sex chromosomes and nondisjunction diseases a. p. biology chapter 15 mr. knowles liberty senior high...

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.