Sex Chromosomes and X Inactivation

process of sex development

1. establishment of chromosomal sex at fertilization

2. differentiation of gonadal sex (by alternative genetic pathways) and development of the gonads (testis or ovaries)

3. sex-specific differentiation & development of other internal + external sexual organs (by actions of many genes)

4. development of secondary sex characteristics, mostly after puberty

disorders of sex development (DSDs)

family of diseases caused by mutations in genes involved in sex development

- gonads and/or phenotypic sex are inconsistent with the chromosomal sex

Y Chromosome

pseudoautosomal region (PAR1) at terminal end of p-arm

- SRY gene located near PAR1 (formerly testes determining factor)

- contains other genes necessary for normal spermatogenesis in males (e.g. AZF regions; DAZ genes)

dosage compensation

mechanism to equalize gene expression between males and females

- since females have 2 copies of X compared to males, there much be mechanism to compensate for the difference in genetic information

SRY (Sex-Determining Region Y)

primary determinant of male sexual development

- transcription factor (HMG box DNA-binding domain; SOX family TF)

- located near PAR1

- rare/incorrect homologous recombination outside of PAR1 results in SRY crossing over to the X chromosome

X inactivation (Lyonization)

inactivation of one X chromosome in females to equalize X-linked gene expression with males

Barr body

inactivated X chromosome condensed into heterochromatin

- densely staining body @ nuclear membrane

X Inactivation Center (XIC)

region of the X chromosome necessary for X inactivation

- in q arm of X chromosome

- contains several genes including XIST

XIST (X inactivation specific transcript)

gene responsible for X inactivation

- encodes a functional non-encoding RNA (no open reading frame = no encoded protein)

- expressed from inactivated X chromosome (increased expression @ late blastocyst stage)

- RNA spreads along length of inactive X chromosome

- mediates heterochromatin formation and inactivation

skewed X inactivation

one X chromosome (paternal or material) is inactivated more often than expected by random chance (outside of normal 70:30 range)

cell selection

process where cells with mutations on the active X chromosome are selected against

- cells carrying mutations on active X chromosome: express mutant gene therefore might have a selective and growth disadvantage

- cells carry mutations on inactive X chromosome: don't express mutated gene therefor no selective and growth disadvantage = survive and outcompete other cells (mutation is "hidden")

X-autosome translocations

balanced translocations between X and autosomes resulting in skewed X inactivation

- selection against cells with the normal X chromosome active

- surviving cells will have the normal X chromosome inactivated, and the translocated X chromosome active

- breakpoint disrupts an X linked gene = only functional copy of gene is on inactive normal chromosome (e.g. female DMD)

alpha thalassemia with mental retardation- X-linked (ATRX)

encodes SWI2/SNF protein (chromatin remodeling)

- X-linked

Rett syndrome

mutations in MECP2 encode MeCP2 (methyl CpG-binding protein 2 - mediates silencing by DNA methylation)

- X-linked dominant

MECP2

encodes MeCP2 (methyl CpG-binding protein 2) which mediates silencing by DNA methylation

- mutations leads to Rett Syndrome

pseudoautosomal region (PAR)

regions of homology between X & Y chromosomes

- normally the only location crossing-over occurs between X & Y

pseudoautosomal region 1 (PAR1)

found at p-arms of both X & Y chromosomes

- 2 copies in both males and females

- genes within this region appear to segregate as though autosomal

- NOT inactivated on the inactive X in females

- enables pairing of X & Y in male meiosis

- homologous recombination between X & Y in this region in males

gonadal development

begins between 6 - 7 weeks post-fertilization

- by default, ovarian development occurs unless SRY gene on Y chromosome is present (SRY turns on testicular development)

AZF regions

mutations in multiple genes in these regions causes azoospermia

DAZ genes

4 copies of an identical gene necessary for spermatogenesis

- deleted in azoospermia

46, XX +SRY

infertile phenotypic males with testes

- infertile due to missing other Y genes for spermatogenesis

- gain-of-function

46, XY -SRY

infertile phenotypic female with ovaries

- infertile since 2 X chromosomes required for oocyte maintenance

- loss-of-function

X inactivation (Lyonization) process

- gametogenesis: X chromosomes are activated and remain active through fertilization

- zygote + early embryo: both X chromosome are active

- ~1 week post-fertilization, late blastocyst stage: 1 X chromosome (paternal or maternal) randomly inactivated

- as those cells divide, all daughter cells will maintain inactivation of the same X

female X mosaicism

all females are --- with respect to X chromosome

- expected maternal X : paternal X inactivation ratio = 50:50

- actual ratios: 70:30 (maternal : paternal)

- doesn't manifest in obvious phenotype normally, but will in some diseases

X-linked hypohidrotic ectodermal dysplasia

mosaic distribution of sweat glands

- diagnosis: starch-iodine test

X-linked ocular albinism

mosaic pattern of retinal pigmentation

incontinentia pigmenti

swirling patterns of hyperpigmented skin

- X-linked dominant

# Barr bodies = # X chromosomes - 1

equation for calculating Barr bodies

- only 1 X chromosome remains active

- if > 2 X chromosomes, all but one will be inactivated

random X inactivation

incomplete & nonuniform

- PAR1 is NOT inactivated (2 copies in males & females = no need for dosage compensation)

- 10 - 15% of X chromosome escapes inactivation

- another ~10% is variably inactivated

true

T/F: in female carriers of X-linked diseases, the mutant allele is commonly found on the inactive X chromosome so it is not expressed and has no effect on the phenotype

severe combined immunodeficiency disease (SCID)

2 most common forms: X-linked recessive and autosomal recessive

clinical presentations:

- death or dysfunction of B, T, and NK lymphocytes

- no functional adaptive immune system

X-linked SCID

- X-linked recessive

- deficiency in IL2RG

IL2RG

mutations caused X-linked SCID

ADA deficiency

- autosomal recessive SCID

- deficiency in adenosine deaminase (ADA)

adenosine deaminase (ADA)

mutation causes autosomal recessive SCID

alpha thalassemia with mental retardation- X-linked (ATRX)

clinical presentations:

- mental retardation

- characteristic facies

- alpha-Thalassemia

Rett syndrome

clinical presentations:

- leading cause of intellectual disabilities in females (many cases are diagnosed as autism)

- onset: 6 - 18 months with failure to meet milestones

- characteristic hand-wringing

- progressive microcephaly

- ~50% seizures