AP Biology, Chapter 19
The Organization and Control of Eukaryotic Genomes

Summary
Introduction

THE STRUCTURE OF CHROMATIN
	Introduction
	Chromatin structure is base on successive levels of DNA packing 
		1. Compare the structure and organization of prokaryotic and eukaryotic genomes.
			a. Prokaryotes
				i. Several million base pairs
				ii. Circular chromosome
				iii. Attached proteins control and pack it
			b. Eukaryotes
				i. Billions of base pairs
				ii. 2 to hundreds of linear chromosomes
				iii. Larger amounts of protein control and pack it
		2. Describe the current model for progressive levels of DNA packing.
			a. Mitotic chromosomes
				i. Nucleosomes are the 11 nm beads on a string
				ii. Folded into a 30-nm chromatin fiber
				iii. 30-nm fibers form looped domains attached to protein scaffold
				iv. Looped domains coil and fold
			b. Interphase
				i. Same up to looped domains
				ii. Looped domains attached to inside surface of nuclear envelope
		3. Explain how histones influence folding in eukaryotic DNA.
			a. Nucleosomes = DNA wound around clusters of 8 histones with space in 
			between
			b. Add histone H1, nucleosomes fold into a 30-nm chromatin fiber
		4. Distinguish between heterochromatin and euchromatin.
			a. More condensed, non-transcribed = heterochromatin
			b. Less condensed, transcribed = euchromatin 

GENOME ORGANIZATION AT THE DNA LEVEL
	Introduction
	Repetitive DNA and other noncoding sequences account for much of the eukaryotic 
	genome
		5. Describe the structure and functions of the portions of eukaryotic DNA that do not 
		encode protein or RNA.
			a. 97% noncoding in humans
			b. Includes regulatory sequences, introns, tandem repeats
		6. Define and distinguish between the three types of satellite DNA.
			a. Origin of the term
				i. Repeats have distinct GC:AT ratio from the rest of the genome
				ii. In the centrifuge it forms an extra, satellite band
			b. Types
				i. Regular, mini-, and micro-
				ii. >100,000 base pairs, 100-100,000, and 10-100
		7. Explain how tandemly repeated nucleotide triplets can lead to human disease.
			a. Fragile X syndrome
				i. Many more repeats in leader of 1st exon
				ii. String of repeats gets longer with generations
			b. Huntington's disease
				i. Extra CAG repeats in the genes coding region, extra glutamines
				ii. Again the number of repeats increases with generations
			c. For both, the longer the strings, the more severe the disease
		8. Describe the role of telomeres and centromeres.
			a. Both have most of the regular satellite DNA
			b. Centromeres
				i. Spindle latches on here
				ii. May organize chromatin during interphase
			c. Telomeres
				i. Extra repeats lost with each replication
				ii. Binds proteins that prevent fraying
		9. Describe the structure and proportion of interspersed repetitive DNA.
			a. Scattered (non-tandem), repeated units 100s-1000s of bases long
			b. 25-40% of mammalian genomes
			c. Some are transcribed, most are transposons
	Gene families have evolved by duplication of ancestral genes
		10. Using the genes for rRNA as an example, explain how multigene families of identical 
		genes can be advantageous for a cell.
			a. rRNA genes tandemly repeated in identical copies
			b. Allows cells to rapidly makes millions of ribosomes
		11. Using alpha-globin and beta-globin genes as examples, describe how multigene 
		families of nonidentical genes probably evolve; include the role of transposition in your 
		description.
			a. Divergent DNA sequences allows reconstruction of evolutionary history
			b. Steps
				i. Single ancestral globin gene undergoes duplication
				ii. The copies diverge by mutation into  and β
				iii. Transposition moves one of the two to a different chromosome
				iv. More duplication and mutation makes embryonic, fetal, and adult in 
				each gene family 
		12. Define pseudogenes.
			a. Show much homology and linkage with related genes
			b. Nonfunctional; lack regulatory sequences or harbor disabling mutations
	Gene amplification, loss, or rearrangement can alter a cell's genome
		13. Describe the process and significance of gene amplification.
			a. Gene amplification in amphibians
				i. Amphibian development: many small circles of rDNA
				ii. Allows many ribosomes to be made and a burst of translation
			b. Gene amplification in cancer
				i. Small circular DNAs appear carrying drug-resistance genes
				ii. Selects for chemotherapy-resistant cells
			c. Selective gene loss: insects show tissue-specific chromosome deletion or loss
		14. Define and explain the significance of transposons and retrotransposons.
			a. Transposons
				i. DNA regions that can copy and move themselves
				ii. May cause mutation if they land in structural or regulatory genes
				iii. Can cut out and move adjacent DNA
			b. Retrotransposons
				i. Copy themselves using an RNA intermediate
				ii. Carry a gene for reverse transcriptase to reconvert to DNA
				iii. Includes many of the interspersed repetitive sequences
		15. Explain how genetic recombination during development results in millions of different 
		kinds of antibody molecules.
			a. Exons for constant antibody domains are present in few copies
			b. Exons for variable domains are on the same chromosome in many forms
			c. During leukocyte development the variable and constant domains are 
			randomly edited together

