Transcript Genetic Disorders Mendelian Disorders

Genetic Control of
Growth & Maturation
Gregor Mendel
(1822-1884)
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Mendel studied the
inherited traits of pea
plants.
Gregor Mendel (1822-1884)
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From his observations Mendel deduced that:
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Each characteristic must be determined by a
hereditary factor
There is a pair of hereditary factors; one from
each parent
Gregor Mendel (1822-1884)
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The law of uniformity: When two homozygotes with
different alleles are crossed, all the offspring are
identical and heterozygous.
The law of segregation: Each individual possesses
two genes for a particular characteristic, only one of
which can be transmitted.
The law of independent assortment: Members of
different gene pairs segregate to offspring
independently of one another.
Mendel’s Observations
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Generation 1:
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Generation 2:
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Yellow Round x Green Wrinkled
All Yellow Round offspring
Yellow Round x Yellow Round
Generation 3:
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Yellow Round, Yellow Wrinkled, Green Round.
Green Wrinkled
Explanation of Mendel’s Observations
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Generation 1:
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Generation 2:
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Yellow Round (YYRR) x (Green Wrinkled (yyrr)
Yellow Round (YyRr) x Yellow Round (YyRr)
Generation 3:
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9 Yellow Round (YYRR or YyRr)
3 Yellow wrinkled (Yyrr or Yyrr)
3 Green Round (yyRR or yyRr)
1 Green Wrinkled (yyrr)
Pea Experiment
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Click on the link below when you are
connected to the internet
Pea Soup Website
Gene
Alleles
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The two copies of
each gene are
called alleles,
which may be
identical (AA and
aa) or different
(Aa).
Homozygous
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Refers to the state of
carrying identical
alleles at one or more
gene loci (e.g. AABB or
aabb).
Heterozygous
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Refers to the state of
carrying different alleles
at one or more gene loci
(e.g. AaBb).
Segregation
of Alleles
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Law of segregation is that
alleles segregate, or
separate, when the F1
generation produces
gametes.
Alleles reside at specific loci,
or sites, on the chromosomes
within the DNA molecule.
A pair of homologous chromosomes contains two alleles at each
locus and during gamete formation of meiosis, each gamete
receives only one member of each homologous pair of
chromosomes. Therefore, each gamete also receives only one
allele of a particular locus.
Cytogenetics
The study of Chromosomes
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1903 Sutton and Boveri idependently proposed that the
vehicle of hereditary factors or genes were the thread-like
structures seen by light microscopy in the nucleus of each
cell.
Chromosomes because of their affinity to take up certain
stains (Greek: chroma, colour; soma, body).
Chromosomes are only being seen during the metaphase
stage of cell division when they are maximally contracted.
Plant Chromosomes: von Nägeli in 1842.
Animal Chromosomes: Flemming (mitosis) 1882.
Karyotype
Chromosome Complement of the Cell (1956)
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Karyotyping is the process
of imaging the
chromosomes of the cell
23 pairs of chromosomes
44 autosomes + 2 sex
chromosomes
46, XX = Normal female
46, XY = Normal male
Genotype
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The genetic make up of the individual.
Typically, one refers to an individual's
genotype with regard to a particular gene of
interest
It refers to what combination of alleles the
individual carries (either homozygous or
heterozygous).
Phenotype
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Any feature or characteristic of an organism
or any group of characteristics (e.g.
metabolism, physiology, or morphology).
The phenotype is the result of the interaction
of the gene and environmental components.
Human Genome Project
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The Human Genome Project (HGP) aimed to map
and understand of all the genes of human beings.
In 1911, Alfred Sturtevant, then an undergraduate
researcher in the laboratory of Thomas Hunt
Morgan, realized that he could - and had to, in order
to manage his data - map the locations of the fruit fly
(Drosophila melanogaster) genes whose mutations
the Morgan laboratory was tracking over
generations. Sturtevant produced the very first gene
map.
Human Genome Project
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The hereditary material of all multi-cellular organisms
is the famous double helix of deoxyribonucleic acid
(DNA), which contains all of our genes.
DNA, in turn, is made up of four chemical bases,
pairs of which form the "rungs" of the twisted, laddershaped DNA molecules. All genes are made up of
stretches of these four bases, arranged in different
ways and in different lengths.
Human Genome Project
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By February 2003 HGP researchers fully mapped the
the human genome.
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determining the order, or "sequence," of all the bases in our
genome's DNA;
making maps that show the locations of genes for major
sections of all our chromosomes;
and producing what are called linkage maps, through which
inherited traits (such as those for genetic disease) can be
tracked over generations.
