Lecture 9: Genetics
and Heritable Disease
Evidence of a Pluripotent Human Embryonic Stem
Cell Line Derived from a Cloned Blastocyst
Objectives:
Woo Suk Hwang et al.
1 College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea;
Understand the basis of genetic inheritance
Understand the basis of genetic variation
Relate meiosis, to sex and haploid cells
Understand chromosome structure and how it
affects general health
Explain how small changes in DNA information
result metabolic changes
• Somatic cell nuclear transfer.
• Pluripotent embryonic stem cell line
• Cloned human blastocyst.
– Capable of differentiating into embryoid bodies
– Containing cell derivatives from all three
embryonic germ layers
Key Terms: Gene, Chromosome, Allele, Locus, loci, Mutation,
Diploid and haploid, Phenotype and genotype, Homologous
vs. heterozygous, Meiosis vs. Mitosis, Karyotype, X and Y
chromosome, Sex determination, Linkage, linkage groups,
Full and incomplete linkage, Genetic Markers, Crossover
(Recombination), Pedigree, Autosomal and sex-linked,
Recessive vs. Dominant, Duplication, Inversion and
Translocation, Down Syndrome, Turner Syndrome,
Klinefelter Syndrome, Prisoners Syndrome.
• Capable of continuous proliferation for >70
passages
• Cells maintain normal karyotypes
Chapter 10 & 11 for background
inner cell mass
Trophoblast
(surface layer
of cells of the
blastoyst)
Endometrium
Start of
Start of
amniotic embryonic disk
cavity
Blastocoel
inner cell mass
Start of yolk sac
Uterine cavity
oviduct
uterus
FERTILIZATION
DAYS 6-7
DAYS 10-11
Shorion
Shorionic
villi
Chorionic
cavity
Blood-filled spaces
Smniotic
cavity
ovary
Start of chorionic cavity
IMPLANTATION
endometrium
Connecting
stalk
yolk sac
Fig. 39.21a, p. 666
DAY 14
FERTILIZATION
Meiosis
Nucleus of a
diploid (2n)
Reproductive cell
with two pairs of
homologous
chromosomes
DAY 12
Oviduct
OR
Ovary
OVULATION
Possible alignments
of the two
homologous
chromosomes
during
metaphase I of
meiosis
allelic combinations
possible in gametes:
Opening of
cervix
Zona pellucida
A
A a
a
A
A a
a
B
B b
b
b
b B
B
Vagina
Follicle cell
Granules in cortex
of cytoplasm
The resulting
alignments
at metaphase II:
A
A
a
a
A
A
a
a
B
B
b
b
b
b
B
B
B
A
B
A
1/4 AB
b
a
b
a
1/4 ab
b
A
B
b
A
1/4 Ab
a
Uterus
Sperm
enter
vagina
B
a
Nuclei fuse
1/4 aB
Fig. 10.8, p. 158
1
Key Terms
Cloned human embryo
Embryonic stem cell
Blastula, Blastocyst
Pluripotent
Karyotype
How does cloning work:
– Where does the egg come from
– Where does the DNA come from
– How many copies of each chromosome
Bioethics
Destroying Embryos is the Basis of the
Ethical Debate
Questions:
1.
2.
3.
4.
What is the moral status of the developing
embryo
Is this simply tissue or is it something
more?
Is this a twin? The genetic make up is
identical
What is the purpose?
– Making donor tissue?
– Making a baby?
5.
Is regenerative medicine ethical?
Lecture 8: Genetics
and Heritable Disease
Objectives:
Understand the basis of genetic inheritance
Understand the basis of genetic variation
Relate meiosis, to sex and haploid cells
Understand chromosome structure and how
it affects general health
Explain how small changes in DNA
information result metabolic changes
Key Terms: Gene, Chromosome, Allele, Locus, loci, Mutation,
Diploid and haploid, Phenotype and genotype, Homologous
vs. heterozygous, Meiosis vs. Mitosis, Karyotype, X and Y
chromosome, Sex determination, Linkage, linkage groups,
Full and incomplete linkage, Genetic Markers, Crossover
(Recombination), Pedigree, Autosomal and sex-linked,
Recessive vs. Dominant, Duplication, Inversion and
Translocation, Down Syndrome, Turner Syndrome,
Klinefelter Syndrome, Prisoners Syndrome.
