Chapter 25: Molecular Basis of Inheritance

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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 sugar-phosphate
  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 rapidly-dividing 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 single-stranded
  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
• Chain initiation
• Chain elongation
• 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 tRNA-amino 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 stop-codon
  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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(No Transcript)
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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
• The organization of the chromatin, and
• 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 sickle-cell
  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 patients 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 tumor-suppressor
  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 tumor-suppressor 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.