Download Human Genetics

Biology Today (BIOL 109)
Talk Five:
Human Genetics
Chapters 18 & 19
The structure of DNA
• Composed of 4 nucleotide
bases, 5 carbon sugar and
phosphate.
• Base pair = rungs of a
ladder.
• Edges = sugar-phosphate
backbone.
• Double Helix
• Anti-Parallel
The structure
of DNA
Figure 2.21
DNA
Replication
Figure
2.22a
Remember – the two strands run
in opposite directions
Synthesis of a new (daughter)
strand occurs in the opposite
direction of the old (parental)
strand.
Complementary base-pairing
occurs
A with T and G with C
G and C have three hydrogen
bonds
A and T have two hydrogen
bonds
DNA Replication
• Each new double helix is composed of an old
(parental) strand and a new (daughter)
strand.
• As each strand acts as a template, process is
called Semi-conservative Replication.
• Replication errors can occur. Cell has repair
enzymes that usually fix problem. An error
that persists is a mutation.
• This is permanent, and alters the
phenotype.
The structure of RNA
• Formed from 4
nucleotides, 5 carbon
sugar, phosphate.
• Uracil is used in RNA.
– It replaces Thymine
• The 5 carbon sugar has
an extra oxygen.
• RNA is single stranded.
Central Dogma of Molecular Biology
• DNA holds the code
• DNA makes RNA
• RNA makes Protein
• DNA to DNA is called
REPLICATION
• DNA to RNA is called
TRANSCRIPTION
• RNA to Protein is
called TRANSLATION
Central Dogma of Molecular Biology
• There are exceptions:
• Retroviruses
– Use RNA as the genetic code
– Must make DNA before
making protein product
– This new DNA makes RNA and
then a protein
• Also, one protein is not always
the product of a single gene – we
will talk about this later in the
course!
Transcription – DNA to RNA
Figure 3.3 (1)
(RNA polymerase)
Transcription – DNA to RNA
Figure 3.3 (2)
Transcription – DNA to RNA
Figure 3.3 (3)
Transcription – DNA to RNA
Figure 3.3 (4)
A close-up view of transcription
RNA nucleotides
RNA
polymerase
Newly made
RNA
Direction of
transcription
Template
strand of DNA
• How does the order or sequence of nucleotides in
a DNA and then a RNA molecule determine the
order of amino acids in a protein? (Translation)
TACCTGAACGTACGTTGCATGACT
AUGGACUUGCAUCGAACGUACUGA
Met-Asp-Leu-His-Arg-Thr-Tyr-STOP
DNA
RNA
protein
Translation
• Translation requires:
– Amino acids (AAs)
– Transfer RNA: (tRNA) Appropriate to its time,
transfers AAs to ribosomes. The AA’s join in
cytoplasm to form proteins. 20 types. Loop
structure
– Ribosomal RNA: (rRNA) Joins with proteins
made in cytoplasm to form the subunits of
ribosomes. Linear molecule.
– Messenger RNA: (mRNA) Carries genetic
material from DNA to ribosomes in cytoplasm.
Linear molecule.
Translation
• The mRNA has a
specific “open reading
frame” made up of
three base pairs –codon.
• The tRNA has the
complementary basepairing fit to the codon
–known as an Anticodon
• Each of these codes for
an amino acid
Translation
• Initiation—
– mRNA binds to smaller of ribosome subunits,
then, small subunit binds to big subunit.
– AUG start codon--complex assembles
• Elongation—
– add AAs one at a time to form chain.
– Incoming tRNA receives AA’s from outgoing
tRNA. Ribosome moves to allow this to continue
• Termintion—
Stop codon--complex falls apart
Translation
Figure 3.5 (1)
Translation
Figure 3.5 (2)
Translation
Figure 3.5 (3)
What happens when it all goes
wrong?
– MUTATIONS!!!!!!!!!!
– two general categories
1.result in changes in the amino acids in proteins
A change in the genetic code
2.Change the reading frame of the genetic
message
Insertions or deletions
Mutations
Figure 3.6a
Mutations
Thalidomide
• The structure of thalidomide
is similar to that of the DNA
purine bases adenine (A) and
guanine (G).
• In solution, has almost no
affinity for the other
nucleotides, cytosine (C) and
thymine (T).
• Furthermore, thalidomide can
intercalate into DNA,
presumably at G-rich sites.
From the wikimedia free licensed media file
repository
Thalidomide
• Thalidomide or one of its
metabolites intercalates into
these G-rich promoter regions,
inhibiting the production of
proteins and blocking
development of the limb buds.
• This intercalation would
significantly affect the genes
that rely primarily on guanine
(G) sequences.
• Most other developing tissues
in the embryo rely on
pathways without guanine,
and are therefore NOT
affected by thalidomide
From the wikimedia free licensed media file
repository
Remember Thalidomide?
