Sex Chromosomes and
Nondisjunction Diseases
A. P. Biology
Chapter 15
Mr. Knowles
Liberty Senior High School
Human Chromosomes
• 46 Total (23 pair)
• 22 pair are perfectly matchedautosomes.
• Remaining pair- sex chromosomes.
• Human:
XX normal female
XY normal male
• Y chromosome highly condensed with
a few dozen genes.
•
•
•
•
Chromosomal Basis of Sex
Two similar X’s = human female
Two dissimilar X and Y = human male
NOT true for all diploid organisms.
Both sex chromosomes behave like
homologues during meiosis in the testes
and ovary. They may cross-over at Pro I.
• Each gamete receives one sex chromo.
Spermatogenesis
Oogenesis
44 + XY
44 + XX
22 + X
22 + Y
22 + X
22 + X
Chromosomal Basis of Sex
• Each ovum contains one X
chromosome.
• Sperm have either X OR the
Y chromosome.
What determines sex in humans?
• Before two months, all fetuses are
anatomically the same.
• The gonads are generic and can
become either ovaries or testes.
• Depends upon hormone levels in the
embryo.
• Trigger is the SRY gene on the Y.
Y Chromo. Encodes Few Genes
SRY on the Y Chromosome
The Human Y Chromosome
• Encodes a protein called SRY- the “sexdetermining region of Y”. SRY is a
regulator for other genes on other
chromosomes.
• Responsible for development of testes.
• Without SRY, the gonads develop into
ovaries. Female is default sex in
humans.
SRY Protein Binding to DNA
(Gene Regulation)
Sex-linked Genes Have a Unique
Pattern of Inheritance
• In 1910, Thomas Hunt Morgan saw a
remarkable mutation in Drosophila.
• Saw a mutant male with white eyes!
• Followed Mendel’s techniques- F1
showed that the white phenotype was
recessive to wild-type red eye color.
• F2 - 3:1 red : white but all white eyes
were MALE!
Explanation to Morgan’s
Dilemma
• The gene that causes the white eye
phenotype is on the X chromosome and
not found on the Y.
• Proved that inheritable traits do reside
on the chromosomes.
• Any trait or gene found on the X
chromosome- sex linked.
Mapping the First Chromosome
• In 1913, A. H. Sturtevant located
the relative positions of 5 recessive
genes on the X chromosome of
Drosophila by estimating their
frequency of recombination due to
X-over.
• This was a linkage map.
Genetic Maps
• Cross-over occurs more frequently
between two genes farther apart.
• Use x-over rates in progeny to plot
relative position of genes on
chromosomes- Linkage Map. Distance
is measured in frequency of
recombination between two genes.
• Genes very close are linked- they do not
x-over.
Genetic Map
• A linear sequence of genetic loci on a
particular chromosome. Linkage Maps
are based on frequency of recombination
between two loci.
• What about genes very far apart?
• Linkage maps are NOT a picture of
chromosomes. NOT physical map of
genes.
Cytological Maps of
Chromosomes
• Locate genes with respect to
chromosomal features such as banding
patterns.
• G-banding (Giemsa staining) stains
• C-banding (Centromere staining) stains
heterochomatin of the centromere.
Cytological Mapping of
Chromosome 15
Human Genome Project
• Physical sequencing of the DNA on
each chromosome.
• Shows the distance between loci in
DNA nucleotides.
• Finished Human Genome Project in
Spring 2000. Identified 30,000 genes in
humans in Winter 2001.
• Other genomes sequenced: C. elegans,
D. melongaster, many prokaryotes.
Finished Human
Chromosome 22
X -linked Traits
• If a sex-linked trait is recessive, female
will be heterozygous; one X comes
from the mother and the other X from
the father. Seldom will be homozygous
for the genes on the X chromosome.
• Males only inherit X from the mothercalled hemizygous. More likely to be
affected by X-linked diseases.
>60 X-linked Human Diseases
• Colorblindness
• Duchenne and Becker Muscular
Dystrophies
• Albinism-Deafness Syndrome
• Two proteins (Factor 8 and 9) for blood
clotting. Mutations here cause
Hemophilia, Hemophilia A and B.
• SCID (Boy in the Bubble, Johnny T.)
SCID
• David Vetterlacked
cytokines for
the immune
system.
• Died at age
12.
X Chromosome Genetic Map
Some Diseases Mapped to X
X
Duchenne’s Muscular Dystrophy
• On the X chromosome, the gene for
dystrophin- a protein found attached to
the inner surface of the sarcolemma in
normal muscle fibers (cells).