The HGP has revealed that there are probably
somewhere between 30,000 and 40,000 human genes
50,000 genes to as many as 140,000).
National Human Genome Research Institute
Genetic Variation Program
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Most of any one person's DNA, about 99.5 percent, is
exactly the same as any unrelated person's DNA.
Differences in the sequence of DNA among individuals
are called genetic variation.
Genetic variation explains some of the differences
among people, such as eye color and blood group.
Genetic variation also plays a role in whether a person
has a higher or lower risk for getting particular diseases.
Single gene differences in individuals account for some
traits and diseases, such as the ABO blood group, cystic
fibrosis and sickle cell disease.
Genetic Variation Program
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More complex interrelationships among multiple
genes and the environment are responsible for many
common diseases, such as diabetes, cancer, stroke,
Alzheimer's disease, Parkinson's disease,
depression, alcoholism, heart disease, arthritis and
asthma.
The Genetic Variation program supports research on
genetic variation and how it relates to diseases,
responses to drugs and environmental factors.
Genetic Expression
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If all cells come from the one original zygote, how can the cells in
the body vary so much
Some genes are permanently switched on
– enzymes required for respiration etc
Some genes become switched off because they are no longer
required to be functional in that particular cell or tissue.
Insulin is produced in pancreas cells, which must have the gene
that codes for insulin switched on, and genes that are un-related
to the role of the pancreas can be switched off.
Some other genes that will be functional during specialisation
determine the physical characteristics of the cell, i.e. long and
smooth for a muscle cell or indented like a goblet cell
Height
Height (Women)
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Polygenetic
control
800
600
400
200
Std. Dev = 6.22
Mean = 161.0
N = 5782.00
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6.
18
0
2.
18
0
8.
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0
4.
17
0
0.
17
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6.
16
0
2.
16
0
8.
15
0
4.
15
0
0.
15
0
6.
14
HT
Parental Size
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Average height of siblings approximates
average height of parents
– Parental stature adjusted growth curves
Birth size poorly correlated with adult size
Birth size correlated to mother’s size
Walton and Hammond (1938)
Crossed large Shire horses with small Shetland ponies.
Walton and Hammond (1938)
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Offspring of the crosses delivered to Shire dams were
heavier than that of pure Shetland ponies, but below that
of pure Shire offspring.
In contrast, the reciprocal cross-delivered to the
Shetland dam was of the same weight at birth as the
Shetland purebred foal.
The Shetland mother was able to down regulate the in
utero growth of her foal sired by the much larger Shire
horse, while the in utero environment provided by the
larger Shire mother facilitated enhanced growth.
Allen et al. 2004
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Allen et al. (2004)
Confirmed the original observations of Walton &
Hammond (1938) that a genetically large foal cannot
reach its normal birthweight when gestated in a uterus
that is smaller than normal, and the runting effect
persists throughout life.
Furthermore, that genetically small foals will be born
heavier than usual if gestated in the uteri of larger than
normal mares and, similarly, this increased size
persists to adulthood
14 months of age
3 years of age
Tb-in-P vs Tb-in-Tb
Tb-in-P vs Tb-in-Tb
P-in-Tb vs P-in-P
P-in-P vs P-in-Tb
Allen et al. 2004
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Clear maternal size influence at birth
Lasting effect in postnatal development
Larger mother provided
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Larger placental area
Greater microcotyledon density
Skin Colour
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Skin colour depends on the degree of melanin
found in skin cells.
There are two genes that control the
production of melanin, each of which has a
dominant and recessive expression.
16 combinations of genotype when coding for
skin colour, as seen below.
Skin Colour
# Genotype
1 M1M1M2M2
2 M1M1M2m2
3 M1M1m2m2
4 M1m1m2m2
5 m1m1m2m2
Phenotype
Black Skin
Dark Brown Skin
Brown Skin
Light Brown Skin
White Skin
A person is born with one of five colours.
External factors such as the UltraViolet light from the sun
modify the genetic expression of colour.
Sex Linked Inheritance
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A recessive trait on the X chromosome can
find expression in a male
Sex Linked Inheritance
Father’s contribution determines the sex of the child.
Hemophilia A
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Mainly exhibited in males, due to recessive
gene on X chromosome.
Only exhibited in double recessive females.
Sons of hemophiliac males will not have the
gene
All daughters of male hemophiliacs will be
carriers
Genetic Disorders
Chromosomal Disorders
Numerical (Aneuploidy) due to nondisjunction.
Structural chromosomal due to a break in
chromosome(s).
