The DNA

Structure and Replication
Human Chromosomes
Human Chromosomes
+
2n = 23 pairs = 46 chromosomes
×
22 pairs of autosomes
×
1 pair of sex chromosomes
×
22AA + XX ¬ female
×
22AA + XY ¬ male
+
2 meter of DNA arranged into 46 chromosomes
(23 homologous pairs)
+
1 chromosome consists of two chromatids
+
3 billion base pairs
DNA Structure
+
DNA is a polymer.
+
The monomer units of DNA are nucleotides,
+
The polymer is known as a "polynucleotide.“
+
Each nucleotide consists of:
×
a 5-carbon sugar (deoxyribose),
×
a nitrogen containing base attached to the
sugar
×
a phosphate group
Common Structure of Nucleotide
2-Deoxyribose
H
PYRIMIDIEN
5 principal bases
2-Deoxyribose
H
PURINE
Nucleotide subunits are 
linked together by 
phosphodiester bonds 
Phosphodiester Bonds
Native DNA is a double
helix of complementary
antiparallel chains held
together by:
Hydrogen bonding between
complementary base pairs
(A-T or G-C)
+
Forms a right-handed helix.
+
The strands run antiparallel.
+
There are about 10 base pairs per turn of the
helix.
+
One turn of the helix is 34 Å.
+
The base pairs are 3.4 Å apart.
+
Sugar phosphates on outside, base pairs on
inside.
 Double Helical Structure
 Double Helical Structure
Structure of the Double Helix
+
Three Major Forms
×
B-DNA
×
A-DNA
×
Z-DNA
+
B-DNA is biologically the most common
×
Right-handed (20 Angstrom (A) diameter)
×
Complementary base-pairing (Watson-
Crick)
¤
A-T
¤
G-C
B-form
(a) Hypothesis 1:
Semi-conservative
replication
(b) Hypothesis 2:
Conservative replication
Intermediate molecule
(c) Hypothesis 3:
Dispersive replication
DNA Replication
1) Semiconservative model:
Daughter DNA molecules contain one parental
strand and one newly-replicated strand
DNA Replication
DNA Replication
Requirements
+
Enzyme: DNA Polymerase
+
DNA Template
+
3’ OH (primer of DNA or RNA)
+
Deoxynucleoside triphosphates: dATP, dGTP,
dCTP, dTTP
+
Synthesis is 5’ to 3’
+
Double-stranded DNA
unwinds.
+
The junction of the
unwound molecules is a
replication fork.
+
A new strand is formed by
pairing complementary
bases with the old strand.
+
Two molecules are made.
+
Each has one new and one
old DNA strand.
Replication as a Process
3’-OH attack
incoming nucleotide
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
5’
3’
Problem:
Q: If DNA can only be synthesized in a 5’ to 3’
direction, and both strands are simultaneously
replicated, how can this occur?
A: Discontinuous DNA Replication
3’
5’
5’
3’
growing
fork
3’
5’
5’
3’
?
The Solution
Continuous synthesis
Discontinuous synthesis
DNA replication is semi­discontinuous
The Solution
Features of DNA Replication
+
DNA replication is semiconservative
×
Each strand of template DNA is being copied.
+
DNA replication is bidirectional
×
Bidirectional replication involves two replication forks,
which move in opposite directions
+
DNA replication is semidiscontinuous
×
The leading strand copies continuously
×
The lagging strand copies in segments (Okazaki
fragments) which must be joined
Cell Division
+
Mitosis ¬ two
identical daughter
cells
Cell Division
+
Meiosis ¬ four cell,
half # chromosomes
+
Sperm and ovum are
the products of
meiosis.
Crossing Over
+
Crossing over occurs during meiosis
between two non-sister chromatids
Example
B
e
b
E
x
e
b
B
E
♀ ♂

e = esotropic eye
E = straight eye
b = brown eye
B = blue eye
e
b
B
E

e
b
B
E
e
b B
E
Normal meiosis
Cross over
Example
Taking An Ophthalmic Family History
+
Complete history
×
Pregnancy and birth
×
Past medical history
×
Medication use
×
Detail family history
Pattern of Inheritance
+
Autosomal Dominant Disorders
+
Autosomal Recessive Disorders
+
X-linked Disorders
+
Non-Mendelian Inheritance
×
Mitochondrial Disorders
×
Polygenic Disorders
×
Chromosomal Abnormalities
Autosomal Dominant Disorders
+
Manifested when only one copy of the gene is
abnormal.
+
Passed directly from parents to children of both
sexes.
+
The risk of having affected offspring is 50%.
×
Doesn’t mean it is “safe” after having one or two
affected children.
+
If neither parents is affected, the risk of each
future affected child is not greater than the
population risk.
×
Coloboma and neurofibromatosis have variable
expressivity.
×
Retinoblastoma
Autosomal Dominant Disorders
I
II
III
IV
+
Two copies of an abnormal gene are required.
+
Once parents have a child with a recessive
disorder, the risk of having another affected
child is 25%.
+
Recessive disorder, on average, more severe
than dominant ones.
+
Increases dramatically with
×
Consanguinity
×
Inbreeding
×
Geographically isolated population
Autosomal Recessive Disorders
I
II
III
IV
Autosomal Recessive Disorders
X-linked Disorders
+
Only males are affected.
+
All carrier females have affected father.
+
X-linked dominant disorders are very
rare.
+
Females are severely affected.
+
Females cannot survive, die in utero.
+
Examples:
×
Incontinentia pigmenti (IP)
×
Aicardi’s Syndrome.
I
II
III
X-linked Disorders
I
II
X-linked Disorders
Non-Medelian Inheritance
Mitochondrial Disorder
+
Mitochondria are organelles within human cell.
+
Residing in the cytoplasm.
+
Inherited from mother only.
+
Disorders run in families through the maternal
lineage.
+
Affected women or women carriers never have
affected fathers.
+
Examples:
×
Leber’s hereditary optic neuropathy
×
Chronic progressive external ophthalmoplegia
Polygenic Disorder
+
Not perfect fit with any of the known modes of
inheritance.
+
May be due to an environmental component.
+
Example: refractive error.
+
Also may be considered a multifactoral disorder.
Non-Medelian Inheritance
I
II
III
IV
Non-Medelian Inheritance
Chromosome Abnormalities
+
Trisomy (2n + 1)
×
Klinefelter Syndrome
×
24,XX + 23,Y ¬ 47,XXY
×
1 in 1000 males
×
Hypogonadism (small reproductive organ)
×
Gynaecomastia (enlargement of male breast)
×
Infertile
+
Monosomy (2n – 1)
×
Turner Syndrome
×
Complete or partial monosomy (45,X)
×
1 in 10 000 female
Chromosome Abnormalities
+
Autosomal Trisomy
×
Down Syndrome (trisomy 21)
×
Edward Syndrome (trisomy 18)
×
Patau Syndrome (trisomy 13)
+
Structural abnormality
×
Translocation
×
Inversion
×
Deletion
×
Insertion
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