Sex Chromosomes and Nondisjunction Diseases

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Sex Chromosomes and Nondisjunction Diseases

• A. P. Biology
• Chapter 15
• Mr. Knowles
• Liberty Senior High School

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Human Chromosomes

• 46 Total (23 pair)
• 22 pair are perfectly matched-autosomes.
• Remaining pair- sex chromosomes.
• Human XX normal female
• XY normal male
• Y chromosome highly condensed with a few dozen
  genes.

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Chromosomal Basis of Sex

• Two similar Xs 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.

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Spermatogenesis Oogenesis
44 XY
44 XX

22 X
22 X
22 X
22 Y
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Chromosomal Basis of Sex

• Each ovum contains one X chromosome.
• Sperm have either X OR the Y chromosome.

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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.

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Y Chromo. Encodes Few Genes
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SRY on the Y Chromosome
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The Human Y Chromosome

• Encodes a protein called SRY- the
  sex-determining 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.

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SRY Protein Binding to DNA (Gene Regulation)
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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 Mendels techniques- F1 showed that the
  white phenotype was recessive to wild-type red
  eye color.
• F2 - 31 red white but all white eyes were MALE!

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Explanation to Morgans 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.

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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.

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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.

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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.

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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.

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Cytological Mapping of Chromosome 15
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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.

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Finished Human Chromosome 22
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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 mother- called
  hemizygous. More likely to be affected by
  X-linked diseases.

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gt60 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.)

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SCID

• David Vetter- lacked cytokines for the immune
  system.
• Died at age 12.

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X Chromosome Genetic Map
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Some Diseases Mapped to X
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X
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Duchennes 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 channels- mutations
  keep the channels open too long.
• Candidate for gene therapy-successful in rats.

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X-Section of Duchenne MD
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Muscle X-Section of Duchenne MDNormal Duchenne
MD
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Anti-Dystrophin Antibody StainingNormal Duchenn
e MD
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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.

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X inactivation
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Barr Bodies
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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--gt ova.

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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.

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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

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Calico Cats- An Example of Mosaicism
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What would a carrier with X-linked disease look
like?

• Diseased Phenotype? Normal?

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Anti-Dystrophin Antibody LabelingNormal Carrie
r
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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!

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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.

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Nondisjunction Leads to Abnormal Chromo. in
Zygote

• If the aberrant gamete units with a normal
  gamete, the offspring will have an abnormal of
  chromosomes- aneuploid.
• Aneuploid
• 2n 1 Trisomy
• 2n - 1 Monosomy

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Monosomics

• Organisms which have lost one copy of a
  chromosome.
• Do Not Survive Development!
• Lethal Error!

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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.

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Trisomy 13 Facies- Bilateral Cleft Lip
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Trisomy 18 Syndrome
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Trisomy 21 Karyotype
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Chromosome 21 Genetic Map
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Mapping of Chromosome 21
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Diseases Mapped to Chr. 21
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Tiffany with Downs- Trisomy 21
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Downs Syndrome (Trisomy 21) and Special Olympics
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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.

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Nondisjunction of the Sex Chromosomes

• Two Types
• Nondisjunction of the X Chromosome.
• Nondisjunction of the Y Chromosome.

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X X
NONDISJUNCTION
X X
X
XXX
X
X Y
XXY
Y
Y
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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.

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Klinefelter Syndrome (XXY)
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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.

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Turner Fetus with Cystic Hygroma
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Amber (age 4) with Turners Syndrome
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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.