PATTERN OF INHERITANCE

SEX-LINKED AND
MITOCHONDRIAL INHERITANCE

BACK GROUND
The human X chromosomes is a large
chromosomes (5% of the nuclear
genomes DNA, or 160 miillion bp).
More than 500 coding genes have been
localized to the X chromosomes.
Diseases caused by genes on this
chromosomes are said to be X-linked.
In contrast to the X-chromosomes, the Y
chromosome is quite small (70 Mb) and
contain very few known genes.
More than a dozen dieases are now known
to be caused by mutations in

X-INACTIVATION
Lyon hypothesis
The Lyon hypothesis states that one X-chromosomes
in each cell is randomly inactivated early in the
embryonic development of females. This ensure
that females, who have two copies of the Xchromosomes, will produce X-linked gene
products in quantities roughly similar to the those
in males (dosage compensation)

X-INACTIVATION
Lyon hypothesis
The Lyon hypothesis is supported by cytogenetic
evidence: barr bodies, which are inactive X
chromosomes, are seen only in cells with two or
more X chromosomes. It is also supported by
biochemical and animal studies that revealed
mosaicsm of X-linked traits in female hetrozygotes

X-INACTIVATION
Lyon hypothesis
X inactivation is random, fixed and incomplete. The
latter fact helps to explain why, in spite of X
inactivation, most individuals with abnormal
numbers of sex chromosomes are not
phenotypically normal.

X-INACTIVATION
Lyon hypothesis

The XIST gene is located in the X inactivation center

and is required for X inactivation. It encodes an RNA
product that coats the inactive X chromosomes.
X in activation is also associated with methylation
of the inactive X chromosome, a process that may
help to ensure the long- term stability of inactivation.

CHARACTERISTIC

OF X-LINKED

DOMINANT

INHERITANCE

They are about twice as common in females as males.

Vertical transmission.
Male-male (father-son) transmission are not seen.
Expression less severe in female heterozygotes than in
affected man.
The recurrence risk for heterozygotes female and
normal male mating are: 50% sons affected, 50%
daughters affected.
The recurrence risk for normal female and affected
male mating are: 0% sons affected, 100% daughters
affected.

Sherman paradox

The Fragile X : A Puzzling Patern of Inheritance

Fragile X syndrome is a the single most common
inherited cause of mental retardation & characterized
by a distinctive facial appearance with large ears and
long face, hypermobile joint and macroorchidism in
postpubertal males.
Fragile X syndrome is an X-linked dominant condition
with 80% penetrance in males and only 30%
penetrance in females (variability expression is
thought to be related to X-inactivation)

Sherman paradox

The Fragile X : A Puzzling Pattern of Inheritance

The disease genes that responsible for Fragile X
syndrome :
The gene FMR1. DNA sequences analysis showed that
the 5untranslated region of the gene contains a CGG
repeat unit that is present in 6 to 50 copies in normal
individuals. Those with fragile syndrome have 230 to
1.000 or more CGG repeats (full mutation). Normal
transmitting males & their female offspring have 50
230 repeats (premutation).

CHARACTERISTIC

OF X-LINKED

RECESSIVE

INHERITANCE

Much greater prevalence of affected males, affected

Homozygous females are rare.
Skipped generations may be seen (transmission through
carrier female)
Male-male transmission is not seen.
The recurrence risk for heterozygotes female and normal
male mating are: 50% sons affected, 50% daughters
heterozygous carriers.
The recurrence risk for normal female and affected male
mating are: 0% sons affected, 100% daughters
heterozygous carriers.

PATTERN OF X-LINKED RECESSIVE INHERITANCE

PATTERN OF X-LINKED RECESSIVE INHERITANCE

PATTERN OF X-LINKED RECESSIVE INHERITANCE

PATTERN OF X-LINKED RECESSIVE INHERITANCE

PATTERN OF Y-LINKED INHERITANCE

MITOCHONDRIAL INHERITANCE
The mitochondria (mt) have their own DNA molecules &
unlike nuclear DNA, mtDNA contains no introns.
The mt genome encodes 2 rRNAs, 22tRNA & 13
polypeptides involved in oxidative phosphorylation.
The mutation rate of mtDNA is about 10 times higher
than that of nuclear DNA. This is cause by a lack of
DNA repair mechanism in the mtDNA and possibly
also by damage from free oxygen radicals released
during the oxidativephosphorylation process.

MITOCHONDRIAL INHERITANCE
Since each cell contains population of mtDNA molecule,
a single cellcan harbor some molecules that have
mtDNA mutation and other molecules that do not.
This heterogeneity in DNA composition term
heteroplasmy.
The proportion of mutant mtDNA molecules may
cahange through replicative segregation, chance
variation and selective advantage

MITOCHONDRIAL INHERITANCE
Transcription mt DNA takes place in mitochondria
independently of the nucleus. Because it is located in
the cytoplasma, mtDNA is inherited exclusively
through the maternal line.
Males inherit their mtDNA from their mothers, but they
cannot pass it to their offspring because sperm cells
contain only a few mtDNA that do not enter the egg.

PATTERN OF MITOCHONDRIAL INHERITANCE

SEVERAL MITOCHONDRIAL DISEASES

1. Leber hereditary optic neuropathy (LHON)
Cause by missense mutation in protein coding mDNA genes.
Heteroplasmy is rare in LHON so expression tends to be
relatively uniform and pedigrees usually display a clear pattern
of mitochondrial inheritance.
2. Myoclonic epilepsy with ragged-red fiber disease (MERRF).
Mitochondrial encephalomyopathy and strokelike episodes
(MELAS)
Cause by single-base mutation in a tRNA gene. Heteroplasmy
and highly variable in its expression

3. Kerns-Sayre disease, Pearson syndrome, and Chronic

progressive external ophthalmoplegia (CPEO).
Cause by duplication and deletion