X-linked disease Flashcards
What is weird about the gene to disease ratio of the x chromosome?
X chromosome has 4% of genes but accounts for 10% of diseases including: colour blindness, haemophilia and DMD.
Describe DMD
Duchenne muscular dystrophy - X-linked recessive but comes about becasue of new mutations 30% of the time. It is the biggest gene in humans and contains many different cell specific promoters each with their own 1st exon. The locus has a very high mutation rate and deletion hotspots correlate to recombination hot spots.
Give some examples of X-linked dominant disorders
Hypophosophataemia - gives vitamin D resistent rickets and short stature
Lethal - incontinentia pigmenti - affects males die in utero giving 2:1 F:M children.
How do X-linked disease effect females?
Patchy manifestations of the disease such as in hypohidratic ectodermal dysplasia or oral-facial-digital syndrome. There is extensive intermingling of cell populations so you get an additive effect of both alleles in a tissue.
Cells from these populatios can interact to share metabolic products, have cellular interference and cell competition may eliminate one cell population.
Note skewed inactivation can occur by chance or due to XIC mutations/deletions.
How was the TDF (testis determining factor) located?
Y chromosomes must have something that triggers maleness. Linkage studies wont work due to low recombination. However there are lots of aberrant Y’s around creating XX males and XY females. These can be used to create a deletion map and determine where the important gene is.
This located a region 7Mb proximal to PAR1. Did a chromosome walk - test against lots of different mammals for a common gene and found the SRY gene.
It is in a highly conserved region and expressed at the genital ridge at the correct time. Accounted for 25% of XY females and 80% of XX males.
What is the SRY gene
Small gene expressed in testis. It contains a high mobility group (HMG) where most XY female mutations cluster. Other SRY box related genes (SOX) also carry a related domain and are involved in development and one (SOX9) in sex determination.
Expression of SRY in mice causes cascade of gene interactions regulated by SOX9.
How are the XYF and XXM explained if they don’t always have the SRY?
Usually due to downstream GOF or LOF mutations.
for examples complete androgen insensitivity syndrome - can be XY but female
Congenital adrenal hyperplasia - overproduction of androgens from adrenal glads XX with male phenotype.
Are there any examples of Y linked disease?
Hypertension previously attributed to Y but the data is inconclusive.
CAD has a much higher incidence in men with a specific Y SNP. Transcriptome analysis shows changes in 30 KEGG pathways with greater than 50% of these pathways involving inflammatory or immune signaling cascades.
One Haplogroups in Y chromosomes was shown to give a faster progression to AIDS.
What is the Y important for?
Y carries fertility factors and deletion of the long arm of Y can lead to infertility. Long arm contains the AZF region - azoospermia factor. Many repeat genes so it is difficult to find point mutations that could be causative.
What are the 3 parts to the AZF region?
AZF-A only contains single copy genes and mutations result in no spermatogonia
AZF-B has both single copy and multicopy genes and mutations result in arrest at the spermatocyte stage.
AZF-C has only multi copy genes causes a low sperm count.
All are known to be genomic disorders
What are genomic disorders?
Most mutations are random but some are caused by underlying structural features of the genome. Mostly this is due to paralogs or segmental duplications
Non-allelic homologous recombination between misaligned repeats can cause: duplication, deletions, inversion gene segments and inactivation - all of these leads to dosage problems.
Duplications/deletions are usually due to direct repeats
Inversions are usually due to inverted repeats.
Why do these genomic disorder occur more often in the Y?
Y chromosome contains many more segmental duplications = 34-45% where as the rest of the genome is 5%. These regions are termed ampliconic. This is because the history of the Y is very unusual and also contains the PAR1 and recent transpositions from the X resulting in old shared XY regions.
AZF deletions usually due to nearby repeats such as HERV for AZFa and b2/b4 for AZFc.
Why is the Y termed self correcting?
Many of the amploconic regions contain palindromes.
These regions show low divergence from chimp compared to the spacer regions between them. This is because the two arms are evolving in concert and cause recurrent restoration of the original sequence after a region diverges.
How do the genes in the NRY and PAR differ?
How can the genes in the Y be classified?
PAR - 24 normal genes in single copies
NRY - 156 transcription units but about 0.5 are untranslated. 60 are from 9 families and are all mostly testis specific. 18 are single copy - usually with X copies, only 27 distinct proteins are made. Lots of pseudogenes.
Non random collection of genes with two major classes:
1) single copy with X homologues escaping inactivation and widely expressed.
2) multicopy genes and usually testis specific
+some exceptions.
