8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 1/44
Sex-linked and Mitochondrial
inheritance
Chapter 5
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 2/44
Human X and Ychromosomes - these
are homologous overonly a tiny portion oftheir length (at oneend). Most of the DNAis different between
the chromosomes.The X has manygenes whose functionis not related to sex-determination, while
the few Y-linked genesare mostly involvedwith sex determination.
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 3/44
Sex-linked genes in humans
• Some genes on X-chromosome code for female
traits; some genes on Y chromosome code for
male traits
• X chromosome has 164 million bases; Y
chromosome has 59 million bases
• Current estimate of X-linked genes range from
729-748
• Current estimate of Y-linked genes is 78
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 4/44
LYON HYPOTHESIS
• 1961 English geneticist Mary Lyonproposed this hypothesis to describe Xinactivation
• Consists of 5 tenants – 1. Condensed X chromosome isgenetically inactive
– 2. X inactivation in humans occurs early indevelopment when embryo consists ofabout 32 cells. 1 or 2 days followingfertilization
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 5/44
5 TENANTS OF LYON HYPOTHESIS
• 3. At this stage in each of the 32 cellsone of the X chromosomes is randomlyinactivated
• 4. Inactivation is a mitotically stableprocess
• 5. Net effect of this is to equalize (genedosage) phenotypes in males and
females for genes that are carried onthe X chromosome
RESULTS IN VARIABLE EXPRESSION OFHETEROZYGOTES (X* X)
-MOSAICISM (e.g. COAT COLOUR GENES)
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 6/44
Human Chromosomes
• One X chromosome in females is inactivated early inembryonic development.
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 7/44
PART OF THE X CHROMOSOME IS NOT
INACTIVATED• End-to-end attachment of the short arms of the XY form
bivalent at diplotene-metaphase I.• This is due to 2.6 mb homologous region between X and
Y chromosome with obligatory cross-over during male
meiosis. This region is called pseudoautosomal region(PAR1)• Genes in PAR1 are expressed whether they are on the
active X chromosome or the inactive X chromosome• Another homology region between X and Y PAR2 exist
near the telomere of the long-arm of both X and Y, 320kb, recombination frequency in this region is 2% of malemeiosis, genes in PAR2 also escape inactivation infemale cells
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 8/44
Xist – X inactive-specific transcript
Avner and Heard, Nat. Rev. Genetics 2001 2(1):59-67
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 9/44
X-linked recessive (XR)
Heterozygous normal mother
(carrier)
Hemizygous normal father
50% risk for an affected male
50% for a normal male
100% chance for normal female:
50% carrier female
50% homozygous normal female
Males and females NOT equallyaffected
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 10/44
X-l i n ked r ecessi v e (XR )
Homozygous dominant = normal female (XAXA)
Heterozygous dominant = normal female carrier (XAXa)
Homozygous recessive = affected female (XaXa)
Hemizygous dominant = normal male (XAY)
Hemizygous recessive = affected male (X
a
Y)
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 11/44
Basic pattern ofinheritance of X-Y-
linked genes.Note thatmales are technicallyhemizygous.
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 12/44
X-linked recessive inheritance (XR)
– Affects almost exclusively men
– Affected men born from carrier mother, with 50% risk of disease
– No male to male transmission
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 13/44
X-linked dominant (XD)
One trait, 2 alleles
A = dominant abnormal allelea = recessive normal allele
Must consider which parent has the
abnormal gene when assessing risk
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 14/44
X-L inked D om in an t (XD )
For heterozygous affected females:
50% risk for affected son
50% risk for affected daughter
For hemizygous affected males:
100% risk for affected daughter
0% risk for affected son
Males and females NOT equally
affected
Affected
Father
Normal
Mother
Affected Normal Affected Normal
female male female male
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 15/44
X-l i n ked dom i n an t (XD )
Homozygous dominant = affected female (XAXA)
Heterozygous dominant = affected female (XA
Xa
) Homozygous recessive = normal female (XaXa)
Hemizygous dominant = affected male (XAY)
Hemizygous recessive = normal male (XaY)
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 16/44
XD Pedi gr ee
Affected females risk affected
sons and affected daughters
Affected males risk affected
daughters
No male to male transmission
Difficult to distinguish from
autosomal dominant
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 17/44
X-linked dominant traits
- on average, twice as many females afflicted as males
- males are often more severely affected.
- typically associated with miscarriage or lethality in males.
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 18/44
X-linked dominant inheritance (XD)
– More females than males
– All daughters of affected males are affected, but no sons
– A child of an affected female has 50% risk of disease
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 19/44
Y-linked inheritance (Y)
– Affects only males
– Affected males always have affected fathers
– All sons of an affected male are affected
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 20/44
Hemophilia
• Hemophilia A: X-linked recessive
- Inability to form blood clots, caused by lack of clottingfactor VIII.
- Severe bleeding from wounds
- hemorrhages in the joints and muscles.- Bruising is frequent.
- Variable expression (nonsense vs missense mutations)
• Hemophilia B (Christmas disease) : Clotting defectcaused by lack of factor IX.
