HOW GENES ARE CONTROLLED
CM Lamberty
General Biology
TOBACCO’S SMOKING GUN
Southern US major tobacco producer
 1950’s: ½ of all Americans smoked 1+ packs/day
 “health benefits”
 Rate of lung cancer increased in proportion to
tobacco use
 1990: lung cancer killing over twice as many men
as any other type of cancer
 1996: direct link b/t tobacco and cancer


BPDE from tobacco smoke binds to DNA w/ gene p53
which codes for protein that normally suppresses
tumors
HOW AND WHY GENES ARE REGULATED
Every somatic cell is produced by repeated
rounds of mitosis starting from zygote
 Each cell has same DNA as zygote
 Every somatic cell contains every gene.
 How do cells become different?
 Contol mechanisms turn on certain genes and
turn others off
 Cellular differentiation



Specialized in structure and function
Gene regulation

The turning on or off of genes
PATTERNS OF GENE EXPRESSION

In gene expression
A gene is turned on and transcribed into RNA
 Information flows from
 Genes to proteins
 Genotype to phenotype

Information flows from DNA to RNA to proteins.
The great differences among cells in an organism must
result from the selective expression of genes.


GENE REGULATION IN BACTERIA

Natural selection has favored bacteria that express


Only certain genes
Only at specific times when the products are needed by the cell
So how do bacteria selectively turn their genes on and off?
 An operon includes



A cluster of genes with related functions
The control sequences that turn the genes on or off
The bacterium E. coli used the lac operon to coordinate the
expression of genes that produce enzymes used to break
down lactose in the bacterium’s environment.
 The lac operon uses




A promoter, a control sequence where the transcription
enzyme initiates transcription
An operator, a DNA segment that acts as a switch that is
turned on or off
A repressor, which binds to the operator and physically blocks
the attachment of RNA polymerase
GENE REGULATION IN EUKARYOTIC CELLS

Eukaryotic cells have more complex gene regulating
mechanisms with many points where the process can be
regulated, as illustrated by this analogy to a water
supply system with many control valves along the way.
Chromosome
Unpacking
of DNA
DNA
Gene
Figure 11.3-1
Chromosome
Unpacking
of DNA
DNA
Gene
Transcription
of gene
Intron Exon
RNA transcript
Figure 11.3-2
Chromosome
Unpacking
of DNA
DNA
Gene
Transcription
of gene
Intron Exon
Processing
of RNA
RNA transcript
Flow of mRNA
through nuclearCap
Tail
mRNA in nucleus
envelope
mRNA in cytoplasm
Nucleus
Cytoplasm
Figure 11.3-3
Chromosome
Unpacking
of DNA
DNA
Gene
Transcription
of gene
Intron Exon
Processing
of RNA
RNA transcript
Flow of mRNA
through nuclearCap
Tail
mRNA in nucleus
envelope
mRNA in cytoplasm
Nucleus
Cytoplasm
Breakdown
of mRNA
Figure 11.3-4
Chromosome
Unpacking
of DNA
DNA
Gene
Transcription
of gene
Intron Exon
Processing
of RNA
RNA transcript
Flow of mRNA
through nuclearCap
Tail
mRNA in nucleus
envelope
mRNA in cytoplasm
Nucleus
Cytoplasm
Breakdown
of mRNA
Translation
of mRNA
Polypeptide
Figure 11.3-5
Chromosome
Unpacking
of DNA
DNA
Gene
Transcription
of gene
Intron Exon
RNA transcript
Processing
of RNA
Flow of mRNA
through nuclearCap
Tail
mRNA in nucleus
envelope
mRNA in cytoplasm
Nucleus
Cytoplasm
Breakdown
of mRNA
Translation
of mRNA
Polypeptide
Various changes
to polypeptide
Active protein
Figure 11.3-6
Chromosome
Unpacking
of DNA
DNA
Gene
Transcription
of gene
Intron Exon
RNA transcript
Processing
of RNA
Flow of mRNA
through nuclearCap
Tail
mRNA in nucleus
envelope
mRNA in cytoplasm
Nucleus
Cytoplasm
Breakdown
of mRNA
Translation
of mRNA
Polypeptide
Various changes
to polypeptide
Active protein
Breakdown
of protein
Figure 11.3-7
GENE REGULATION IN EUKARYOTIC CELLS
The Regulation of DNA packing
 Cells may use DNA packing for long-term
inactivation of genes


X chromosome inactivation
Occurs in female mammals
 Is when one of the two X chromosomes in each cell is
inactivated at random

All of the descendants will have the same X
chromosome turned off.
 If a female cat is heterozygous for a gene on the X
chromosome

About half her cells will express one allele
 The others will express the alternate allele

