Eukaryotic Genomes: Organization, Regulation, and
Evolution
Chapter 19 Eukaryotic Genomes: Organization, Regulation, and
Evolution 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 Both prokaryotes and eukaryotes
Must alter their patterns of gene expression in response to changes
in environmental conditions 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 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 (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 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 (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 (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 In interphase cells Most
chromatin is in the highly extended form called euchromatin 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
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 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
Regulation of Chromatin Structure
Genes within highly packed heterochromatin Are usually not
expressed (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
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 Addition of methyl groups
to certain bases in DNA
DNA Methylation Addition of methyl groups to certain basesin DNA Is
associated with reduced transcription in some species Epigenetic
Inheritance
Is the inheritance of traits transmitted by mechanisms not directly
involving the nucleotide sequence 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 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 The Roles of Transcription
Factors
To initiate transcription Eukaryotic RNA polymerase requires the
assistance of proteins called transcription factors 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 inan intron 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
Some specific transcription factors function as repressors
To inhibit expression of a particular gene Some activators and
repressors Act indirectly by influencing chromatin structure
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 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
Mechanisms of Post-Transcriptional Regulation
An increasing number of examples Are being found of regulatory
mechanisms that operate at various stages after transcription 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 The
life span of mRNA molecules in the cytoplasm
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 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 Initiation of Translation
The initiation of translation of selectedmRNAs Can be blocked by
regulatory proteins that bind to specific sequences or structures
of the mRNA Alternatively, translation of all the mRNAsin a cell
May be regulated simultaneously 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 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 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 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 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 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 Tumor-Suppressor Genes
Encode proteins that inhibit abnormal cell division Interference
with Normal Cell-Signaling Pathways
Many proto-oncogenes and tumor suppressor genes Encode components
of growth-stimulating and growth-inhibiting pathways, respectively
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 1Growth
factor Figure 19.12a (a) Cell cyclestimulating pathway. This
pathway is triggered by a growth factor that binds toits 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 toa series of protein kinases. The last
kinase activatesa 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 (b) Cell
cycleinhibiting pathway. In this
The p53 gene encodes a tumor-suppressor protein That is a specific
transcription factor that promotes the synthesis of cell
cycleinhibiting 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 viaprotein kinases and leads to activation
ofp53. 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 cycleinhibiting
pathway. In this 1 3 2 Protein kinases 2 3 Active form of p53 DNA
damage in genome 1 Figure 19.12b 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 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 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)
1Loss of tumor- suppressor gene APC (or other) 4Loss of
tumor-suppressor gene p53 2Activation of ras oncogene 3Loss of
tumor- suppressor gene DCC 5Additional mutations Figure 19.13
Certain viruses Promote cancer by integration of viral DNA into a
cells genome Inherited Predisposition to Cancer
Individuals who inherit a mutant oncogene or tumor-suppressor
allele Have an increased risk of developing certain types of cancer
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 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 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 Transposable Elements and Related
Sequences
The first evidence for wandering DNA segments Came from geneticist
Barbara McClintocks breeding experiments with Indian corn Figure
19.15 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
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 elementrelated DNA
consists of a family of similar sequences called Alu elements 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 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 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 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 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
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 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 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 Subsequent duplications of these genes and random
mutations
Gave rise to the present globin genes, all of which code for
oxygen-binding proteins The similarity in the amino acid sequences
of the various globin proteins
Supports this model of gene duplication and mutation Table 19.1
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 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 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 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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