Eukaryotic Genomes: Organization, Regulation, and Evolution: Powerpoint Lectures For

Chapter 19
Eukaryotic Genomes:
Organization, Regulation, and
Evolution
PowerPoint Lectures for
Biology, Seventh Edition
Neil Campbell and Jane Reece
Lectures by Chris Romero

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
• 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

• 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

• 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
DNA double helix
His- Histone
tones tails
Histone H1 10 nm
Linker DNA Nucleosome

(“string”) (“bad”)
(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
30 nm
Nucleosome
(b) 30-nm fiber
Figure 19.2 b

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

• 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

• 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 Signal
NUCLEUS
Chromatin
Chromatin modification:
DNA unpacking involving
histone acetylation and
DNA demethlation
DNA
Gene available
for transcription
Gene
Transcription
RNA Exon
Primary transcript
Intron
RNA processing
Tail
Cap mRNA in nucleus
Transport to cytoplasm
CYTOPLASM
mRNA in cytoplasm
Degradation
of mRNA
Translation
Polypetide
Cleavage
Chemical modification
Transport to cellular
destination
Active protein
Degradation of protein
Degraded protein
Figure 19.3
Regulation of Chromatin Structure
• Genes within highly packed heterochromatin
– Are usually not expressed

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

• Histone acetylation
– Seems to loosen chromatin structure and
thereby enhance transcription
Unacetylated histones Acetylated histones
(b) Acetylation of histone tails promotes loose chromatin structure that

Figure 19.4 b permits transcription

DNA Methylation
• Addition of methyl groups to certain bases
in DNA
– Is associated with reduced transcription in
some species

Epigenetic Inheritance
• 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 Proximal Poly-A signal Termination
(distal control elements) control elements sequence region
Exon Intron Exon Intron Exon

DNA
Upstream Downstream
Promoter Transcription Poly-A
signal
Primary RNA Exon Intron Exon Intron Exon Cleared 3′ end
transcript 5′ of primary
Chromatin changes
(pre-mRNA) transport
RNA processing:
Transcription Cap and tail added;
introns excised and
Intron RNA exons spliced together
RNA processing
mRNA Translation Coding segment

degradation
Protein processing
and degradation mRNA G P P P
5′ Cap 5′ UTR Start Stop 3′ UTR Poly-A

codon codon (untranslated tail
(untranslated
Figure 19.5 region) region)

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 in
an intron

• An activator
– Is a protein that binds to an enhancer and
stimulates transcription of a gene
Distal control
element Promoter
Activators
Gene
Enhancer TATA
box General
1 Activator proteins bind
to distal control elements transcription
grouped as an enhancer in factors
the DNA. This enhancer has DNA-bending
three binding sites. protein
2 A DNA-bending protein Group of
brings the bound activators Mediator proteins
closer to the promoter.
Other transcription factors, RNA
mediator proteins, and RNA Polymerase II
polymerase are nearby.
Chromatin changes
3 The activators bind to Transcription

certain general transcription
factors and mediator RNA processing
RNA
proteins, helping them form mRNA Translation Polymerase II
an active transcription degradation
Protein processing
initiation complex on the promoter. and degradation
Transcription RNA synthesis

Figure 19.6 Initiation complex
• 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 Albumin
elements gene
Crystallin
gene
Liver cell Lens cell
nucleus nucleus
Available Available
activators activators
Albumin
Albumin gene not
gene expressed
expressed
Crystallin gene Crystallin gene

not expressed expressed
Figure 19.7a, b (a) Liver cell (b) Lens cell
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 Translation
degradation
Protein processing
and degradation
Exons
DNA
Primary
RNA
transcript
RNA splicing or
Figure 19.8 mRNA

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

• RNA interference by single-stranded microRNAs
(miRNAs)
– Can lead to degradation of an mRNA or block its
translation
1 The micro- 3 One strand of 4 The bound
2 An enzyme
2 5 The miRNA-protein
5
RNA (miRNA) called Dicer moves each short double- miRNA can base-pair complex prevents gene
precursor folds along the double- stranded RNA is with any target expression either by
back on itself, stranded RNA, degraded; the other mRNA that contains degrading the target
held together cutting it into strand (miRNA) then the complementary mRNA or by blocking
by hydrogen shorter segments. associates with a sequence. its translation.
bonds. complex of proteins.
Chromatin changes
Transcription
RNA processing
mRNA Translation
degradation
Protein Protein processing

and degradation
complex
Dicer
Degradation of mRNA
OR
miRNA
Target mRNA
Hydrogen Blockage of translation

Figure 19.9 bond

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

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
3 Enzymatic components of the
2 The ubiquitin-tagged protein proteasome cut the protein into
1 Multiple ubiquitin mol- is recognized by a proteasome, small peptides, which can be
ecules are attached to a protein which unfolds the protein and further degraded by other
by enzymes in the cytosol. sequesters it within a central cavity. enzymes in the cytosol.
Chromatin changes
Transcription
RNA processing
Ubiquitin Proteasome
Translation
mRNA
degradation and ubiquitin
to be recycled
Protein processing Proteasome
and degradation
Protein to Ubiquinated Protein

be degraded protein fragments
(peptides)
Protein entering a
proteasome
Figure 19.10
• 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
• 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: Point mutation

