Download 5-Disorders,pedigrees,karyotypes 15-16

Genetic Disorders
&
Sex Linked Traits
Biology
Genetics of Sex
 In humans & other mammals, there are 2 sex
chromosomes: X & Y
 2 X chromosomes
 develop as a female: XX
 an X & Y chromosome
 develop as a male: XY
50% female : 50% male
X
Y
X
XX
XY
X
XX
XY
Genes on sex chromosomes
 Y chromosome
 few genes other than SRY
 sex-determining region
 master regulator for maleness
 turns on genes for production of male hormones

many effects = pleiotropy!
 X chromosome
 other genes/traits beyond sex determination
 mutations:



hemophilia
Duchenne muscular dystrophy
color-blindness
Human X chromosome
 Sex-linked
 usually means
“X-linked”
 more than
60 diseases traced to
genes on X
chromosome
Duchenne muscular dystrophy
Becker muscular dystrophy
Chronic granulomatous disease
Retinitis pigmentosa-3
Norrie disease
Retinitis pigmentosa-2
Ichthyosis, X-linked
Placental steroid sulfatase deficiency
Kallmann syndrome
Chondrodysplasia punctata,
X-linked recessive
Hypophosphatemia
Aicardi syndrome
Hypomagnesemia, X-linked
Ocular albinism
Retinoschisis
Adrenal hypoplasia
Glycerol kinase deficiency
Ornithine transcarbamylase
deficiency
Incontinentia pigmenti
Wiskott-Aldrich syndrome
Menkes syndrome
Androgen insensitivity
Sideroblastic anemia
Aarskog-Scott syndrome
PGK deficiency hemolytic anemia
Anhidrotic ectodermal dysplasia
Agammaglobulinemia
Kennedy disease
Pelizaeus-Merzbacher disease
Alport syndrome
Fabry disease
Immunodeficiency, X-linked,
with hyper IgM
Lymphoproliferative syndrome
Albinism-deafness syndrome
Fragile-X syndrome
Charcot-Marie-Tooth neuropathy
Choroideremia
Cleft palate, X-linked
Spastic paraplegia, X-linked,
uncomplicated
Deafness with stapes fixation
PRPS-related gout
Lowe syndrome
Lesch-Nyhan syndrome
HPRT-related gout
Hunter syndrome
Hemophilia B
Hemophilia A
G6PD deficiency: favism
Drug-sensitive anemia
Chronic hemolytic anemia
Manic-depressive illness, X-linked
Colorblindness, (several forms)
Dyskeratosis congenita
TKCR syndrome
Adrenoleukodystrophy
Adrenomyeloneuropathy
Emery-Dreifuss muscular dystrophy
Diabetes insipidus, renal
Myotubular myopathy, X-linked
Sex-linked Genes
 Genes on the X chromosome are called “sex-
linked”, because they expressed more often in
males than in females
 There are very few genes on the Y chromosome.
 Since males only have one X chromosome, all
genes on it, whether dominant or recessive, are
expressed. . So, most people with sexlinked genetic conditions are male.
Why can females have 2 copies of the X
chromosome, when males only have 1?
 Answer:
In each cell one of the X chromosomes ‘turns off’.
This turned off chromosome is known as a Barr
body.
The effect of Barr bodies can be seen in Calico
colored cats.
X-inactivation
 Female mammals inherit 2 X chromosomes
 one X becomes inactivated during embryonic
development
 condenses into compact object = Barr body
 which X becomes Barr body is random

patchwork trait = “mosaic”
patches of black
XH 
XH Xh
tricolor cats
can only be
female
Xh
patches of orange
Colorblindness
 We have 3 color receptors in the retinas of our eyes.
They respond best to red, green, and blue light.
 Each receptor is made by a gene. The blue receptor is
on an autosome, while the red and green receptors are
on the X chromosome (sex-linked).
Colorblindness
 Most colorblind people are males, who have
mutated, inactive versions of either the red or
the green (sometimes both) color receptors.
Most females with a mutant receptor gene are
heterozygous: the normal version of the receptor
genes gives them normal color vision.
Colorblind Test!