Genes can lead to inherited
diseases
• A gene which doesn’t function on an autosomal
chromosome can lead to devastating diseases
• Autosomal chromosomes are 22 pairs of
chromosomes which do not determine gender
• Such diseases can be caused by both a
dominant or a recessive trait
Autosomal Recessive Disorders
• Tay-Sachs Disease:
– Jewish people in USA (E. Euro descent)
– Not apparent at birth
– 4 to 8 months
• Neurological impairment evident
• Gradually becomes blind and helpless
• Develops uncontrollable seizures/paralyzed
• Allele is on Chromosome 15
– Lack of enzyme hexosaminidase A (Hex A)
• Lysosomes don’t work, build up in brain
Autosomal Recessive Disorders
• Cystic Fibrosis
– Most common in USA (Caucasian)
– 1 in 20 caucasians is a carrier
– Mucus in bronchial and pancreas thick/viscous
– Breathing and food digestion problems
• Allele is on chromosome 7
– Cl ions can not pass through plasma membrane
channels
• Cl ions pass –water goes with it. No water,
thick mucus
Autosomal Recessive Disorders
• Phenylketonuria (PKU)
– Affects in in 5,000 newborns
– Most common nervous system disorder
• Allele is on chromosome 12
– Lack the enzyme needed for the metabolism of
the amino acid phenylalanine
– A build up of abnormal breakdown pathway
• Phenylketone
• Accumulates in urine. If diet is not checked,
can lead to severe mental retardation
Autosomal Dominant Disorders
•
•
•
•
•
Neurofibromatosis
Very common genetic disorder
Tan spots on skin
Later tumors develop
some sufferers have large head and ear and
eye tumors.
• Allele is on chromosome 17
– Gene controls the production of a protein
called neurofibromin
– This naturally stops cell growth
Autosomal Dominant Disorders
• Huntington Disease
• Leads to degeneration of brain cells
• Severe muscle spasms and personality
disorders
• Attacks in middle age
• Allele is on chromosome 4
– Gene controls the production of a protein
called huntington
– Too much AA glutamine. Changes size and
shape of neurons
Incomplete Dominant traits
• Sickle Cell Anemia
• Controlled by intermediate phenotypes at a
ratio of 1:2:1
• Red blood cells are not concave
• Normal Hemoglobin (HbA). Sickle cell (HbS)
• HbA-HbA-normal
Hbs-Hbs – sickle cell
• HbA-Hbs- have the trait
Mutations
- any change in the nucleotide sequence of
DNA
Normal hemoglobin DNA
Mutant hemoglobin DNA
mRNA
mRNA
Normal hemoglobin
Glu
Sickle-cell hemoglobin
Val
Figure 10.21
Sickle Cell Anemia
Individual homozygous
for sickle-cell allele
Sickle-cell (abnormal) hemoglobin
Abnormal hemoglobin crystallizes,
causing red blood cells to become sickle-shaped
Sickled cells
Clumping of cells
and clogging of
small blood vessels
Breakdown of
red blood cells
Physical
weakness
Impaired
mental
function
Anemia
Heart
failure
Paralysis
Pain and
fever
Pneumonia
and other
infections
Accumulation of
sickled cells in spleen
Brain
damage
Damage to
other
organs
Rheumatism
Spleen
damage
Kidney
failure
Figure 9.21
Genetic engineering
Genetic engineering
• The direct alteration of a genotype
– Human genes can be inserted into human cells for
therapeutic purposes
– Genes can be moved from one species to another
• Moving genes from human to human or
between species requires the use of special
enzymes known as restriction enzymes.
– These cut DNA at very specific sites
– They restrict DNA from another species –
isolated from bacteria.
Genetic
engineering
Figure 4.1
•Each restriction enzyme cuts the DNA at a specific site, defined by the
DNA sequence
•Enzymes which produce “sticky ends” are more useful
•Allows gene of interest to be inserted into a vector
•Also need a DNA probe
•Radioactive ssDNA that will bind to gene of interest so you can locate
it
Genetic engineering
• Transferred DNA is denatured to give ssDNA
• The probe will bind to gene of interest by
Complementary base-pairing - A with T and G with C
Genetically
engineered
Figure
4.3 (1) insulin
Genetically
engineered
Figure
4.3 (2) insulin
Genetically
engineered
Figure
4.3 (3) insulin
Genetically
engineered
Figure
4.3 (4) insulin
Genetically engineered insulin
• Why do some people not like the idea?
The plasmid also needs a “marker
gene”
This is usually an antibiotic resistance
gene
Some people fear that the insulin
which is extracted from the bacteria
would also contain a gene product to
make anyone who uses the insulin
resistant to antibiotics!
Gene therapy
• Can treat human diseases
– eg – severe combined immune deficiency syndrome
(SCIDS)
• Bubble- Boy/Girl syndrome
• The enzyme which causes this is on chromosome 20
– Called adenosine deaminase (ADA)
• Many problems
– Difficult to transfer large genes
– Insert in a way that the gene expresses to protein
correctly
– TRANSLATION!!!!!!!!!!!!
Gene
Figuretherapy
4.4 (1)
Gene
Figuretherapy
4.4 (2)
Gene
Figuretherapy
4.4 (3)
Gene
Figuretherapy
4.4 (4)
Gene
Figuretherapy
4.4 (5)
Virus has genetic defect to
prevent viral reproduction
and spreading to other cells
Gene
Figuretherapy
4.4 (6)
Virus vector must get
the gene into the
nucleus of the patient’s
lymphocyte
Gene
Figuretherapy
4.4 (7)
Gene has to be incorporated
into cell’s DNA where it will
be transcribed
Also inserted gene must not
break up some other
necessary gene sequence
Gene therapy
• The genetically engineered lymphocytes
injected into the patient should out grow the
“natural” (defective) lymphocytes
• As ADA-deficient cells to not divide as fact
as those with the active enzyme
• Not permanent - need repeat injections as
injected lymphocytes are mature and have
limited life span
• Stem cells would get around this problem
(later!)
Genetic Profiling
• We could screen everyone’s DNA for
mutations.
• How would this affect insurance?
• How would this affect health care?
• What about “reproductive control”?
• What do you think?
The end!
Any questions?