L24 Sex chromosomes and sex determination Flashcards
Disorders of Sex Development (DSD)
see onenote
- defined as congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical
- most common birth defect in humans
- DSD is rapidly increasing
- fertility is rapidly decreasing
- most forms of DSD remain unexplained genetically - environment?
What are DSD?
- 4 points
Discordance between any aspect of sexual phenotype:
- genetic sex
- gonadal sex
- phenotypic sex
- brain sex
Clinical presentation of DSD
- birth
- adolescence
DSD recognised at birth
- indeterminate sex (ambiguous genitalia)
DSD recognised in adolescence
- a girl with testes or dysgenetic gonads and a Y chromosome
- SRY or SF1 mutation
Difficult to diagnose and to treat
Difficult decisions are required in DSD management
see onenote
- gender assignment vs gender identity
- genital surgery on infants
- unable to consent for themselves
- removal or not of gonads; cancer risk
Discordance of Genetic sex
- the types
see onenote
XY females
XX males
XXY Kleinfelters
XO Turners
Genetic sex determination
- translocation of SRY
see onenote
- sex chromosome evolved from autosomes
- PAR (pseudoautosomal region) important for segregation
- SRY sometimes recombined to X
Sex chromosomes abnormalities
see onenote slides and diagram
- single X required for male development
- 2 X required for normal female development
- small % of genes escape x-inactivation and x-imprinted genes
- dosage of the pseudoautosomal region
Early gonad differentiation in the mouse embryo
see onenote slides
Regulatory networks during sex determination
see onenote
SRY - conservation
see onenote
- SRY is poorly conserved
- only found in some mammal groups
- SOX9 highly conserved
- autosomal
SRY switch gene
see onenote
- single exon gene
- high mobility group (HMG) box
- binds to DNA and bends it
- structural protein
- poorly conserved
- expressed in testes
SRY - Randy
- XX mouse with SRY transgene
- developed testes
- male behaviour
- male secondary sexual characteristics
- but infertile…why?
SRY and SOX9 in mouse gonads
see onenote
- SRY transient expression in males only (Y)
- ~12 hours in mouse
- triggers up-regulation of SOX9 (autosomal)
SOX9 - the testis determinant
see onenote
- has SRY-like HMG-box containing gene #9
- mutations throughout the gene, unlike in SRY
- highly conserved between species >90%
- expressed in developing cartilage and testes
- autosomal - needed in both male and female
Campomelic dysplasia and XY sex reversal
- severe deficiency in cartilage formation - skeletal defects
- due to mutations in sox9
- 75% of CD patients are XY sex reversed females
- sox9 plays critical role in testis development
SOX9 promoter
see onenote
- auto-regulation for maintenance
Diagnostic tool for human DSDs
see onenote
Do they have the sry gene?
Do they have the sox9 gene?
Ability of sox9 to generate testes
see onenote slides
Could induce testis if you had sox9 expression in gonad
sox9 is necessary and sufficient for testis development
Does not need sry gene as long as you have a switch to turn on sox9
- but needs Y chromosome for fertility?
FOXL2
see onenote
- granulosa cell expression
- antagonistic to sox9 in the supporting cells
- suppression of foxl2 = expression of sox9
- knockout of foxl2 = partial sex reversal
- mutation of foxl2 = ovarian failure
Important for coordinating ovarian development
Granulosa cell
A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals.
FoxL2:SOX9
see onenote
- foxl2 can bind to sox9 promoter when bound to estrogen receptor
- suppresses sox9
- activates/permits ovarian development