 You will see circles with many colors of
dots
 The dot pattern makes up a number
 What number do you see?
With Color Vision:
This one you can even see in black and
white
Color Blind Test
What
number
do you
see?
Color Blind Test
What
number
do you
see?
This what you would see if you were
color blind
What
number
do you
see?
Color Blind Test
What
number
do you
see?
Color Blind Test
What
number
do you
see?
Color Blind Test
What
number
do you
see?
Color Blind Test
What
number
do you
see?
With color vision you see this:
But if you were red-green colorblind….
You would see the #:
5
What do the colorblind see?
Types of Colorblindness
NORMAL
RED
YELLOW
GREEN
CYAN
BLUE
MAGENTA
PROTAN:
DEUTERAN:
TRITAN:
Red Blind
Green Blind
Blue Blind
Types of Colorblindness –
Normal
Protanopia: no red
No color vision
Deuteranopia: no green
Tritanopia: no blue
How to write Alleles for X-Linked Traits
 Women:
Normal: XBXB
Carrier: XBXb
Colorblind: XbXb
 Men:
Normal: XBY
Colorblind: XbY
Hemophilia
 Hemophilia is a disease in which the blood does not clot when
exposed to air. People with hemophilia can easily bleed to death
from very minor wounds. Hemophilia is another sex-linked
trait.
 Hemophilia is treated by injecting the proper clotting proteins,
isolated from the blood of normal people. In the early 1980’s,
the blood supply was contaminated by HIV, the AIDS virus, and
many hemophiliacs contracted AIDS at that time.
 Small cuts, scrapes and bruises can be life threatening
 1 in 10, 000 males
 1 in 100,000,000 females
sex-linked recessive
Hemophilia
Hh
XHXhx HH
XH Y
XH
female / eggs
male / sperm
XH
XH
Y
XH XH
XHY
XH Xh
Xh
XH
Xh
XH Xh
carrier
Xh Y
disease
XHY
Y
Common amongst royalty in Europe
Queen Victoria
= Carrier
Pedigrees
Following Traits in Families
Pedigree: A diagram that follows the traits
through a family
Circles and Squares represent
people
Shaded circles/squares represent
people that have the trait “being
followed”
A half-shaded symbol represents a
‘carrier’
Pedigree analysis
 Pedigree analysis reveals Mendelian patterns in human
inheritance
 data mapped on a family tree
= male
= female
= male w/ trait
= female w/ trait
Simple pedigree analysis
11
33
44
What’s the
likely inheritance
pattern?
22
55
66
Genetic counseling
 Pedigree can help us understand the past & predict the future
 Thousands of genetic disorders are inherited as simple recessive
traits
 from benign conditions to deadly diseases
 albinism
 cystic fibrosis
 Tay sachs
 sickle cell anemia
 PKU
•Douglas and Lauren have three children,
two girls and a boy.
This line indicates a family
Douglas
Children are left
to right, oldest to
youngest
Lauren
•Douglas has brown hair. We will ‘follow’
this trait. Show the brown hair trait by
shading in the circle
Douglas
Lauren
•Lauren has blonde hair so we do not shade
her in.
Douglas
Lauren
•Their oldest daughter and youngest son
have brown hair also.
Douglas
Lauren
•Shade them in as well.
Douglas
Lauren
Sex-Influenced Traits
 Some traits appear to be specific to one
sex, but are not sex-linked: their genes
are not on the X chromosome. It is
sex-influenced.
 Baldness is dominant in males:
heterozygotes and homozygotes both
become bald. In females, baldness is
recessive: only homozygotes (which are
relatively rare) become bald. Also,
females tend to lose hair more evenly
than men, giving a sparse hair pattern
rather than completely baldness.
Errors of Meiosis
Chromosomal Abnormalities
Chromosome Structure Variations
 Chromosomes can be broken by X-rays and by
certain chemicals. The broken ends spontaneously
rejoin, but if there are multiple breaks, the ends join
at random. This leads to alterations in chromosome
structure.
 Breaking the chromosome often means breaking a
gene. Since most genes are necessary for life, many
chromosome breaks are lethal or cause serious
defects.
