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 matched-autosomes.

• 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

22 + X 22 + Y

44 + XX

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 “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.

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 mother- called 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 Vetter-

lacked 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 channels- mutations 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 chromosomes- aneuploid.

• 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.

X X

X X

X YX

Y

XXX X

XXY Y

NONDISJUNCTION

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.