• Dystrophin regulates Ca+ ion channelsmutations keep the channels open too
long.
• Candidate for gene therapy-successful in
rats.
X-Section of Duchenne MD
Muscle X-Section of
Duchenne MD
Normal
Duchenne MD
Anti-Dystrophin Antibody
Staining
Normal
Duchenne MD
Female Mammals are like
Floor Tile!
• Males and females have the same amount
of proteins encoded by the X-linked genes!
HOW?
• One X chromosome in each female cell
becomes inactive during embryonic
development- X -inactivation.
• Males = Female X-linked gene activity.
X inactivation
Barr
Bodies
X - Inactivation
• The inactive X chromo. Becomes
condensed and attaches to the inside
of the nuclear envelope- Barr Body.
• Most genes are NOT expressed.
• Barr Body Chromosomes are
reactivated in ovary cells--> ova.
X - Inactivation
• Mary Lyon - showed that the
selection of which X will become the
Barr body is random and
independent in each embryonic cell
present at the time of X-inactivation.
• After the X is inactive in a particular
cell, all the mitotic descendents of
that cell have the same X inactivated.
Females are Protein Mosaics!
• Mosaics- half of her cells have the
active X derived from the mother,
half of her cells have the active X
from the father.
• If heterozygous, the same tissue will
express one allele from one X
chromosome and another allele from
the other X chromosome
Calico Cats- An Example of
Mosaicism
What would a carrier
with X-linked disease
look like?
Diseased Phenotype?
Normal?
Anti-Dystrophin Antibody
Labeling
Normal
Carrier
Mechanism of X-Inactivation
• Attachment of CH3 groups to cytosines.
• A gene is active only on the Barr body
chromosome-XIST (X-inactive specific
transcript)- encodes an RNA. These
RNA molecules bind to the
chromosome from which they were
made.
• But which X will have an active XIST
gene? Unknown!
Alteration of
Chromosome Numbers
• Primary Nondisjunction- members
of a pair of homologous chromosomes
do not move apart properly during
anaphase of meiosis I.
• Unequal distribution of chromosomes
in the daughter gametes.
Nondisjunction Leads to
Abnormal Chromo. # in Zygote
• If the aberrant gamete units with a
normal gamete, the offspring will have
an abnormal # of chromosomesaneuploid.
• Aneuploid:
2n + 1 = Trisomy
2n - 1 = Monosomy
Monosomics
• Organisms which have lost one
copy of a chromosome.
• Do Not Survive Development!
• Lethal Error!
Trisomics
• Most do not survive either.
• Some trisomies do survive for a time:
Trisomy 13, 15, 18-severe
developmental defects, die within a few
months.
Trisomy 21- Down Syndrome.
Trisomy 22- mentally retarded.
Trisomy 13 Facies- Bilateral
Cleft Lip
Trisomy 18 Syndrome
Trisomy 21 Karyotype
Chromosome 21 Genetic
Map
Mapping of Chromosome 21
Diseases Mapped to Chr. 21
Tiffany with Down’s- Trisomy 21
Down’s Syndrome (Trisomy 21)
and Special Olympics
Trisomy 21 Phenoytpe
• Slower skeletal development- short stature.
• Below normal I.Q.
• 11 X more likely for leukemia. Cancer gene
located on 21.
• Often have Alzheimer-like dimentia.
Alzheimer gene located on 21.
• Usually die prematurely.
• Caused by a nondisjunction event during
oogenesis.
Nondisjunction of the Sex
Chromosomes
Two Types:
• Nondisjunction of the X
Chromosome.
• Nondisjunction of the Y
Chromosome.
XX
NONDISJUNCTION
XX
XY
X
XXX
Y
XXY
X
Y
Nondisjunction of the X
• “Super Females” XXX- Female with
one functional X and two Barr bodies;
sterile but appears normal.
• XXY- Klinefelter Syndrome- sterile
male with female characteristics, some
mental retardation; underdeveloped
male characteristics; occurs in 1/ 500
male births.
Klinefelter Syndrome (XXY)
Without an X Chromosome!
• OY- zygote is inviable; all humans
require at least one copy of the X
chromosome.
• XO - Turner Syndrome- sterile
female, short stature, webbed neck,
and immature sex organs, lower I.Q.;
occurs in 1/ 5,000 female births.
Turner Fetus with Cystic
Hygroma
Amber (age 4) with Turner’s
Syndrome
Nondisjunction Also Occurs
in Males!
• “Super Males” XYY- fertile males of
normal appearance; occurs in 1/ 1,000
male births.
• Historically thought to be 20 X higher in
institutionalized males. Not true.