Chapter 11 for background
Lecture 9 Outline
Intro to genetics
Chromosomes and genes
Karyotypes
Variation
Heridity
Genetic disorders
The big problems
Extra and missing chromosomes
The small problems
Mutations
Genetic Screening
Genetic Terminology
Genes
Units of information
about heritable traits
In eukaryotes,
distributed among
chromosomes
Each gene has a
particular locus
(Location on a
chromosome)
Alleles
Different molecular
forms of a gene
Arise through mutation
Diploid cell has a pair of
alleles at each locus
Alleles on homologous
chromosomes may be
same or different
2
Genetic Terminology
Genotype- the alleles
a person has
Phenotype- the
observable trait a
person has
Dominant- Alleles
affect masks the other
allele it is paired with
Recessive- Alleles
affect is masked by
the other allele it is
paired with.
VISUAL
REPRESENTATION
Homozygous- Pair of
alleles for a trait are
identical
Heterozygous- Pair of
alleles for a trait are not
identical
Hybrid- Inherit nonidentical alleles for a trait
A pair of homologous chromosomes,
each in the unduplicated state (most
often, one from a male parent and its
partner from a female parent)
Heterozygous
Homozygous
Pair of Chromosomes
Gene
A gene locus (plural, loci), the
location for a specific gene on
a specific type of chromosome
Locus (loci)
A pair of alleles (each being a
certain molecular form of a gene)
at corresponding loci on a pair of
homologous chromosomes
Alleles
Heterozygous
Homozygous
Homologous Chromosomes
Homologous autosomes are
identical in length, size, shape,
and gene sequence
Sex chromosomes are
nonidentical but still homologous
Homologous chromosomes
interact, then segregate from one
another during meiosis
Three pairs of genes (at three
loci on this pair of homologous
chromosomes); same thing as
three pairs of alleles
Human Karyotype
1
13
2
3
4
14
15
16
5
17
6
18
7
8
9
19
20
21
10
22
11
12
XX
(or XY)
DNA
DNA and proteins
Nucleosome
arranged as cylindrical fiber
Histone
Karyotype Preparation
Cotton Rat
(Sigmodon hipsidus)
– This is when cells are most condensed and
easiest to identify Arrested cells are broken
open
•Number has nothing to do
with complexity of the
organism
Metaphase chromosomes are fixed and
stained (how many copies of each chromosome
Chromosomes are photographed through
microscope
•The Alaskan king crab has
208 chromosomes.
•The fruit fly has 4.
Cultured cells are arrested at metaphase
in one cell?)
Karyotypes
Pied Kingfisher (Ceryle rudis)
Carrion Beetle
(Phosphuga atrata)
Photograph of chromosomes is cut up and
arranged to form a karyotype diagram
3
Sex Chromosomes
Discovered in late 1800s
Sex Determination
eggs
sperm
X
Mammals, fruit flies
Y
X
– XX is female, XY is male
Female germ cell
X
X
X
XX
XX
Y
XY
XY
Human X and Y chromosomes function
as homologues during meiosis
(In some organisms XX is male, XY female but for this
The Y Chromosome
Fewer than two dozen
genes identified
One is the master gene
for male sex
determination
– SRY gene (Sexdetermining region
of Y)
SRY present, testes
form
SRY absent, ovaries
form
The X Chromosome
Carries more than 2,300
genes
Genetic Variation
Why aren’t there just two types of
people?
Recombination
Duplication
Inversion
Deletion
Transversion
Effect of Y
Chromosome
appearance of structures
that will give rise to
external genitalia
appearance of
“uncommitted” duct system
of embryo at 7 weeks
7 weeks
Y
present
Y
absent
Y
present
Most genes deal with
nonsexual traits
Genes on X
chromosome can be
expressed in both
males and females
X
sex chromosome combinations possible
in new individual
class XX is female and XY is male, no tricky stuff)
The Sex Chromosomes
Male germ cell
Y
absent
testes
ovaries
10 weeks
ovary
testis
birth approaching
Recombination
A
B
C
A
B
C
a
b
c
a
b
c
A
B
C
a
b
c
a
B
C
A
B
C
b
c
(homologus recombination)
Chromosomes Mix
The ends of homologus
chromosomes are
exchanged
A
a
b 11.3, p.
c 172
Fig.