Genetic Disorders
Chromosomal Disorders
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Numerical (Aneuploidy) due to nondisjunction
 1st
or 2nd division of meiosis. An extra copy of a
chromosome (trisomy) or a missing copy of a
chromosome (monosomy).
 Aneuploidy can also occur at mitosis after
conception and leads to chromosomal mosaicism, a
mixture of two or more cell lines each having a
different number of chromosomes.
Genetic Disorders
Mendelian Disorders
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Caused by a mutant allele or pair of mutant alleles at a
single gene locus.
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Autosomal dominant or autosomal recessive.
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Either inherited or due to a new mutation.
Homo vs Heterozygous, Male vs Female?
Variable expressivity.
Penetrance
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percentage of individuals exhibiting symptoms or signs
E.g. reduced penetrance in neurofibromatosis, a disorder
characterized by multiple brown skin patches and benign
growths.
Genetic Disorders
Mendelian Disorders
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Autosomal recessive disorders only manifest in the
homozygote.
Both sexes can be affected and heterozygotes (or carriers)
are normal phenotypically.
Most individuals affected by an autosomal recessive
disorder are born to healthy carrier parents.
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25% chance of homozygous normal
50% chance of unaffected heterozygote carriers
25% chance of having a homozygous affected offspring..
Cystic fibrosis is an autosomal recessive disorder
progressive lung damage and poor growth
Genetic Disorders
Mendelian Disorders
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Autosomal recessive disorders only manifest in the
homozygote.
Both sexes can be affected and heterozygotes (or carriers)
are normal phenotypically.
Most individuals affected by an autosomal recessive
disorder are born to healthy carrier parents.
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25% chance of homozygous normal
50% chance of unaffected heterozygote carriers
25% chance of having a homozygous affected offspring..
Cystic fibrosis is an autosomal recessive disorder
progressive lung damage and poor growth
Genetic Disorders
Mendelian Disorders
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Autosomal recessive disorders only manifest in the
homozygote.
Both sexes can be affected and heterozygotes (or carriers)
are normal phenotypically.
Most individuals affected by an autosomal recessive
disorder are born to healthy carrier parents.
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25% chance of homozygous normal
50% chance of unaffected heterozygote carriers
25% chance of having a homozygous affected offspring..
Cystic fibrosis is an autosomal recessive disorder
progressive lung damage and poor growth
Genetic Disorders
Multifactorial Disorders
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Multifactorial disorders occur in more than one member of
the family but do not follow a mendelian pattern of
inheritance.
Interaction between environmental factors and a number of
genes
Cleft lip, palate, spina bifida and common disorders in
adults (e.g. diabetes mellitus, cancer, schizophrenia) are
thought to be multifactorial in origin.
The risk for an individual of developing a multifactorial
disorder is determined by the number of affected members
in the family and the relationship to the patient.
Chromosome Aneuploidy
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Aneuploidy = wrong number
Sex Chromosome Aneuploidies
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Wrong complement of sex chromosomes
E.g. 47,XXX; 45,X0
Autosomal Aneuploidies
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Trisomy 21: Down Syndrome
47, XXX
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1 : 960
Normal in appearance
Usually fertile
15-25% are mildly mentally retarded
Occurs due to nondisjunction in meiotic division
of female
Turner’s Syndrome
•1 : 2,500 live female births
(1:5,000 total live births).
•There are indications that as few
as 1:50 45, X0 conceptions are
born alive. The others
spontaneously abort. This
suggests that the monosomy
tends to be lethal.
Turner’s
Syndrome
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"Webbing" of the neck is often
seen at birth and beyond.
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The skin between the mastoid
region and the shoulder
expands before birth to cover a
swollen jugular lymph sac.
The swelling usually goes down
before birth, but the excess skin
persists as a redundant fold.
A broad, shield-shaped chest
and widely spaced nipples are
also typical in this syndrome.
Short for their age; as adults
they rarely exceed 5 feet in
height.
Turner’s
Syndrome
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Ovarian dysgenesis and are
infertile.
Cardiovascular
abnormalities.
Many have a low posterior
hairline.
Behind siblings in
intellectual development.
Poor sexual development
internally and externally.
45, Y0
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Given that 45, X0 individuals exist, one might expect
the viability of its male counterpart, 45, Y0. However,
no such adults, children or embryos have been
reported.
Indeed, Y0 or YY cells have never been observed. It
has been suggested that these theoretically possible
chromosome constitutions are incompatible with life,
even with life as a very early embryo. Apparently there
are genes necessary for life located on the X
chromosome
Klinefelter Syndrome
47, XXY
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Incidence 1 : 1080
Klinefelter Syndrome
47, XXY
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Small testes, hyalinization
of seminiferous tubules;
aspermatogenesis
Often tall with
disproportionately long
limbs.