THE CONTROL OF GENE EXPRESSION
	Introduction
	Each cell of a multicellular eukaryote expresses only a small fraction of its genes
		16. Define differentiation and describe at what level gene expression is generally 
		controlled.
			a. Differentiation = cellular change in form and function
			b. Control
				i. At transcriptional level
				ii. Involves DNA-binding proteins
				iii. Coordinated by external signals
	The control of gene expression can occur at any step in the pathway from gene to 
	functional protein: an overview
	Chromatin modifications affect the availability of genes for transcription
		17. Explain how DNA methylation and histone acetylation affects chromatin structure and 
		the regulation of transcription.
			a. DNA methylation
				i. Methyl groups may be added/removed especially to C
				ii. Inactive DNA is often highly methylated; demethylation activates
				iii. Methyl inactivation during development is passed on after mitosis
				iv. Methylating enzymes recognize methylation on one strand, add 
				methyl to opposite strand
				v. Explains genomic imprinting
			b. Histone acetylation
				i. Histone acetylation loosens DNA binding
				ii. Acetyltransferases may be associated with transcription factors
	Transcription initiation is controlled by proteins that interact with DNA and with each 
	other
		18. Describe the eukaryotic processing of pre-mRNA.
			a. 5'-cap and poly(A) tail added
			b. Introns removed
		19. Define control elements and explain how they influence transcription.
			a. Noncoding sequences
			b. Regulate by binding transcription factors
		20. Explain the potential role that promoters, enhancers, activators, and repressors play 
		in transcriptional control.
			a. Promoters
				i. RNA polymerase binding sites; transcription initiation sites 
				ii. Depends on previous binding of transcription factors
			b. Enhancers
				i. Distant (distal) control elements
				ii. DNA folds so their bound transcription factors contact initiation 
				complex
			c. Activators
				i. Transcription factors bound to enhancers
				ii. DNA folding brings them to the transcription complex
			d. Repressors
				i. Proteins that block transcription 
				ii. Bind to silencer control elements
		21. Describe the two basic structural domains of transcription factors.
			a. Sequence-specific DNA binding domain
			b. Protein-binding domain(s) to interact with other transcription factors and RNA 
			polymerase
		22. Explain how eukaryotic genes can be coordinately expressed and give some 
		examples of coordinate gene expression in eukaryotes.
			a. Some operons (gene clusters giving a single transcript) in eukaryotic cells
			b. Coordinately controlled genes have the same combination of control elements
				i. Steroid receptor in a transcriptional activator
				ii. Signal-transduction pathways can activate common activators
	Posttranscriptional mechanisms play supporting roles in the control of gene 
	expression
		23. Describe the process of alternative splicing.
			a. Different mRNAs are produced from the same pre-mRNA
			b. Controlling regulatory proteins bind to pre-mRNA
		24. Describe factors that influence the lifetime of mRNA in the cytoplasm. Compare the 
		longevity of mRNA in prokaryotes and eukaryotes.
			a. Breakdown
				i. Shortening of the poly(A) tail
				ii. Removal of the 5' cap
				iii. Degradation by nuclease
			b. Lifetime
				i. Prokaryote: very short
				ii. Eukaryotes: some very long
		25. Explain how gene expression may be controlled at the translational and post-
		translational level.
			a. Translational level
				i. Initiation can be blocked
				ii. Regulatory proteins may bind to the 5' leader
				iii. Global controls can block all translation
				iv. mRNAs may be stored 
			b. Post-translational level
				i. Processing may be required for functionality
				ii. Protein must be routed to its functional location
				iii. Proteins may be tagged for destruction in proteasomes with ubiquitin 