4
Duplication
Gene sequence that is repeated several to
hundreds of times
Duplications occur in normal chromosomes
May have adaptive advantage
– Useful mutations may occur in copy
normal chromosome
one segment repeated
three repeats
animation
Inversion
A linear stretch of DNA is reversed
within the chromosome
Translocation
A piece of one chromosome becomes
attached to another nonhomologous
chromosome
Most are reciprocal (switch ends)
Chromosome
Nonhomologous
chromosome
Reciprocal translocation
Translocation
Chromosome
Nonhomologous
chromosome
Deletion
Loss of some segment of a
chromosome
Most are lethal or cause serious
disorder
Reciprocal translocation
5
Genetic Inheritance
Monogenetic Inheritance
Pedigree
Pedigree for Polydactly
Chart that shows genetic connections
among individuals
female
I
male
Standardized symbols
Knowledge of probability and Mendelian
patterns used to suggest basis of a trait
Conclusions most accurate when drawn
from large number of pedigrees
II
5,5
6,6
*
III
IV
6
5,5
6,6
6,6
5,5
6,6
5,5
7
5,5
6,6
5,5
6,6
5,5
6,6
5,5
6,6
5,6
6,7
12
V
6,6
6,6
*Gene not expressed in this carrier.
Autosomal Recessive
Inheritance Patterns
If parents are
both
heterozygous,
child will have a
25% chance of
being affected
Galactosemia
Caused by autosomal recessive
allele
Gene specifies a mutant enzyme in
the pathway that breaks down
lactose
enzyme 1
LACTOSE
enzyme 2
GALACTOSE
+
glucose
enzyme 3
GALACTOSE-1PHOSOPHATE
GALACTOSE-1PHOSOPHATE
intermediate
in glycolysis
6
Autosomal
Dominant Inheritance
Huntington Disorder
Autosomal dominant allele
Trait typically
appears in
every
generation
Causes involuntary movements,
nervous system deterioration, death
Symptoms don’t usually show up until
person is past age 30
People often pass allele on before they
know they have it
X-Linked Recessive
Inheritance
Examples of X-Linked Traits
Color blindness
Males show
disorder more
than females
Son cannot
inherit disorder
from his father
Polygenetic inheritance
(familial)
Alcoholism
Intelligence
Homosexuality????
– Inability to distinguish among some of all
colors
Hemophilia
– Blood-clotting disorder
– 1/7,000 males has allele for hemophilia A
– Was common in European royal families
Children of alcoholics are 4 times as likely
to become alcoholics as children of
nonalcoholic parents…
-They learn to be alcoholics from watching mom
or dad? Behavior/imprint/condition theory B. F. Skinner & Pav
-Society made him do it: poverty, culture, education…
-Genetics: my genes made me do it…
D2, a dopamine receptor in the brain, has been
linked to alcohol sensitivity in mice
= mechanism/disease theory Correlation factor ~ 0.32,
Contemporary
moral
standards
considered a weak Association
•Alcohol dehydrogenase (ADH) affects the
amount of alcohol in the bloodstream.
•Alcoholics have higher levels of ADH in their
blood than do non-alcoholics.
•This suggests that genetically predisposed
people have a reduced or less functional ADH
or ALDH enzyme.
Alcoholism
Scientific
Ideology & Therapeutic
View of humans
7
Heredity factor = anywhere from .4 to .7
Headstart programs can increase IQ
Twin studies: shared environment
mediates genetic factors until
adulthood
A Mystery of Heritable traits: What is this condition?
Here are the clues:
1) The trait is referred to by biologists as a "stable bimorphism, expressed behaviorally."
2) Its exists in the form of two basic internal, invisible orientations, over 90% of the population
accounting for the majority orientation and under 10% (one reliable study puts the figure at 7.89%) for
the minority orientation, though there is still debate about actual percentages.
3) Only a very small number of people are truly equally oriented both ways.
