Download Chapter 25: Molecular Basis of Inheritance

Chapter 25: Molecular Basis
of Inheritance
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DNA Structure and Replication
In the mid-1900s, scientists knew that
chromosomes, made up of DNA
(deoxyribonucleic acid) and proteins,
contained genetic information.
However, they did not know whether the
DNA or the proteins was the actual
genetic material.
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Various reseachers showed that DNA
was the genetic material when they
performed an experiment with a T2
virus.
By using different radioactively labeled
components, they demonstrated that
only the virus DNA entered a bacterium
to take over the cell and produce new
viruses.
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Viral DNA is labeled
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Viral capsid is labeled
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Structure of DNA
The structure of DNA was determined by
James Watson and Francis Crick in the
early 1950s.
DNA is a polynucleotide; nucleotides are
composed of a phosphate, a sugar, and
a nitrogen-containing base.
DNA has the sugar deoxyribose and four
different bases: adenine (A), thymine
(T), guanine (G), and cytosine (C).
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One pair of bases
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Watson and Crick showed that DNA is a
double helix in which A is paired with T
and G is paired with C.
This is called complementary base pairing
because a purine is always paired with a
pyrimidine.
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When the DNA double helix unwinds, it
resembles a ladder.
The sides of the ladder are the sugarphosphate backbones, and the rungs of
the ladder are the complementary
paired bases.
The two DNA strands are anti-parallel –
they run in opposite directions.
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DNA double helix
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Replication of DNA
DNA replication occurs during
chromosome duplication; an exact copy
of the DNA is produced with the aid of
DNA polymerase.
Hydrogen bonds between bases break
and enzymes “unzip” the molecule.
Each old strand of nucleotides serves as
a template for each new strand.
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New nucleotides move into
complementary positions are joined by
DNA polymerase.
The process is semiconservative
because each new double helix is
composed of an old strand of
nucleotides from the parent molecule
and one newly-formed strand.
Some cancer treatments are aimed at
stopping DNA replication in rapidlydividing cancer cells.
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Overview of DNA replication
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Ladder configuration and DNA
replication
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Gene Expression
A gene is a segment of DNA that specifies
the amino acid sequence of a protein.
Gene expression occurs when gene
activity leads to a protein product in the
cell.
A gene does not directly control protein
synthesis; instead, it passes its genetic
information on to RNA, which is more
directly involved in protein synthesis.
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RNA
RNA (ribonucleic acid) is a singlestranded nucleic acid in which A pairs
with U (uracil) while G pairs with C.
Three types of RNA are involved in gene
expression: messenger RNA (mRNA)
carries genetic information to the
ribosomes, ribosomal RNA (rRNA) is
found in the ribosomes, and transfer
RNA (tRNA) transfers amino acids to
the ribosomes, where the protein
product is synthesized.
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Structure of RNA
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Two processes are involved in the
synthesis of proteins in the cell:
Transcription makes an RNA molecule
complementary to a portion of DNA.
Translation occurs when the sequence of
bases of mRNA directs the sequence of
amino acids in a polypeptide.
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The Genetic Code
DNA specifies the synthesis of proteins
because it contains a triplet code: every
three bases stand for one amino acid.
Each three-letter unit of an mRNA
molecule is called a codon.
Most amino acids have more than one
codon; there are 20 amino acids with a
possible 64 different triplets.
The code is nearly universal among living
organisms.
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Messenger RNA codons
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Central Concept
The central concept of genetics involves
the DNA-to-protein sequence involving
transcription and translation.
DNA has a sequence of bases that is
transcribed into a sequence of bases in
mRNA.
Every three bases is a codon that stands
for a particular amino acid.
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Overview of gene expression
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Transcription
During transcription in the nucleus, a
segment of DNA unwinds and unzips,
and the DNA serves as a template for
mRNA formation.
RNA polymerase joins the RNA
nucleotides so that the codons in
mRNA are complementary to the triplet
code in DNA.
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Transcription and mRNA synthesis
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Processing of mRNA
DNA contains exons and introns.
Before mRNA leaves the nucleus, it is
processed and the introns are excised
so that only the exons are expressed.
The splicing of mRNA is done by
ribozymes, organic catalysts composed
of RNA, not protein.
Primary mRNA is processed into mature
mRNA.
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Function of introns
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Translation
Translation is the second step by which
gene expression leads to protein
synthesis.
During translation, the sequence of
codons in mRNA specifies the order of
amino acids in a protein.
Translation requires several enzymes
and two other types of RNA: transfer
RNA and ribosomal RNA.
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Transfer RNA
During translation, transfer RNA (tRNA)
molecules attach to their own particular
amino acid and travel to a ribosome.
Through complementary base pairing
between anticodons of tRNA and
codons of mRNA, the sequence of
tRNAs and their amino acids form the
sequence of the polypeptide.
