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Sex Chromosomes and
inheritance
X-Linked Traits
1
Sutton’s Hypothesis
Genes are structures localized
on chromosomes
Each of the two alleles is on
one chromosome of a couple
of chromosomes
2
Each allele of a
gene is located on
one chromosome of
a couple.
At the end of
meiosis each
gamete contains
only one allele of
each gene.
If two genes (4
alleles ) are
considered we can
observe
independent
segregation of the
alleles of the two
genes
(Mendel’s 3rd
law)
4
Chromosomal sex determination
Insect, protenor belfragei (Stevens, 1900)
FEMALE MALE 14 CHROMOSOMES 13 7 BIVALENTI 6 + 1
GAMETES [F >>7] [M>>6] [M>>7] 7 + 7 = 14 FEMALE
XX
7 + 6 = 13 MALE
X0
5
6
HUMAN KARYOTYPE
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Sex and Chromosomes
FEMALE
MALE
XX
XY
BIRDS, SOME REPTILES
ZW
ZZ
8
In some species environmental factors are relevant for
sex determination
9
HUMAN KARYOTYPE
10
zanzara
Meiotic pairing between
X and
topo
Y
is at terminal regions
called pseudo-autosomal
renna
marmotta
hamster cinese
11
DIAKINESIS IN MAN
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Homologous regions between X and Y: pseudo autosomal
region
Testis Determining Factor=TDF
(sex
determinig region Y)
TDF = SRY
13
Female : XX >>
X+X+
X+X
XX
Male XY >>
X+Y
XY
Drosophila Melanogaster
15
Inheritance of X‐linked Gene for Eye Colour in Drosophila
The first X‐linked gene found in Drosophila was the recessive white eye mutation (Morgan, 1910). When a homozygous red‐eyed female (dominant) is crossed with a white‐eyed male (recessive), all individuals in the F1 are red‐eyed. X*
White (r)
Y
X
Red (D)
X X*
XY
X
Red (D)
X X*
XY
17
When we cross the individuals from F1………
X
Red (D)
Y
X
Red (D)
XX
XY
X*
White (r)
XX*
X*Y
18
…but when the cross is between a white‐eyed female and red‐eyed male, male offspring in the F1 have white eyes.
X
Red (D)
Y
X*
White (r)
XX*
X*Y
X*
XX*
X*Y
19
When heterozygous red eyed females are crossed with white‐
eyed males, both sexes segregate 1: 1
X*
White (r)
Y
X*
X*X*
X*Y
X
Red (D)
XX*
XY
20
These experiments demonstrate that eye color gene in this case is carried by the X chromosome, but not by the Y.
X-Linked Recessive Diseases
22
X-Linked Recessive Disease
Rare Gene: Haemofilia 2:10.000
no male to male transmission
23
Haemophilia in old ages
Circumcision
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Pedigree showing inheritance of hemophilia, an X‐linked trait, in the descendants of Queen Victoria. Many of the descendants in the third and fourth generations (third and fourth rows) have been omitted because the mutant gene was not transmitted to them.
Daltonism
Normal reads: 74
Daltonic reads: 21
26
X-Linked Recessive Disease
Common Allele
G6PDH Deficiency
VICIA FABA
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Some drugs can cause haemolysis in GSPDH deficient subjects
this peripheral smear of RBCs shows Heinz bodies. Heinz bodies are precipitated, oxidized hemoglobin. They are found in glucose‐6‐phosphate dehydrogenase deficiency (G6PD). 310200 MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD
Gene map locus Xp21.2
310200 MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD
Gene map locus Xp21.2
a | In Duchenne muscular dystrophy (DMD) patients, with a deletion of exons 45–54, an out‐of‐
frame transcript is generated in which exon 44 is spliced to exon 55. Owing to the frame shift, a stop codon occurs in exon 55, which prematurely aborts dystrophin synthesis. b | Using an exon‐internal antisense oligonucleotide (AON) in exon 44, the skipping of this exon can be induced in cultured muscle cells. Accordingly, the transcript is back in‐frame and a Becker muscular dystrophy (BMD)‐like dystrophin can be synthesized Fabry disease: symptoms in carriers: Late onset of symtoms.
MacDermot et al. (2001) reported clinical manifestations and impact of disease in
60 females with Fabry disease. The median cumulative survival was 70 years,
representing an approximate reduction of 15 years from the general population.
Six of 32 women had renal failure, 9 of 32 (28%) died of cerebrovascular
complications, and 42 (70%) had experienced neuropathic pain. Twenty (30%)
female patients had some serious or debilitating manifestation of Fabry disease.
X-Linked Dominant Diseases
•Females are affected twice as males •Affected males transmit the disease to all daughters but to no sons 34
#300049 HETEROTOPIA, PERIVENTRICULAR,
X‐LINKED DOMINANT
Alternative titles; symbols HETEROTOPIA, FAMILIAL NODULAR
PERIVENTRICULAR NODULAR HETEROTOPIA 1; PVNH1
HETEROTOPIA, PERIVENTRICULAR NODULAR, WITH FRONTOMETAPHYSEAL DYSPLASIA, INCLUDED
Gene map locus Xq28
TEXT A number sign (#) is used with this entry because X‐linked periventricular heterotopia is caused by mutation in the gene encoding filamin‐A (FLNA; 300017).
DESCRIPTION Periventricular heterotopia (PVNH) is a genetically heterogeneous condition. See also PVNH2 (608097), PVNH3 (608098), PVNH4 (300537), and PVNH5 (612881)
If we know that the child is affected with an X‐linked disease, than we can deduct the genotypes.
Be aware of exceptions!
Fragile X Syndrome
• Second most common cause of mental retardation (after Down syndrome)
• Cytogenetic abnormality appears as a constriction in the long arm of X‐chromosome during folate deficient culture conditions
• Mutation is present in an untranslated portion of the Familial Mental Retardation Gene (FMR‐1)
• Loss of function mutation
Fragile-X
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 July 2005 09:03 PM)
© 2005 Elsevier
Fragile X Transmission
• Male carrier
– detected by pedigree analysis and genetic tests
– 20% are clinically and cytogenetically normal
• Daughters are obligate carriers
– 50% are affected (i.e. retarded)
– transmit disease to grandsons of male carrier
• Risk of phenotypic effects
– depends on position in pedigree
– Sherman paradox
• Anticipation
– defect worsens with each successive generation
Fragile-X Pedigree
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 July 2005 09:03 PM)
© 2005 Elsevier
Fragile X Diagnosis
• Cytogenetics
• PCR based molecular methods of repeats in FMR‐1 gene
– normal – 10 ‐55 repeats
– permutation – 55‐200 repeats in carrier state
– mutation – 200 ‐ 4000 in full clinical syndrome
• Affected females
– unfavorable lyonization
Genetic and phenotypic heterogeneity
A
B
*
*
C
*
D
E
*
*
A-E: different genes
Same phenotype
* mutation
Different phenotypes
*
*
*
*
*
One gene, different mutations
*
Same phenotype
*
*
Different phenotypes
Same phenotype
One gene, identical mutations