Intelligence is less than in
normal siblings.
About 40% of these males
have gynecomastia
47,XYY “the criminal type”
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Adults with 47, XYY syndrome may exhibit a
pockmarked face owing to severe acne during puberty.
Growth is often accelerated during mid-childhood, so
adults with this syndrome are often very tall. Severe
acne may develop in puberty, leading to a pock-marked
face in adult life.
On the other hand, not all individuals are so affected by
acne. Indeed, both physical abnormalities and
behavioral aberrances may be absent.
47,XYY “the criminal type”
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Nevertheless, one study showed that among
institutionalized male juvenile delinquents, one in 35
had a 47, XYY karyotype. This rate is 24 times the
incidence of 47, XYY karyotype in all newborn males.
On the basis of this, the association with behavioral
problems is significant.
Down Syndrome
Trisomy 21
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Virtually all individuals with Down syndrome
are mentally retarded, with the IQ most
often in the 25 to 50 range.
Congenital malformations of the heart are
present in over half of these persons, and
there is a 15-fold increase in risk for
developing leukemia.
Characteristic face and physique.
Down Syndrome - Trisomy 21
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Risk increases with
maternal age
Maternal
Age
20-24
25-29
30-34
35
37
39
41
43
45+
Incidence
1:1400
1:1100
1:700
1:350
1:225
1:140
1:85
1:50
1:25
Mosaicism
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Two or more cell
types containing
different
numbers of
chromosomes.
This example is
for Down
Syndrome but it
can occur for all
aneuploidies.
Trisomy 18 – Edwards Syndrome
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47, XX, +18 or 47, XY, +18
1 : 3,300 live births. It is more severe than Down
syndrome.
Estimated that 95% of trisomy 18 fetuses abort
spontaneously. Of those born alive, 30% die within a
month of birth, 50% by two months and only 10%
survive the first year of life.
Failure to thrive, mental retardation. Half or more show
growth deficiency and hypertonicity after the neonatal
period. Over 130 abnormalities associated with trisomy
18 have been noted in the literature.
Trisomy 18 – Edwards Syndrome
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Clenched fist and over lapping fingers.
Edward syndrome babies exhibit an
unusual posture of the hands. The
hands are clenched with the index
finger overlapping the next and the 5th
over the 4th
Also common is "rocker bottom
deformity" of the feet - prominent
calcaneus bones and dorsiflexion,
resulting in a convex plantar surface.
Short sternum, narrow pelvis
Patau Syndrome - trisomy 13
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47, XX, +13 or 47, XY, +13
1 : 5,000 live births, and the sex ratio is close to 1:1.
Half of the infants with it die within a month of birth.
Severe mental retardation and varying degrees of
incomplete development of the brain are
characteristic.
Growth retardation, sloping forehead, eye and ear
malformations.
Patau Syndrome - trisomy 13
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Of the many abnormalities that can
occur in this defect, the most
consistent are cleft lip (60 to 80% of
the cases), cardiac malformations
(80%), and the brain defects
coupled with severe mental
retardation.
Almost all organ systems may show
defects.
Patau Syndrome - trisomy 13
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Because of the high mortality
(only 18% survive the first year),
coupled with severe organ
defects including the brain, at
least some pediatricians believe
that no medical means should be
employed to prolong the life of
these individuals
Cri-du-chat Syndrome
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In 1963, French geneticist
Jerome Lejeune first described
the syndrome noting the mewing,
cat-like cry in affected newborns.
He was a pro-life pediatrician
who discovered many
connections between
chromosome abnormalities and
diseases.
He devoted a major part of his
career treating children affected
by Down’s syndrome.
Cri-du-chat Syndrome
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46, XX, 5p- or 46, XY, 5p5p- indicates deletion of the short arm of
chromosome number 5.
Deletion of the long arm would be abbreviated 5q-, q
indicating the long arm of this chromosome.
Also present in 100% of the cases are microcephaly,
mental retardation and slow growth.
Almost all exhibit optic hypertelorism (widely spaced
eyes), and 85% exhibit epicanthic folds.
Cri-du-chat Syndrome
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Also present in 100% of the cases are microcephaly,
mental retardation and slow growth.
Almost all exhibit optic hypertelorism (widely spaced
eyes), and 85% exhibit epicanthic folds.
Common symptoms are webbing of the fingers and
toes, abnormal motor skill development, and a single
line in the palm of the hand, known as a Simian
crease.
This is a rare condition, occurring about once in every
50,000 live births.