PATTERN OF INHERITANCESEX-LINKED AND MITOCHONDRIAL INHERITANCE

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 mitochondrial DNA.BACK GROUND

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 X-chromosomes, will produce X-linked gene products in quantities roughly similar to the those in males (dosage compensation)X-INACTIVATIONLyon 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 hetrozygotesX-INACTIVATIONLyon 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-INACTIVATIONLyon hypothesis

X-INACTIVATIONLyon hypothesisThe 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.

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.

CHARACTERISTIC OF X-LINKED DOMINANT 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 paradoxThe Fragile X : A Puzzling Patern 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).

Sherman paradoxThe Fragile X : A Puzzling Pattern of 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.

CHARACTERISTIC 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 X-LINKED RECESSIVE INHERITANCE

PATTERN OF Y-LINKED 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.

MITOCHONDRIAL INHERITANCE

PATTERN OF MITOCHONDRIAL INHERITANCE

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 expression3. Kerns-Sayre disease, Pearson syndrome, and Chronic progressive external ophthalmoplegia (CPEO).Cause by duplication and deletionSEVERAL MITOCHONDRIAL DISEASES