 Also, chromosomes with structural variations often
have trouble going through meiosis, giving embryos
with missing or extra-large regions of the
chromosomes.
Chromosome Variations
 Aneuploidy: having an extra or
missing chromosome–fairly common in
sperm and eggs. Errors in meiosis causes
chromosomes to not separate equally into
the gametes.
rate of aneuploidy
in males is
constant: 1-2% of
sperm have an
extra or missing
chromosome.
Chromosome Variations
 In females, the rate increases
with age.
 This is illustrated by the
frequency of Down
syndrome births at different
ages of mother.
 Down syndrome is the most
frequent result of aneuploidy.
Chromosomes
 Karyotype:
 ordered display of an individual’s chromosomes.
 Collection of chromosomes from mitotic cells.
 Staining can reveal visible band patterns, gross anomalies.
 Karyotypes
arrange
chromosomes
in order by size:
Largest to
smallest
Chromosomes
 Some large like
#1
 Some small like
#22
Homologous pairs
 Same Length
 Centromere in same
location
 Same bands (genes)
Centromere Position
 The centromere is not
exactly in the center of the
chromosome
 “p” arm: (p=petite) the
shorter arm of the
chromosome
 “q” arm: the longer arm of
the chromosome
Locus (plural=loci)
 The position that a given gene
occupies on a chromosome. (Its
like an address for your genes)
 Written like this: 15p23
Example: 15p23=Chrom 15 small arm, 23rd
band from the centromere
Trisomy:
*Having 3 chromosomes of each kind
instead of 2
*Normally trisomy results in death.
1 Example
Down Syndrome:
 a genetic condition in which the individual has 3
copies of the 21st chromosome.
 Genotype: 3 copies of 21st chromosome
Down Syndrome:
 Phenotype: Skin folds above the eye, some
cardiac deformities, some levels of mental
disability, large tongue.
 Occurs about 1 in 1000 births.
Sex chromosomes abnormalities
 Human development more tolerant of wrong
numbers in sex chromosome
 But produces a variety of distinct syndromes in
humans
 XXY = Klinefelter’s syndrome male
 XXX = Trisomy X female
 XYY = Jacob’s syndrome male
 XO = Turner syndrome female
Klinefelter’s syndrome
 XXY male
 one in every 2000 live births
 have male sex organs, but are sterile
 feminine characteristics
 some breast development
 lack of facial hair
 tall
 normal intelligence
Klinefelter’s syndrome
Jacob’s syndrome male
 XYY Males
 1 in 1000 live male
births
 extra Y chromosome
 slightly taller than
average
 more active
 normal intelligence, slight learning disabilities
 delayed emotional maturity
 normal sexual development
Trisomy X
 XXX
 1 in every 2000 live births
 produces healthy females
 Why?
 Barr bodies
 all but one X chromosome is inactivated
Turner syndrome
 Monosomy X or X0
 1 in every 5000 births
 varied degree of effects
 webbed neck
 short stature
 sterile
A few oddities
 It is possible to be XY and female. Two ways this can happen:

1. the SRY gene can be inactivated by a mutation. If SRY
doesn’t work, testes don’t develop and the embryo develops as
a normal female.

2. In a condition called “androgen insensitivity”, the person
is XY with a functional SRY gene, but her cells lack the
testosterone receptor protein, so the cells don’t ever get the
message that the testosterone is sending. Testes develop in the
abdominal cavity, and no ovaries, fallopian tubes, or uterus
develop. At puberty, the internal testes secrete testosterone,
which gets converted into estrogen and the body develops as a
normal (but sterile) adult female.
Hermaphrodites ?!?
 Hermaphrodite: An individual that
has all female reproductive parts, and
all male reproductive parts
 No such thing in Humans
Hermaphrodites
In some cases, the cells respond a little bit to testosterone
produced by the testes. The embryo develops with ambiguous
genitalia, neither completely male not completely female.
Another condition, congenital adrenal dysplasia, causes the
adrenal glands to produce an abnormally large amount of
testosterone in a female embryo, This can also cause
development of ambiguous genitalia.
 Another rare condition: a chimera occurs when two separate
embryos fuse together. This can result in a person with some
XX cells and some XY cells. This condition is extremely rare:
more people say they have it than actually do.
