability of initiation factors. Availability of tRNAs, AAs and other protein synthesis factors. (review Chapter 17). Polypeptide Changes Changes to the protein structure after translation. Ex: Cleavage Modifications Activation Transport Degradation Movie – Protein Processing Protein Degradation By Proteosomes using Ubiquitin to mark the protein. Gene Expression and Cancer Cancer - loss of the genetic control of cell division. Balance between growthstimulating pathway (accelerator) and growthinhibiting pathway (brakes). Proto-oncogenes Normal genes for cell growth and cell division factors. Genetic changes may turn them into oncogenes (cancer genes). Ex: Gene Amplification, Translocations, Transpositions, Point Mutations Proto-oncogenes Tumor-Suppressor Genes Genes that inhibit cell division. Ex - p53, p21 Cancer Examples RAS - a G protein. When mutated, causes an increase in cell division by over-stimulating protein kinases. Several mutations known. Cancer Examples p53 - involved with several DNA repair genes and “checking” genes. When damaged, can’t inhibit cell division or cause damaged cells to apoptose. Comment p53 is known to be sensitive to cigarette smoke. Damage by smoke often leads to lung cancer. Over-activity of p53 causes problems too. Carcinogens Agents that cause cancer. Ex: radiation, chemicals Most work by altering the DNA, or interfering with control or repair mechanisms. Multiple Hit Hypothesis Cancer is the result of several control mechanisms breaking down. Ex: Colorectal Cancer requires 4 to 5 mutations before cancer starts. Colorectal Cancer Summary DNA packaging and gene expression are very complex with lots of opportunities for control points. Be able to discuss how DNA is organized and packed. Summary Be able to discuss mechanisms for regulating DNA and protein synthesis (know several ways) How control of DNA can lead to cancer.