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Transfer RNA: amino acid carrier
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Ribosomal RNA
Ribosomal RNA, also called structural
RNA, is made in the nucleolus.
Proteins made in the cytoplasm move
into the nucleus and join with
ribosomal RNA to form the subunits of
ribosomes.
A large subunit and small subunit of a
ribosome leave the nucleus and join in
the cytoplasm to form a ribosome just
prior to protein synthesis.
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A ribosome has a binding site for mRNA
as well as binding sites for two tRNA
molecules at a time.
As the ribosome moves down the mRNA
molecule, new tRNAs arrive, and a
polypeptide forms and grows longer.
Translation terminates once the
polypeptide is fully formed; the
ribosome separates into two subunits
and falls off the mRNA.
Several ribosomes may attach and
translate the same mRNA, therefore the
name polyribosome.
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Polyribosome structure and
function
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Translation Requires Three
Steps
During translation, the codons of an
mRNA base-pair with tRNA
anticodons.
Protein translation requires these steps:
1) Chain initiation
2) Chain elongation
3) Chain termination.
Enzymes are required for each step, and
the first two steps require energy.
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Chain Initiation
During chain initiation, a small ribosomal
subunit, the mRNA, an initiator tRNA,
and a large ribosomal unit bind
together.
First, a small ribosomal subunit attaches
to the mRNA near the start codon.
The anticodon of tRNA, called the
initiator RNA, pairs with this codon.
Then the large ribosomal subunit joins.
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Initiation
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Chain Elongation
During chain elongation, the initiator
tRNA passes its amino acid to a tRNAamino acid complex that has come to
the second binding site.
The ribosome moves forward and the
tRNA at the second binding site is now
at the first site, a sequence called
translocation.
The previous tRNA leaves the ribosome
and picks up another amino acid before
returning.
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Elongation
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Chain Termination
Chain termination occurs when a stopcodon sequence is reached.
The polypeptide is enzymatically cleaved
from the last tRNA by a release factor,
and the ribosome falls away from the
mRNA molecule.
A newly synthesized polypeptide may
function along or become part of a
protein.
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Termination
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Review of Gene Expression
DNA in the nucleus contains a triplet
code; each group of three bases stands
for one amino acid.
During transcription, an mRNA copy of
the DNA template is made.
The mRNA is processed before leaving
the nucleus.
The mRNA joins with a ribosome, where
tRNA carries the amino acids into
position during translation.
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Gene expression
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Control of Gene Expression
The lac operon model explains how one
regulator gene controls the
transcription of several structural
genes — genes that code for proteins.
The promoter is a short sequence of DNA
where RNA polymerase first attaches
when a gene is to be transcribed.
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The operator is a short sequence of DNA
where the repressor protein binds to
the operator and prevents RNA
polymerase from attaching to another
portion of DNA called the promoter.
Transcription does not occur until
lactose binds to the repressor
preventing the repressor from binding
to the operator.
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Now RNA polymerase binds to the
operator and brings about transcription
of the genes that code for enzymes
necessary to lactose metabolism.
Structural genes code for enzymes of a
metabolic pathway that are transcribed
as a unit.
A regulator gene codes for a repressor that
can bind to the operator and switch off
the operon; therefore, a regulator gene
regulates the activity of structural genes.
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The lac operon
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Control of Gene Expression in
Eukaryotes
In eukaryotes, cells differ in which genes are
being expressed.
Levels of control in eukaryotes include:
transcriptional control,
posttranscriptional control,
translational control, and
posttranslational control.
The first two methods occur in the nucleus;
the second two, in the cytoplasm.
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Eukaryotic control of gene
expression
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Transcriptional Control in
Eukaryotes
Rarely are there operons in eukaryotic
cells.
Instead, transcriptional control in
eukaryotes involves:
1) The organization of the chromatin,
and
2) Regulator proteins called
transcription factors.
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Activated Chromatin
The existence of chromosome puffs in
developing eggs of many vertebrates
suggests that DNA must decondense in
order for transcription to occur.
The chromosomes within many vertebrate
egg cells are called lampbrush
chromosomes because they have many
decondensed loops; here mRNA is
synthesized in great quantity.
This form of transcriptional control is useful
when the gene product is tRNA or rRNA.
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Lampbrush chromosomes
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Transcription Factors
Transcription factors regulate
transcription of DNA in eukaryotes.
Signals received from inside and outside
the cell turn on particular transcription
factors.
Activation probably occurs when the
transcription factors are
phosphorylated by a kinase.
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Gene Mutations
A gene mutation is a change in the
sequence of bases within a gene.
Frameshift Mutations
Frameshift mutations involve the addition
or removal of a base during the
formation of mRNA; these change the
genetic message by shifting the
“reading frame.”
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Point Mutations
The change of just one nucleotide
causing a codon change can cause the
wrong amino acid to be inserted in a
polypeptide; this is a point mutation.