Twins
 2% of births
 Monozygotic (Identical) 30% of twins
A single zygote splits into two. This happens between 1 to
9 days after the zygote forms.
The twins share the same genome
Twins
 Dizygotic (Fraternal) 70% of twins
Two separate eggs are fertilized with two separate
sperm. Two totally independent zygotes are created.
The twins have different genomes
Twins
 Conjoined twins – very rare (1 in 200,000)
Identical twins who fail to completely separate after the 13th day after
fertilization
This may be due to the fusion, or incomplete separation of zygotes
May be two fully formed individuals connected at various locations, or
rarely, parasitic twins, where one is much smaller and less formed, or
even completely contained.
Genetic Disorders
Biology
Unit 6
Velekei
Recessive Disorders
 Disorders that are only expressed in
the phenotype when 2 recessive
alleles are present.
 DD = Normal
 Dd = Carrier
 dd = Affected by disorder
2 Examples
of Recessive Disorders
Tay-Sachs Disease
 Cause: gene to make the enzyme Hex-A
is not working. Hex-A is an enzyme
that breaks down lipids in the brain.
 Result: Without this enzyme the lipid
accumulates on nerve cells, specifically
in the brain causing severe brain
damage. Victims of this disease to not
live past age 5
Tay-Sachs Brain
Common in Eastern European Ashkenazi Jews
 This is a group of
people descendent of
medieval Jews from
the Rhineland area.
(Rhineland: near the
river Rhine in
Germany)
 Common in this
population (1 in 30)
How is Tay-Sachs disease passed?
Each parent must be a Carrier
Offspring:
25% Normal
50% Carriers
25% Tay-Sachs
Cause of Cystic Fibrosis
 A defect in the CFTR gene
 The CFTR gene makes a protein that controls
the movement of salt and water in and out of
your body's cells.
 In people who have CF, the gene makes a
protein that doesn't work well.
Results of Cystic Fibrosis
 Thick mucus is produced by the body
 Mucus fills lungs causing lung infections
 Mucus blocks pancreas which causes digestive
problems
 Mucus can block bile ducts in liver causing
liver failure.
Cystic Fibrosis
Cystic Fibrosis
Most common in Caucasian
(white) populations
(1 in 2500 to 3500)
1 in 17,000 African
Americans
1 in 31,000 Asian
Americans
Carriers of Cystic Fibrosis
Offspring:
25% Normal
50% Carriers
25% Cystic Fibrosis
Dominant Disorders
Disorders expressed in heterozygous and
homozygous dominant individuals
 DD = Affected
 Dd = Affected
 dd = Normal
2 Examples
1) Huntington’s Disease
Cause:
Brain cells degenerate over time
Results:
 Mood swings, loss of muscle control,
loss of memory and inability to learn, death
 Usually adult-onset, appears around ages 40-50
 Outlook is 10-15 years of survivability
 hh = Normal
 HH or Hh = will get and die of this disease
Huntington’s is most common in certain parts of
Venezuela (700 in 100,000)
Generally affect 3-7 in 100,000 of European ancestry
Less common in African-American & Asian American
Person with Huntington’s (heterozygous)
and a person without Huntington’s
Hh x hh
Offspring:
50% Huntington’s
50% Normal
2) Marfan’s Syndrome
 Cause: Defective gene for fibrillin-1 that
results in abnormal connective tissue
 Results: Aorta may stretch or become weak,
causing aortic rupture, the leading cause of death
 Eye/lens problems
 Excessive long bone growth (long arms & fingers)
 Hypermobile joints (too flexible)
Sickle Cell: Autosomal Co-Dominant
Disorder
 Mutation in the hemoglobin gene affecting the
shape of red blood cells
 1/3 of people in Sub-Saharan Africa have this
gene
Sickle Cell: Cross two heterozygous
individuals
25%
 Normal Hemoglobin: _____
50%
 Sickle Cell Trait: _____
 Sickle Cell Anemia: _____
25%
H
S
H HH HS
S HS
SS
Sickle Cell: Autosomal Co-Dominant
Disorder
 Sickle shaped cells are resistant to Malaria