4) Evidence from art history suggests the incidence of the two different orientations has been constant
for five millennia.
5) A person's orientation cannot be identified simply by looking at him or her; those with the
minority orientation are just as diverse in appearance, race, religion, and all other characteristics as
those with the majority orientation.
6) Since the trait itself is internal and invisible, the only way to identify an orientation in someone else
is by observing in them the behavior or reflex that express it. However-7) --The trait itself is not a "behavior." It is the neurological orientation expressed, at times,
behavioraly. A person with the minority orientation can engage, usually due to coercion or social
pressure, in behavior that seems to express the majority orientation--several decades ago, those with
the minority orientation were frequently forced to behave as if they had the majority orientation--but
internally the orientation remains the same. As social pressures have lifted, the minority orientation
has become more commonly and openly expressed in society.
8) Neither orientation is a disease or mental illness. Neither is pathological.
9) Neither orientation is chosen.
10) Signs of one's orientation are detectable very early in children, often, researchers have established,
by age two or three, and one's orientation has probably been defined at the latest by age two, and quite
possibly before birth.
These first intriguing observations began to catch the attention of researchers. The trait looked
biological in origin. The data was indicating that the trait had a genetic source:
11) Adoption studies show that the orientation of adopted children is unrelated to the orientation of
their parents, demonstrating that the trait is not environmentally rooted.
12) Twin studies show that pairs of identical (monozygotic) twins, with their identical genes, have a
higher-than-average chance of sharing the same orientation compared to pairs of randomly selected
individuals; the average (or "background") rate of the trait in any given population is just under 8%,
while the twin rate is just over 12%, over 30% higher.
13) The incidence of the minority orientation is strikingly higher in the male population-- about 27%
higher-- than it is in the female population, a piece of information that gives indications to the
biological conditions creating the trait.
14) Like the trait eye color, familial studies show no direct parent-offspring correlation for the two
versions of the trait, but the minority orientation clearly "runs in families," handed down from parent
to child in a loose but genetically characteristic pattern.
15) This pattern shows a "maternal effect," a classic telltale of a genetically-loaded trait. The minority
orientation, when it is expressed in men, appears to be passed down through the mother.
That’s the clinical profile for this trait. What are we talking about???
Human handedness! (Were you fooled?)
Despite what some would like you to believe, however,
this is not a good analogy for what is currently known
about the habitability of homosexuality.
Current research (up to 2001) suggests a very weak
correlation of homosexual behavior and genetic traits
(<0.25). Despite much $, effort and social
pressure, the correlation data remain very low. Contemporary
moral standards
Because of great social pressure, no
doubt, more work will be forthcoming
soon. Given what you know about objective
and subjective science, how can you
judge the validity of this work?
Homosexuality
Scientific
ideology
Chromosome Number Problems
Aneuploidy
Genetic Disorders
Big Changes
Individuals have one
extra or less
chromosome
(2n + 1 or 2n - 1)
Major cause of human
reproductive failure
Most human
miscarriages are
aneuploids
Polyploidy
Individuals have three
or more of each type of
chromosome (3n, 4n)
Common in flowering
plants
Lethal for humans
– 99% die before birth
– Newborns die soon after
birth
8
Nondisjunction
Down Syndrome
Trisomy of chromosome 21
n+1
n+1
n-1
chromosome
alignments at
metaphase I
Mental impairment and a variety of
additional defects
Can be detected before birth
Risk of Down syndrome increases
dramatically in mothers over age 35
n-1
nondisjunction
at anaphase I
alignments at
metaphase II
anaphase II
Turner Syndrome
Inheritance of only one X (XO)
98% spontaneously aborted
Survivors are short, infertile females
– No functional ovaries
– Secondary sexual traits reduced
– May be treated with hormones, surgery
Klinefelter Syndrome
XXY condition
Results mainly from nondisjunction in
mother (67%)
Phenotype is tall males
– Sterile or nearly so
– Feminized traits (sparse facial hair,
somewhat enlarged breasts)
– Treated with testosterone injections
XYY Condition
Taller than average males
Most otherwise phenotypically normal
Genetic Disorders…
Some mentally impaired
Once thought to be predisposed to
criminal behavior, but studies now
discredit
Small Changes
9
Sickle Cell Anemia
Sickle Cell Anemia
Recessive trait
Most common inherited blood disorder
in US
Symptoms– Chronic hemolytic anemia
– Severe pain
– Rapid septicemia (infection)
– Asplenia (no spleen left)
Inheritance of a Molecular
Disease
Sicklemia and Sickle Cell Anemia
– Tested blood from parents of patients
Sicklemia- 1% sickled
Sickle Cell Anemia- 30-60% sickled
Molecular Disease
– Hemoglobin is the target
Same size and weight
Different charge! (Back to Biochemistry ☺)
Hemoglobin and Sickle Cell Anemia
Single base mutation in DNA
– A to T transversion
Single amino acid change in the protein
– Glutamine to Valine
– Polar charged R group to non-polar R group
H 2N
H 2C
O
H 3C H CH 3
C
CH 2
C
H 2N H
O
C
H 2N H
O
OH
OH
Glutamine
Sticky Situation
Valine
Cell Sickling
Polymers of hemoglobin
deform red blood cells
Normal
Low Oxygen
Sickle
Hemoglobin Polymerizes
10
How Was the Mutation
Selected?
