Sex-Linked and Nontraditional
Modes of Inheritance
Minh Thong Le, PhD.
Etiology and genes
• Multiple gene disease
• Single gene disease (or monogenic):
OMIM database, 1960s by Dr. Victor A. McKusick
155 Mb
60 Mb
16.5 kb
X CHROMOSOME INACTIVATION
• Dosage compensation in sex chromosomes
proteins
• Lyon’s hypothesis (1960)
• Early random inactivation of one Chr. X on each female
cell
• Random but fixed process
• Females = mosaics (50|50)
• Males = hemizygous
Females = mosaics (50|50)
Cell memory maintained by epigenetic mechanisms
Cell memory maintained by epigenetic mechanisms
Examples: Calico cat
Examples: X-linked ocular albinism (melanin defect)
Mom
Son
New findings of X inactivation
• Start from day 7 – 10 after fertilization
• Initiated at X inactivation center (~ 1 Mb) and expand
• Placenta has only Xmale inactivated
• Reactivation in female germline stem cell
• Barr body number is only one less than number of X
chromosomes (Only one X chr. active in each cell == normal
dose of protein)
• Incomplete inactivation (15% escaped)
XXY
X inactivation mechanisms
• Long noncoding RNA
(lncRNA): XIST gene in
inactivation center
• Late replication
• Condensation
• Methylation
• Histone deacetylation
SEX-LINKED INHERITANCE
• Y linked
• X linked
• Recessive
• Dominant
• But:
• Variable expression
• Incomplete penetrance
• Random X inactivation
X-Linked Recessive Inheritance
• Complicated, depend on sex of affected peoples
and genotypes of the parents
• Well known disease:
• Hemophilia A
• Duchenne muscular dystrophy
• Red–green colorblindness
Other diseases
X-Linked Recessive Inheritance: consequence
• Female:
• Homozygous of disease gene: expressed disease phenotype
• Heterozygous carrier: differ from autosome recessive
• 50 % cells normal
• 50 % cells expressed disease phenotype
• In total, 50 % of normal protein level is sufficient  mild or no effect
• Male:
• Hemizygous of disease gene  express the disease
X-Linked Recessive Inheritance: frequency
• Frequency of disease much different between male and
female
• Frequency of disease allele q == recurrence of affected male >>>
female q2
• Ex: hemophilia A: 1 per 10,000 males
• q = 0.0001
•  Affected female = q2 = 1/100000000
X linked disease is much more common in male than in female
X-Linked Recessive Inheritance: transmitting pattern
Common pedigree
• No father to son transmission (at least not by father’s gene)
• But all daughters receives bad gene from affected dad
X-Linked Recessive Inheritance: transmitting pattern
Common matings
X-Linked Recessive Inheritance: transmitting pattern
Less common mating
X-Linked Recessive Inheritance: other cases
• Female with heterozygous for recessive disease also
affected:
• X inactivation is random (! Not 50|50)
• About 5% of female heterozygotes exhibit hemophilia A
and are termed manifesting heterozygotes.
• Mildly affected
• Case of female express all disease on Chr. X ???
• Chr X – segment rearrangement
X-Linked Dominant Inheritance: characteristics
• Less prevalence
• Twice common in females
than males
• No father-to-son
transmission
• Less skipped generations
• Ex:
• Hypophosphatemic rickets
(impaired reabsorb
phosphate ==> abnormal
bone)
• Incontinentia pigmenti type 1
(only in female)
• Rett syndrome: MECP2 gene
mutation (chr condensasion
disorder)
X-Linked Dominant Inheritance: transmitting pattern
X-Linked Dominant Inheritance vs Recessive Inheritance
Y-Linked Inheritance
• Very simple to see ^^
• Direct transmitted
from father to son
• Ex:
• Hearing loss by DFNY1
gene
SEX-LIMITED AND SEX-INFLUENCED TRAITS: not sex linked
• Sex-limited: occurs in only one of the sexes
• Due to anatomical differences
• Ex: Inherited uterine or testicular defects
• Sex influenced:
• Not mainly due to the sex chr gene but partly relate
(may be elevated the effect)
• Ex: male-pattern baldness: both male (more common) and
female
• Related in part to sex differences in hormone levels
• Autosomal genes
MITOCHONDRIAL INHERITANCE
• Critical important for cell survival
• Genome size: 16,569 bp
• 2 rRNA
• 22 tRNAs
• 13 polypeptides relate to oxidative
phosphorylation
• ~ 1000 nuclear genes have products
transfer to mitochondria
• Mainly in maternal line (very less
and rare in pathernal line)
• Mutation rate: 10 time higher
than nuclear
MITOCHONDRIAL INHERITANCE
• Heteroplasmy: portion of mutant mtDNA per normal in each cell (more
mutant  more effected
• Random divided in cell propagation
•  high variation in effects (diganostics???)
• More serious effect in organs need lot of energy (nervous system)
• Ex: Leber hereditary optic neuropathy (LHON) (miss sense mutation =>
optic nerve death)
• Other: single-base mutations, deletion, and duplications
• late-onset deafness
• Some cases of Alzheimer disease
• Contribute to aging process
MITOCHONDRIAL INHERITANCE: transmitting pattern
• Only female to offprings
• Complete penetrance (but in variation)
GENOMIC IMPRINTING
• Mendel’s theory: same phenotype if the mutant allele inherited from
mom or dad: But not always true
• Many gene in humans are inactived (not transcripted to RNA) from
specific parent (other copy is active)
• Resulting in the protein dose
• ~ 100 human genes are imprinted
• Imprinted genes located in gene clusters
• Imprinted genes: heavily methylated, histone hypoacetylation,
condensation of chromatin == X inactivation in mechanism
GENOMIC IMPRINTING
Imprinting pattern must be reset during gemetogenesis
GENOMIC IMPRINTING: Beckwith–Wiedemann Syndrome
Risk of increased kidney tumor
Uniparental disomy, in this case affecting chromosome 11
Loss of maternal methylation of IGF2
Beckwith–Wiedemann Syndrome:
• 20 – 30 % cases: pathernal uniparent disomy of chr 11 or loss of
methylation of DMR1
• Normal: IGF2male active & IGF2female inactive  only 1 copy active
• Affected: pathernal uniparent disomy  2 active copies  increased
dose
• 50 – 60 % cases: loss of methylation in DMR2