sex chromosomes and nondisjunction diseases a. p. biology chapter 15 mr. knowles liberty senior high...
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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 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.
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Spermatogenesis Oogenesis
44 + XY
22 + X 22 + Y
44 + XX
22 + X 22 + X
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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 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!
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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.
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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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>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.)
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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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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 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 MD
Normal Duchenne MD
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Anti-Dystrophin Antibody Staining
Normal Duchenne 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--> 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 Labeling
Normal Carrier
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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 Down’s- Trisomy 21
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Down’s 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
X X
X YX
Y
XXX X
XXY Y
NONDISJUNCTION
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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 Turner’s 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.