Lecture 4 - Genetics of Sex III Flashcards
Describe colourblindness.
X-linked recessive
An affected male may have no affected children but all daughters will be carriers.
A carrier mother will pass the gene to half of her children, so half of the sons will be colourblind, and half of the daughters will be carriers.
How does the severity of a phenotype affect genetic disease transmission?
The more severe, the less likely to be passed on, as severely affected individuals will not be able to pass on their genes.
Describe haemophilia A
X-linked recessive
Deficiency of factor VIII
One of the earliest inheritance patters to be recognised due to prevalence in European royalty and their predilection to intermarry.
Describe duchenne’s muscular dystrophy
Serious X linked recessive.
Most commonly a de novo mutation in the mother passed to half of her sons.
30% of affected males sporadic mutations.
Affected females almost non-existent
Half of daughters carriers
Sons die young so don’t pass on mutation.
Why is the DMD gene have such a high mutation rate?
It’s the largest mammalian gene known.
Responsible for cell specific products, each of which having its own specific promoters and N-terminals.
There is commonly alternative splicing at the 3’ end
Deletion hotspots.
Describe hypophosphataemia
X-linked dominant
Affected male will pass only to his daughters and will pass to all of his daughters.
Affected female will pass to half of her offspring.
Describe incontinentia pigmenti
X-linked dominant
Affected females will pass to half of her daughters but none of her sons; this is because the mutation is lethal in males in utero.
Affected females also show skewed X-inactivation, presumably to compensate for the deleterious gene.
Affects NEMO gene involved in transcription, immune, inflammatory and apoptotic pathways.
Why do women show patchy manifestation of X-linked traits?
Women are mosaic due to variable X-inactivation, and show the two intermingling cell lines.
Patterns can follow the lines of blaschko, a developmental pattern of skin.
Describe X inactivation with respect to the manifestation of X-linked disease states
The two cell lines can interact;
-Metabolic co-operation (sharing of gene products)
-Cellular interference (induce function or repel movement of another)
-Cell competition (small growth differences leads to the eventual elimination of one type.)
Therefore affected cells may be supported by surrounding unaffected cells, or may die out and be replaced by the other healthy cell line.
How was the SRY gene isolated?
Deletion mapping from sex-reversed individuals and carriers of an aberrant Y.
Was not possible to use linkage analysis due to the lack of recombination on the Y chromosome
Is there a Y linked inheritance for hairy ears?
Well documented pedigree
affected males would have affected sons but no affected daughters.
This was later discovered to be incorrect when an affected female was found - it is likely affected females had just been shaving their ears.
Describe complete androgen insensitivity syndrome
46XY karyotype with intact SRY but female phenotype
Produce correct male hormones
BUT mutations in androgen receptor gene meant cells could not respond.
Describe congenital adrenal hyperplasia
deficiency of 21-hydrolase enzyme in kidney
Both XX and XY can inherit mutations
Results in overproduction of androgens from adrenal glands
So XX individuals exhibit male phenotype
Give examples of non-SRY mutated sex reversals
Complete androgen insensitivity syndrome
Congenital adrenal hyerplasia
Describe Y-linked non-syndromic deafness (DFNY1)
True Y linked deafness
Incredibly rare
Due to complex rearrangement of genes including insertion of 160kb from chr1