• Willebrand disease: AR, mutation in the carrier protein ofFactor VIII
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 21/44
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 22/44
Duchennes Muscular Dystrophy (DMD)
-X-linked recessive-1 in 3500 males afflicted
- 5-10% of carrier females have muscle weakness, afew have severe disease- age on onset between 1 and 6 yrs
- confined to wheel chair by age 11 and death by age 20
-The disease is caused by a defect in a gene that codes for a
protein called dystrophin (most mutations are deletions)-Dystrophin stabilizes cytoskeleton during muscular
contraction-Mutations in dystrophin leads to progressive weaknessand loss of muscle
-Creatine kinase: elevated about 20 times above the upper
limit: Used in diagnosis of DMD
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 23/44
Becker Muscular Dystrophy (BDM)
- X-linked recessive
- has partially functional dystrophin
- later age of onset, milder symptomsand longer life span
• DMD and BDM are different allelic
forms of the same disease.
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 24/44
Color blindness
8% males have red-green color blindness
red color blindness – can’t see red
green color blindness – can’t see greens
both are X-linked recessive traits
(map to the X chromosome)
Blue color blindness
autosomal recessive
maps to chromosome 7
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 25/44
Hypophosphatemic rickets
X-linked dominant traitKidneys are impaired in their ability to reabsorb phosphateAbnormal ossification, with bending and distortion of thebones
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 26/44
Incontinentia Pigmenti type I
• X-linked dominant
• Abnormal skin pigmentation
• Missing teeth• Ocular abnormalities
• Neurological abnormalities
• Seen only in females• Lethal to males before term
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 27/44
Rett syndrome
• X-linked dominant
• Autistic behavior
• Mental retardation• Seizures
• Gait ataxia
• Caused by mutations in MECP2 gene
• 1 in 10,000-15,000 females affected
• Mostly lethal in males before term
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 28/44
Fragile X Syndrome
Note elongated face, prominent ears
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 29/44
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 30/44
Clinical Features in Fragile X Males
• Delayed developmental
– Walk (20.6 months)
– First clear words (20 months)
• Pre-pubertal:
– Developmental delay (especially speech)
– Mental retardation (IQ 30-50)
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 31/44
Mitochondrial inheritance
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 32/44
Mitochondrion • Organelle providing cellularenergy.
• Contains small circular DNA.
• No crossing over or DNA
repair.
• Many copies of themitochondrial genome per cell.
• 37 genes, no histones, nointrons.
• Maternal inheritance
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 33/44
Mitochondrial Inheritance
- mitochondria are maternally inherited
-oocyte cytoplasm to egg transmission
Key features of mitochondrial inheritance
- only females can transmit defected genes to offspring
- both male and female offspring can be affected
- phenotype often related to defect in energy production.
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 34/44
Mitochondrial Inheritance
• Mitochondria and their genome are transmittedfrom a mother to all of her offspring.
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 35/44
tRNA Gene Organization in Human Mitochondrial Genome
• 22 tRNA genes
• Separate polypeptide-encoding genes
• The primary transcripts are cleaved on either sideof each tRNA gene to produce monocistronictranscripts
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 36/44
Mitochondrial DNA• maternally inherited
• No recombination
• mtDNA encodes 13 of 67 components of theOXPHOS system
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 37/44
Heteroplasmy = different % of normal &
abnormal mitochondria in single cells or tissues
and or and
x x x x x x
o o o o o o
o o o o o o
O o o
x x x x
o o o o o
x x o o o
o o o ox
o o o o o
o o o o
x x x x x
o o o
Homoplasmic – cells contain one type of mtDNA
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 38/44
The mitochondrial genome is a
hotspot for mutations• 93% of mtDNA is coding DNA
• Respiratory chain and the oxidative
damage to mtDNA• mtDNA is not protected by histones
• Many round of replication
• Some DNA damage cannot be repaired(like thymidine dimer).
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 39/44
Mitochondrial Inheritance
Disease phenotype dependent upon:
gene(s) involved type of mutation
(missense/nonsense/deletion)
% normal vs abnormal mitochondria
tissue involved
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 40/44
Proportion of
mutant mtDNA
and tissue in
which theyreside influence
phenotype
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 41/44
“Mitochondrial Theory” of Aging
• Normal mitochondrial function generates
significant oxidative stress
• This oxidative damage mutates themtDNA
• Mutated mtDNAabnormal energy
metabolism MORE oxidative stress!
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 42/44
Examples of Mitochondrial Disorders
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 43/44
Mitochondrial disorders
Leber hereditary optic neuropathy (LHON)- Mainly in young adult males
- characterized by optic nerve degeneration resulting in lossof central vision.
- >90% of affected families have mutations at nucleotides11778, 3460 or 14484, that encode components ofcomplex I of the respiratory chain.
8/8/2019 Medical-Genetics-ch5-2009 Medical Students [Compatibility Mode]
http://slidepdf.com/reader/full/medical-genetics-ch5-2009-medical-students-compatibility-mode 44/44
Myoclonic Encephalopathy with Ragged
Red Fibers (MERRF)• ataxia
• epilepsy
• muscle weakness
• lactic acidemia
• ragged red fibers seen in muscle biopsy
• abnormal energy metabolism in muscles
• Caused by missense mutation in the mt
tRNA lys gene (A8344G) in 80% of cases
Top Related