In a silent mutation, the change in the
codon results in the same amino acid.
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If a codon is changed to a stop codon,
the resulting protein may be too short
to function; this is a nonsense
mutation.
If a point mutation involves the
substitution of a different amino acid,
the result may be a protein that cannot
reach its final shape; this is a missense
mutation.
An example is Hbs which causes sicklecell disease.
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Sickle-cell disease in humans
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Cause and Repair of Mutations
Mutations can be spontaneous or caused
by environmental influences called
mutagens.
Mutagens include radiation (X-rays, UV
radiation), and organic chemicals (in
cigarette smoke and pesticides).
DNA polymerase proofreads the new
strand against the old strand and detects
mismatched pairs, reducing mistakes to
one in a billion nucleotide pairs
replicated.
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Transposons: Jumping Genes
Transposons are specific DNA
sequences that move from place to
place within and between
chromosomes.
These so-called jumping genes can
cause a mutation to occur by altering
gene expression.
It is likely all organisms, including
humans, have transposons.
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Cancer: A Failure of Genetic
Control
Cancer is a genetic disorder resulting in
a tumor, an abnormal mass of cells.
Carcinogenesis, the development of
cancer, is a gradual process.
Cancer cells lack differentiation, form
tumors, undergo angiogenesis and
metastasize.
Cancer cells fail to undergo apoptosis, or
programmed cell death.
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Cancer cells
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Angiogenesis is the formation of new
blood vessels to bring additional
nutrients and oxygen to a tumor;
cancer cells stimulate angiogenesis.
Metastasis is invasion of other tissues by
establishment of tumors at new sites.
A patient’s prognosis is dependent on
the degree to which the cancer has
progressed; early diagnosis and
treatment is critical to survival.
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Origin of Cancer
Mutations in at least four classes of
genes are associated with the
development of cancer.
1) The nucleus has a DNA repair system
but mutations in genes for repair
enzymes can contribute to cancer.
2) Mutations in genes that code for
proteins regulating structure of
chromatin can promote cancer.
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3) Proto-oncogenes are normal genes
that stimulate the cell cycle and tumorsuppressor genes inhibit the cell cycle;
mutations can prevent normal
regulation of the cell cycle.
4) Telomeres are DNA segments at the
ends of chromosomes that normally
get shorter and signal an end to cell
division; cancer cells have an enzyme
that keeps telomeres long.
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Regulation of Cell Division
Proto-oncogenes are part of a
stimulatory pathway that extends from
membrane to nucleus.
Tumor-suppressor genes are part of an
inhibitory pathway extending from the
plasma membrane to the nucleus.
The balance between stimulatory signals
and inhibitory signals determines
whether proto-oncogenes or tumorsuppressor genes are active.
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Plasma membrane receptors can receive
growth stimulatory factors and growth
inhibitory factors.
Cytoplasmic proteins can therefore be
turned on or off and in turn either
stimulate or inhibit certain genes in the
nucleus.
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Oncogenes
Proto-oncogenes can undergo mutations
to become cancer-causing oncogenes.
An oncogene may code for a faulty
receptor in the stimulatory pathway.
Or an oncogene may produce either an
abnormal protein product or
abnormally high levels of a normal
protein product that stimulates the cell
cycle to begin or to go to completion;
both lead to uncontrolled growth.
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About 100 oncogenes have been
discovered that cause increased
growth and lead to tumors.
Alteration of a single nucleotide pair can
convert a normal rasK proto-oncogene
to an oncogene implicated in lung,
colon, and pancreatic cancer.
The rasN oncogene is associated with
leukemia and lymphoma.
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Tumor-Suppressor Genes
Tumor-suppressor genes ordinarily
suppress the cell cycle; when they
mutate they stop suppressing the cell
cycle and it can occur nonstop.
RB tumor-suppressor gene malfunctions
are implicated in cancers of the breast,
prostate, bladder, and small-cell lung
carcinoma.
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Another major tumor-suppressor gene is
p53, a gene that is more frequently
mutated in human cancers than any
other known gene.
The p53 protein acts as a transcription
factor and as such is involved in
turning on the expression of genes
whose products are cell cycle
inhibitors.
P53 can also stimulate apoptosis.
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Causes of cancer
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Chapter Summary
Since DNA is the genetic material, its
structure and functions constitute the
molecular basis of inheritance.
Because the DNA molecule is able to
replicate, genetic information can be
passed from one cell generation to the
next.
DNA codes for the synthesis of proteins;
this process also involves RNA.
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In prokaryotes, regulator genes control
the activity and expression of other
genes.
In eukaryotes, the control of gene
expression occurs at all stages, from
transcription to the activity of proteins.
Gene mutations vary; some have little
effect but some have a dramatic effect.
Loss of genetic control over genes
involved in cell growth and/or cell
division cause cancer.
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