Genetics of Sex and the Sex Chromosomes Flashcards
How is sex determined in humans?
By the Y chromosome. It provides the initial genetic switch in the sex determination process
How did sex chromosomes evolve?
From autosomes
Selective pressure and accumulation of difference reinforced ability for the two proto-sex chromosomes to diverge
Which sex has more mutation?
Males
What is the parental age effect?
Older the parents, more likely for their child to carry a mutation
What is the dual role of meiotic recombination?
- Genetic diversity
2. Ensures accurate segregation of gametes
In which PAR region is recombination required for correct segregation of sex chromosomes?
PAR1
Which sex has more recombination?
Females
How does PRDM9 initiate recombination?
Acts on top of chromatic loops
Zinc finger domain interacts with specific DNA seqs
Set domain methylates lysine, opens chromatin
Allows SPO11 to induce double strand breaks and hence crossing over
What is non-disjunction?
Failure of meiotic
segregation
What is the consequence of non-disjunction?
Aneuploid gametes: games that don’t have the correct number of chromosomes
What is the only well-documented risk factor for Down syndrome?
Advanced maternal age
Two factors that are involved in non-disjunction?
Poorly placed recombination
Increased vulnerability with age
Features of meiosis I trisomy?
Usually one single exchange
Prone to loss of chiasmata prior to spindle attachment
50% risk non-disjunction
Features of meiosis II trisomy?
Increased exchange in centromere-proximal region
Entanglement of homologous until anaphase
What is the role of cohesins in chromosome disjunction?
Regulated separation of sister chromatids
Where are cohesin rings established?
During replication i.e. in vitro
What occurs in normal females in somatic cells?
One X chromosome is inactivated. Hypoactivation.
Seen as Barr body
What happens if there are extra X chromosomes?
All except one are inactivated. (n-1) rule
How is X inactivation maintained?
It is clonally maintained. Inactivated X expressed relevant products to give rise to its own inactivation
Is the same X inactivated in all cells?
No. Cells are somatic mosaics
What are the characteristics of the inactive X?
Heterochromatinised
Late replicating
Associated with nuclear envelope
Promoters hypermethylated
What is the X-inactivation centre?
Part of the counting mechanism
Two XICs are required, and must be on different copies of the X
Which X is the XIST transcribed from and where does it remain?
The inactive X
Stays associated with the inactive X and remains in the nucleus
Where do families with skewed X-inactivation have mutations?
In XIST promoter
What happens when mouse XIST is knocked out?
X can’t be inactivated
What happens in transgenic XIST mice?
Transgene can initiate inactivation
Inactivation is random
What does the transgenic XIST mice experiment show?
Shows that XIST contains controlling centre
What happens when transgene XIST is on the autosome?
Autosome starts showing some gene inactivation
See long range cis effects associated of XIST RNA and some gene inactivation
What is Tsix?
XIST antisense gene, transcribed from opposite strand
What does tsix knockout mouse show?
It shows preferential inactivation of mutant X
Indicates its a repressor
Where is tsix expressed?
Initially from both X’s, then from active X after onset of X inactivation
What does tsix do?
Block xist action so xist RNA only accumulates on future inactive X and not on the future active X
How many hours does it take to “lock-in” X-inactivation?
72 hours
Why is X-inactivation important?
For dosage compensation
Which areas escape X-inactivation?
Genes within PAR1
Why are autosomal aneuploidies poorly tolerated?
Because of gene dosage problems
Why are sex chromosomal aneuploidies well tolerated?
Y is not essential for viability. At least one X chromosome is essential, but extra X’s are inactivated so doesn’t matter
What is the general pattern of inheritance?
1 set of each autosome from each parent
Males - Y from father, X from mother
Females - X from father, X from mother
mtDNA from mother to all children
Example of X-linked recessive trait
Colour-blindness
Duchenne muscular dystrophy
Example of X-linked dominant trait
Hypophosphatemia
Incontinentia pigment
What is the SRY?
Sex-determining region Y. It is the testis-determining factor
Example of Y-linked inheritance
Hairy ears
What problems can non-allelic homologous recombination between misaligned repeats cause?
Duplication / deletion of genes - lead to dosage problems
Inversions of gene segments - gene inactivation
How are AZFa and AZFc infertility disorders caused?
Aberrant recombination between repeated sequences