Point mutation
gene moved to new locus, Gene amplification: within a control
within the gene
under new controls multiple copies of the gene element
New Oncogene Oncogene

promoter
Normal growth-stimulating Normal growth-stimulating Normal growth-stimulating Hyperactive or

protein in excess protein in excess protein in excess degradation-
resistant protein
Figure 19.11
Tumor-Suppressor Genes
• 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
1 Growth
MUTATION
factor
Hyperactive
Ras
Ras protein
GTP (product of
3 G protein oncogene)
(a) Cell cycle–stimulating pathway. issues signals
This pathway is triggered by 1 a growth Ras on its own
P
factor that binds to 2 its receptor in the P
P P GTP
plasma membrane. The signal is relayed to 3 P P
a G protein called Ras. Like all G proteins, Ras
is active when GTP is bound to it. Ras passes
the signal to 4 a series of protein kinases. 4 Protein kinases
The last kinase activates 5 a transcription
2 Receptor (phosphorylation
activator that turns on one or more genes cascade)
for proteins that stimulate the cell cycle. If a
NUCLEUS
mutation makes Ras or any other pathway
component abnormally active, excessive cell 5 Transcription
division and cancer may result. factor (activator)
DNA
Gene expression
Protein that
stimulates
the cell cycle
Figure 19.12a
• The p53 gene encodes a tumor-suppressor
protein
– That is a specific transcription factor that
promotes the synthesis of cell cycle–inhibiting
proteins
(b) Cell cycle–inhibiting pathway. In this
pathway, 1 DNA damage is an intracellular
signal that is passed via 2 protein kinases
and leads to activation of 3 p53. Activated 2 Protein kinases MUTATION
p53 promotes transcription of the gene for a
Defective or
protein that inhibits the cell cycle. The
missing
resulting suppression of cell division ensures
transcription
that the damaged DNA is not replicated.
factor, such as
Mutations causing deficiencies in any
UV p53, cannot
pathway component can contribute to the 3 Active
light activate
development of cancer. form transcription
of p53
1 DNA damage
DNA
in genome
Protein that
inhibits
the cell cycle
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
EFFECTS OF MUTATIONS
cancer, can result if the cell cycle is
overstimulated, as in (a), or not Protein
Protein absent
inhibited when it normally would be, overexpressed
as in (b).
Cell cycle Increased cell Cell cycle not

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

• Certain viruses
– Promote cancer by integration of viral DNA into
a cell’s 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

• 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 Introns and
transposable regulatory
elements sequences
and related (24%)
sequences
(44%)
Unique
noncoding
Repetitive DNA (15%)
DNA
unrelated to
transposable
elements
Alu elements
(about 15%)
(10%)
Simple sequence
Large-segment
Figure 19.14 DNA (3%)
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
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
New copy of
Transposon transposon
DNA of genome
Transposon
is copied Insertion
Mobile transposon
(a) Transposon movement (“copy-and-paste” mechanism)
New copy of
Retrotransposon retrotransposon
DNA of genome
RNA
Reverse Insertion
transcriptase
Figure 19.16a, b (b) Retrotransposon movement

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

Other Repetitive DNA, Including Simple Sequence DNA
• 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
DNA
18S 5.8S 28S
rRNA
5.8S
Figure 19.17a Part 28S
of the ribosomal
RNA gene family 18S

• The classic examples of multigene families of
nonidentical genes
– Are two related families of genes that encode
globins β-Globin
Heme
Hemoglobin
α-Globin
α-Globin gene family β-Globin gene family
Chromosome 16 Chromosome 11
ζ ψζ ψ ψα α2 α1 ψℑ ∈ Gγ Aγ ψβ δ β
α 21
Figure 19.17b The human

α-globin and β-globin
Fetus
gene families and adult Embryo Fetus Adult
Embryo

• 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
Transposable Gene
element
Nonsister
chromatids
Crossover
Incorrect pairing
of two homologues
during meiosis
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
Duplication of
ancestral gene
Evolutionary time
Mutation in
both copies α β
Transposition to
different chromosomes
Further duplications α β
and mutations
ζ α ∈ γ β
ζ ψ ζ ψ α ψ α α2 α1 ψ θ ∈ Gγ Aγ ψβ δ β
2 1
α-Globin gene family β -Globin gene family
Figure 19.19 on chromosome 16 on chromosome 11
• 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 EGF EGF EGF
Epidermal growth
factor gene with multiple
EGF exons (green)
Exon Exon
shuffling duplication
F F F F
Fibronectin gene with multiple
“finger” exons (orange) F EGF K K
K
Plasminogen gene with a Exon
“kfingle” exon (blue) shuffling
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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Chapter 19

Lectures by Chris Romero

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

• The association of DNA and histones

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

• Each “bead” is a nucleosome

Linker DNA Nucleosome

(b) 30-nm fiber

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Protein scaffold Loops

(c) Looped domains (300-nm fiber)

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

(d) Metaphase chromosome

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

• During development of a multicellular organism

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

• In each type of differentiated cell

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Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Figure 19.4a (a) Histone tails protrude outward from a nucleosome

Unacetylated histones Acetylated histones

(b) Acetylation of histone tails promotes loose chromatin structure that

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Exon Intron Exon Intron Exon

mRNA Translation Coding segment

5′ Cap 5′ UTR Start Stop 3′ UTR Poly-A

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

• Distal control elements, groups of which are

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3 The activators bind to Transcription

Transcription RNA synthesis

• Some activators and repressors

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Crystallin gene Crystallin gene

• The same regulatory sequences

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Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Figure 19.8 mRNA

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Protein Protein processing

Hydrogen Blockage of translation

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• Alternatively, translation of all the mRNAs

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Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Protein to Ubiquinated Protein

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Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Translocation or transposition: Point mutation

New Oncogene Oncogene

Normal growth-stimulating Normal growth-stimulating Normal growth-stimulating Hyperactive or

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Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

(c) Effects of mutations. Increased

Cell cycle Increased cell Cell cycle not

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