Malaria
–Mosquito born plasmodium
parasite
–Some sickling is good
Heterozygotes Have the
Advantage!
Prenatal Diagnosis
Amniocentesis (1-2%)
– Amniotic fluid removed
Chorionic villus sampling (0.3%)
– Cells from the chorion (surrounds
ammnion)
Fetoscopy (2-10%)
– Direct visualization, removal of blood
from umbilical vein
Genetic Screening
Large-scale screening programs
detect affected persons
Newborns in United States routinely
tested for PKU (phenylketonuria)
– Early detection allows dietary
intervention and prevents brain
impairment
Amniocentesis
Removal of about 20 ml of
amniotic fluid containing
suspended cells that were
sloughed off from the
fetus
A few biochemical
analyses with some of the
amniotic fluid
Centrifugation
Quick determination of fetal
sex and analysis of purified
DNA
Fetal cells
Biochemical analysis for the
presence of alleles that cause
many different metabolic
disorders
Growth for
weeks in
culture
medium
Fig. 11.19, p. 186
Karyotype analysis
Phenotypic Treatments
Symptoms of many genetic disorders
can be minimized or suppressed by
– Dietary controls
– Adjustments to environmental conditions
– Surgery or hormonal treatments
Preimplantation Diagnosis
Used with in-vitro
fertilization
All cells have same
genes
One cells is removed
and its genes are
analyzed
If the cell is
homozygous for the
damaging trait
carried by parents it
is not implanted.
Bioethics
Sex Selection
Non-lethal trait
selection
Late on set genetic
diseases
Markers vs. Genotypes
– Probability
Variable severity
11
Chromosomes & Cancer
•Some genes on chromosomes control cell growth and
division
•If something affects chromosome structure at or near these
loci, cell division may spiral out of control
Philadelphia
Chromosome
First abnormal
chromosome to be
associated with a cancer
Associated with a chronic
leukemia
– Overproduction of white
blood cells
VISUAL
REPRESENTATION
An Altered Gene
When the reciprocal
translocation occurred, a
gene at the end of
chromosome 9 fused with
a gene from chromosome
22
This hybrid gene encodes
an abnormal protein that
stimulates uncontrolled
division of white blood
cells
A pair of homologous chromosomes,
each in the unduplicated state (most
often, one from a male parent and its
partner from a female parent)
Heterozygous
Some genes on chromosomes control
cell growth and division
If something affects chromosome
structure at or near these loci, cell
division may spiral out of control
Homozygous
A gene locus (plural, loci), the
location for a specific gene on
a specific type of chromosome
This can lead to cancer
A pair of alleles (each being a
certain molecular form of a gene)
at corresponding loci on a pair of
homologous chromosomes
Translocation
Chromosome
Nonhomologous
chromosome
Reciprocal translocation
Lecture 10
Viruses, cells and STD’s
Chapter 35
– Concepts and Applications
– Viruses section
– Inflammation and immunity
12