The aim of this lecture is to recognize group of terms

that will help us to understand genetic rather only

saying why there is an equalization in X-linked traits

between male and female and why females less severely

affected by X-linked dominant inheritance

INTRODUCTION

Females carry two X chromosomes and therefore have two

copies of all the genes on that chromosome. Males are XY and

have only one copy of all genes on the X chromosome. At

first glance, it would seem that females should have higher

levels of all products encoded by genes on the X chromosome.

Is this true, or is there a mechanism that equalizes the

expression of genes on the X chromosome so that males and

females each have the same amounts of gene products encoded

by genes on the X chromosome?

Ex/ the gen coding for clotting factor VIII lcated on X-

chromosome. Because normal females have two copies of the

clotting-factor gene and normal males have only one, does the

blood of females contain twice as much of this clotting factor

as males? The answer is straightforward: Careful

measurements indicate that females have the same amount of

this clotting factor as males.

How does this happen? A process called dosage compensation

equalizes the amount of X chromosome gene products in

both sexes.

How genes are inactivated?

It one of the inactivation method involve in activation

of specific genes on specific chromosomes by a process

called methylation” will be discus later”.

1- It is now known that parental origin often

determines whether the maternal or paternal allele of

certain genes will be expressed. This pattern of

differential expression is called genomic imprinting.

2- Imprinting is not a mutation or permanent change in a

gene or a chromosome region. What is affected is the

expression of a gene, not the gene itself; imprinting does not

violate the Mendelian principles of segregation or

independent assortment.

3- Remember that a chromosome received by a female from

her father is transmitted as a maternal chromosome in the

next generation. In each generation, the previous imprinting

is erased, and a new pattern of imprinting defines the

chromosome as either paternal or maternal.

4- It is important to say now Imprinting does not affect all genes.

Only genes in certain regions of human chromosomes 4p, 8q,

15q, 17p, 18p, 18q, and 22q are imprinted, and so on imprinting

do not effect X-linked traits.

Ex/ Willi syndrome (PWS) and Angelman syndrome (AS).

These two disorders are caused by mutations in the same region

of chromosome 15 but have very different symptoms. Deletion

of paternal genes on chromosome 15 results in PWS, and

deletion of maternal genes from the same region of chromosome

15 produces AS.

- In the late 1940s, Murray Barr and his colleagues were studying nerve

conduction in cells from cats. Under the microscope, he saw a small, dense

spot on the inside of the nuclear membrane in cells from female cats that did

not appear in cells from male cats. A geneticist, Susumo Ohno, suggested that

this spot—now called the Barr body—might actually be a genetically inactive

X chromosome found in all female mammals.

- About a decade later, Mary Lyon was studying the inheritance of coat color

in mice. In female mice heterozygous for X-linked coat-color genes, Lyon

found a unique phenotype that was different than either homozygous parent

and was not a blend of parental coat colors. Instead, the female mice had

patches of the parental colors in a random arrangement. Males, hemizygous

for either gene, never showed such patches and had coats of uniform color.

male nucleusfemale nucleus

Mary Lyon put her genetic results together with Ohno’s suggestion about

Barr bodies in the cells of mammalian females and proposed her

hypothesis (known as the Lyon hypothesis) about how dosage

compensation works:

1- Only one X chromosome is genetically active in the body cells of

female mammals. The second X chromosome is inactivated and tightly

coiled to form the Barr body.

2- The inactivated chromosome can come from either parent.

3- Inactivation takes place early in development. After four to five rounds

of mitosis following fertilization

4- each cell of the embryo randomly inactivates one X chromosome

except where one of the X chromosomes is abnormal (deletion,

insertion, inversion, etc.) An abnormal X is always inactivated.

However, if there is a translocation between an X chromosome and an

autosome, the normal X is inactivated and the translocat X remains

active

5- This inactivation is permanent (except in germ cells), and all

descendants of a particular cell will have the same X chromosome

inactivated.

6- Because genes on only one X chromosome are expressed in females,

this equalizes the amounts of products from X-linked genes in males

and females.

7- The Lyon hypothesis means that female mammals

are actually mosaics, constructed of two different cell

types: Some cells express genes from the mother’s X

chromosome, and some cells express genes from the

father’s X chromosome.

Conclusion:

the severity of X-linked dominant disease in female

is usually less than in male

1 in 5,000 births

45 chromosomes X only

#23 MonosomyNondisjunction

96-98% do not survive to birthNo menstruationNo breast developmentNarrow hipsBroad shoulders and neck

It is thought that in early stages of

embryology (before switching of to one of

the two X chromosomes), both of the X

chromosomes are needed but no one knows

how and why they are important.

NOTE/The human Y chromosome is composed of two different

parts: a pseudoautosomal region that is homologous-Often used

loosely to indicate that sequences are very similar- to a region of

the X chromosome and which is responsible for sex

chromosome pairing and a Y-specific part that encodes the sex

determining gene. Genes within the pseudoautosomal region are

not sex linked .

Inactivation begins and is regulated from a region on the X

chromosome called the X inactivation center (Xic). One of the

first steps is expression of the XIST gene, located in the Xic.

When XIST is expressed, the X chromosome becomes coated

with XIST RNA . This causes almost all genes on the coated

chromosome to become inactivated and form a Barr body. The

small region not inactivated is called the pseudoautosomal

region and contains genes homologous to those on the Y

chromosome. Once an X chromosome is inactivated, all copies

made in subsequent cell divisions are also inactivated.