Two cell populations
in adult cat:
Early embryo:
X chromosomes
Allele for
orange fur
Active X
Inactive X
Cell division
and X chromosome
inactivation
Allele for
black fur
Inactive X
Active X
Orange
fur
Black
fur
Figure 11.4
GENE REGULATION IN EUKARYOTIC CELLS

The Initiation of Transcription


The initiation of transcription is the most important
stage for regulating gene expression.
In prokaryotes and eukaryotes, regulatory proteins
Bind to DNA
 Turn the transcription of genes on and off


Unlike prokaryotic genes, transcription in eukaryotes is
complex, involving many proteins, called transcription
factors, that bind to DNA sequences called enhancers.
 Repressor proteins called silencers
Bind to DNA
 Inhibit the start of transcription


Activators are
More typically used by eukaryotes
 Turn genes on by binding to DNA

Enhancers (DNA control sequences)
RNA polymerase
Bend in
the DNA
Transcription Promoter
factor
Gene
Transcription
Figure 11.5
GENE REGULATION IN EUKARYOTIC CELLS

RNA Processing and Breakdown

The eukaryotic cell



RNA processing includes the





Addition of a cap and tail to the RNA
Removal of any introns
Splicing together of the remaining exons
In alternative RNA splicing, exons may be spliced together in
different combinations, producing more than one type of
polypeptide from a single gene.
Eukaryotic mRNAs



Localizes transcription in the nucleus
Processes RNA in the nucleus
Can last for hours to weeks to months
Are all eventually broken down and their parts recycled
Small single-stranded RNA molecules, called microRNAs
(miRNAs), bind to complementary sequences on mRNA
molecules in the cytoplasm, and some trigger the breakdown of
their target mRNA.
Exons
DNA
1
2
3
4
5
Figure 11.6-1
Exons
1
DNA
RNA
transcript
1
2
2
4
3
3
4
5
5
Figure 11.6-2
Exons
1
DNA
RNA
transcript
2
RNA splicing
mRNA
1
2
3
5
4
3
2
1
4
3
5
or
5
1
2
4
Figure 11.6-3
5
GENE REGULATION IN EUKARYOTIC CELLS

The Initiation of Translation
 The
process of translation offers additional opportunities for
regulation.

Protein Activation and Breakdown

Post-translational control mechanism
Occur after translation
 Often involve cutting polypeptides into smaller, active final
products


The selective breakdown of proteins is another control
mechanism operating after translation.
CELL SIGNALING
In a multicellular organism, gene regulation can
cross cell boundaries.
 A cell can produce and secrete chemicals, such as
hormones, that affect gene regulation in another cell.


Homeotic Genes
SIGNALING CELL
Secretion
Signal molecule
Plasma membrane
TARGET
CELL
Nucleus
Figure 11.8-1
SIGNALING CELL
Secretion
Signal molecule
Plasma membrane
Reception
Receptor protein
TARGET
CELL
Nucleus
Figure 11.8-2
SIGNALING CELL
Secretion
Signal molecule
Plasma membrane
Reception
Receptor protein
TARGET
CELL
Signal transduction
pathway
Nucleus
Figure 11.8-3
SIGNALING CELL
Secretion
Signal molecule
Plasma membrane
Reception
Receptor protein
TARGET
CELL
Signal transduction
pathway
Transcription factor
(activated)
Nucleus
Figure 11.8-4
SIGNALING CELL
Secretion
Signal molecule
Plasma membrane
Reception
Receptor protein
TARGET
CELL
Signal transduction
pathway
Transcription factor
(activated)
Nucleus
Transcription
Response
mRNA
Figure 11.8-5
SIGNALING CELL
Secretion
Signal molecule
Plasma membrane
Reception
Receptor protein
TARGET
CELL
Signal transduction
pathway
Transcription factor
(activated)
Nucleus
Transcription
Response
mRNA
New protein
Translation
Figure 11.8-6
HOMEOTIC GENES
Master control genes that regulate groups of
other genes that determine what body parts will
develop in which locations
 Mutations can produce bizarre effects


Similar homeotic genes help direct embryonic
development in nearly every eukaryotic organism.
DNA MICROARRAYS
A DNA microarray allows visualization of gene
expression.
 The pattern of glowing spots enables the researcher
to determine which genes were being transcribed in
the starting cells.
 Researchers can thus learn which genes are active in
different tissues or in tissues from individuals in
different states of health.