THE MOLECULAR BIOLOGY OF CANCER
	Introduction
	Cancer results from genetic changes that affect the cell cycle
		26. Distinguish between proto-oncogenes and oncogenes. Describe three genetic 
		changes that can convert proto-oncogenes to oncogenes.
			a. Distinction
				i. Oncogenes: cancer causing genes discovered in retroviruses
				ii. Homologous normal genes are proto-oncogenes
			b. Proto-oncogene  oncogene
				i. Transposition to another regulatory context
				ii. Amplification (really duplication)
				iii. Point mutation in structural sequence
				iv. Result: increase or decrease amount or activity
		27. Explain how mutations in tumor-suppressor genes can contribute to cancer.
			a. Tumor-suppressor genes make proteins that inhibit cell division
			b. Mutation might eliminate inhibitory activity
				i. Loss of DNA-repair ability
				ii. Loss of ability to adhere
				iii. Loss of cell cycle control
	Oncogene proteins and faulty tumor-suppressor proteins interfere with normal 
	signaling pathways
		28. Explain how excessive cell division can result from mutations in the ras oncogenes.
			a. Normal function of Ras proto-oncogene
				i. Growth factor binds to tyrosine-kinase linked receptor
				ii. Activates G protein
				iii. Activates Ras protein 
				iv. Activates a series of protein kinases
				v. Causes expression of cell cycle stimulating protein
			b. Mutation in ras
				i. May not need G protein stimulation; activates kinases on its own
				ii. Ras may be hyperactive or more long-lasting 
		29. Explain why a mutation knocking out the p53 gene can lead to excessive cell growth 
		and cancer. Describe three ways that p53 prevents a cell from passing on mutations 
		caused by DNA damage.
			a. Normal function of p53 proto-oncogene
				i. Growth-inhibiting factor binds to receptor
				ii. Activates G protein
				iii. Activates a series of kinases
				iv. Activates p53, an activating transcription factor
				v. Turns on a gene making an inhibitory protein
			b. Mutation in p53
				i. Cannot activate gene expression
				ii. Inhibitory protein not expressed
			c. Other protective functions of p53
				i. Activates p21; slows cell cycle after DNA damage, allows time for 
				repair
				ii. Turns on DNA repair genes
				iii. Triggers apoptosis in cells with irreparable damage
	Multiple mutations underlie the development of cancer
		30. Describe the set of genetic factors typically associated with the development of 
		cancer.
			a. Activation of one (dominant) oncogene
			b. Inactivation of both alleles of (recessive) tumor-suppressor genes
			c. Activation of telomerase
		31. Explain how viruses can cause cancer. Describe several examples.
			a. Integrate their DNA into host cell chromosomes
			b. Causes mutation
			c. Can deliver or amplify oncogenes
		32. Explain how inherited cancer alleles can lead to a predisposition to certain cancers.
			a. Defective DNA repair genes; recessive, one good gene protects
			b. Inactive tumor-suppressor alleles; recessive, one good gene suppresses