mRNA
isolated
Figure 11.11-1
mRNA
isolated
cDNA made
from mRNA
Reverse transcriptase and fluorescently
labeled DNA nucleotides
Fluorescent cDNA
Figure 11.11-2
mRNA
isolated
cDNA made
from mRNA
cDNA mixture
added to wells
Reverse transcriptase and fluorescently
labeled DNA nucleotides
Fluorescent cDNA
DNA microarray
Figure 11.11-3
mRNA
isolated
Reverse transcriptase and fluorescently
labeled DNA nucleotides
cDNA made
from mRNA
cDNA mixture
added to wells
Unbound cDNA
rinsed away
Fluorescent cDNA
DNA microarray
Nonfluorescent
spot
Fluorescent
spot
Fluorescent
cDNA
DNA microarray
(6,400 genes)
DNA of an
DNA of an
expressed gene unexpressed gene
Figure 11.11-4
CLONING PLANTS AND ANIMALS

The Genetic Potential of Cells

Differentiated cells
All contain a complete genome
 Have the potential to express all of an organism’s genes

Differentiated plant cells can develop into a whole new
organism.
 The somatic cells of a single plant can be used to
produce hundreds of thousands of clones.
 Plant cloning

Demonstrates that cell differentiation in plants does not
cause irreversible changes in the DNA
 Is now used extensively in agriculture

THE GENETIC POTENTIAL OF CELLS

Regeneration
Is the regrowth of lost body parts
 Occurs, for example, in the regrowth of the legs of
salamanders

REPRODUCTIVE CLONING OF ANIMALS
Nuclear transplantation
 Involves replacing nuclei egg cells with
nuclei from differentiated cells
 Has been used to clone a variety of
animals


In 1997, Scottish researchers produced
Dolly, a sheep, by replacing the nucleus of
an egg cell with the nucleus of an adult
somatic cell in a procedure called
reproductive cloning, because it results in
the birth of a new animal.
PRACTICAL APPLICATIONS OF
REPRODUCTIVE CLONING

Other mammals have since been produced using
this technique including
Farm animals
 Control animals for experiments
 Rare animals in danger of extinction

HUMAN CLONING

Cloning of animals
Has heightened speculation about human cloning
 Is very difficult and inefficient.


Critics raise practical and ethical objections to
human cloning
THERAPEUTIC CLONING AND STEM CELLS


The purpose of therapeutic cloning is not to produce
viable organisms but to produce embryonic stem cells
Embryonic stem cells (ES cells)
Are derived from blastocyst
 Can give rise to specific types of differentiated cells


Adult Stem Cells
Are cells in adult tissue
 Generate replacements for nondividing differentiated cells


Embryonic vs. Adult Stem cells
Adult cells are partway along the road to differentiation
 Usually give rise to only a few related types of specialized
cells.

UMBILICAL CORD BLOOD BANKING

Umbilical Cord Blood
Can be collected at birth
 Contains partially differentiated stem cells
 Has had limited success in the treatment of a few
diseases

American Association of Pediatrics recommends cord
blood banking only for babies born into a family with
know genetic risk
THE GENETIC BASIS OF CANCER



In recent years, scientists have learned more about
genetics of cancer
As early as 1911, certain viruses were known to cause
cancer
Oncogenes are
Genes that cause cancer
 Found in viruses


Proto-oncogenes
Normal genes w/ potential to become oncogenes
 Found in many animals
 Often genes that code for growth factors, proteins that
stimulate cell division


For a proto-oncogene to become an oncogene, a
mutation must occur in the cell’s DNA
THE GENETIC BASIS OF CANCER

Tumor-suppressor genes
Inhibit cell division
 Prevent uncontrolled cell growth
 May be mutated and contribute to cancer

THE PROGRESSION OF A CANCER
Over 150,000 Americans will be stricken by
cancer of the colon or rectum this year
 Colon cancer

Spreads gradually
 Is produced by more than one mutation

THE PROGRESSION OF A CANCER

The development of a malignant tumor is
accompanied by a gradual accumulation of
mutations that
Convert proto-oncogenes to oncogenes
 Knock out tumor-suppressor genes

“INHERITED” CANCER
Most mutations that lead to cancer arise in the
organ where the cancer starts
 In familial or inherited cancer

A cancer-causing mutation occurs in a cell that gives
rise to gametes
 The mutation is passes on from generation to
generation


Breast cancer
Is usually not associated with inherited mutations
 In some families can be caused by inherited, BRCA1
cancer genes

CANCER RISK AND PREVENTION

Cancer
Is one of the leading causes of death in US
 Can be caused by carcinogens, cancer-causing agents
found in the environment, including

Tobacco products
 Alcohol
 Exposure to ultraviolet light from the sun.


Exposure to carcinogens
Is often an individual choice
 Can be avoided


Some studies suggest that certain substances in
fruits and vegetables may help protect against a
variety of cancers
EVOLUTION CONNECTION:
THE EVOLUTION OF CANCER IN THE BODY
Evolution drives the growth of a
tumor
 Like individuals in a population of
organisms, cancer cells in the body

Have the potential to produced more
offspring than can be supported by
the environment
 Show individual variation which

Affects survival and reproduction
 Can be passed on to the next generation
of cells
