Download Sex Chromosomes and Sex

Sex Determination and Sex Chromosomes
Harry Ostrer, M.D.
I) Male Sex Determination
A) Genetically determined. Important genes have been identified by cases of genetic sex
reversal: 46,XX males and true hermaphrodites (gonadal tissue of both types) and 46,XY
females.
B) Major genes identified: SRY, SOX9, WT1, SF1, DAX1, XH2, WNT4A – Expressed in
developing testis.
C) Sex reversal can be familial. Examples are heritable SRY mutations and heritable Y-to-X
translocation.
D) Most cases of true hermaphroditism represent chimeras (product of two zygotes) or
mosaics (products of two different post-zygotically derived sex chromosome
aneuploidies or mutations).
II) Pseudoautosomal regions
A) Regions with sequence homology between the X and Y chromosomes.
B) These regions pair and recombine during male meiosis.
C) They are located on tips of sex chromosomes.
III) Sex-limited region
A) Linked to sexual phenotypes
B) Most genes in sex-limited region of Y have a male-only pattern of expression.
Examples: testis determination and spermatogenesis.
C) Other genes have homologues on the X and Y chromosomes although recombination
does not occur between these homologues.
IV) X chromosome inactivation
A) Described by Mary Lyon in 1961 (“Lyon hypothesis”).
B) In females, one of the two X chromosomes is inactivated in each somatic cell
(“Lyonized”).
1) X-inactivation occurs early during development. In each cell, selection of the
X-chromosome to be inactivated is random.
2) Inactivation is stable and is transmitted to the progeny cells.
C) X-inactivation originates at a specific site on the long arm of the X chromosome
(termed, the "X chromosome inactivation center" or Xce) and spreads over the
chromosome.
1) X chromosome inactivation can skip over regions of the X chromosome
affecting some genes, but not others.
2) Some of the loci that escape X chromosome inactivation have homologous
genes on the sex-limited region of the Y chromosome.
3) Degree of inactivation at a given locus is variable, ranging from complete to
none at all.
D) Skewing of X chromosome inactivation occurs as a consequence of the following:
1) Chance alone (as evidenced by discordance in monozygotic twins).
2) Heritable differences at Xce.
3) Selection for or against a mutant allele (Example: X-linked
adrenomyeloneuropathy due to a defect in the ABCD1 gene. In females cells
in which the chromosome with the mutant allele is inactivated are selected
against).
4) Balanced X-autosomal translocations - inactivation of the translocated X
chromosome spreads to the autosomal segment.
E) Molecular correlates of X chromosome inactivation:
1) XIST gene (for “X inactive-specific transcript”) is expressed from the inactive
X chromosome.
2) Regions of the inactive X chromosome are modified, with 5-methyl cytosine
at specific CG dinucleotides (mCG).
3) Late replication of inactive X chromosome.
V) Sex chromosome expression in germ cells.
A) Inactivation of X and Y linked genes occurs during meiosis in male germ cells.
1) This is the result of pairing and condensation of the sex chromosomes into a
“sex vesicle.”
2) Following meiosis, some X and Y linked genes are once again expressed.
B) X chromosome reactivation in oocytes.
1) For oogenesis to occur, expression of both alleles of several loci may be
important.
2) Individuals with a single X chromosome or with a deletion of one of several
different regions of the X chromosome have accelerated regression of the
ovarian follicles and thus, gonadal dysgenesis and infertility.
VI) X-linked phenotypes
A) Over 1200 conditions have been described. Some conditions have distinctive
phenotypic features, whereas others are non-specific (e.g., over 40 different forms
of X-linked mental retardation).
B) A hallmark is the absence of male-to-male transmission
C) More likely expressed in males than females. Expression of the phenotype in females
may be due to:
1) X-linked dominant trait (e.g. X-linked hypophosphatemic rickets); includes Xlinked dominant traits with male lethality which are expressed only in females
and usually as sporadic cases (e.g., incontinentia pigmenti, Rett syndrome).
2) A female being homozygous for the mutant allele.
3) A females being hemizygous with a 45,X karyotype
4) Skewed X chromosome inactivation.
VII) Aberrant X chromosome transmission. Unlike autosomal monosomies and most trisomies,
this is non-lethal.
A) 47,XXX
1) Mild developmental delay to no phenotype.
2) Only one of the X chromosomes is active.
3) Multiple copies of the genes that are not subject to X inactivation affect the
phenotype.
B) 47,XXY - Klinefelter Syndrome
1) Tall stature, a eunuchoid habitus, breast development, small testes with hyalinization
of the testicular tubules and infertility.
2) Only one of the X chromosomes is active.
3) Multiple copies of the genes that are not subject to X inactivation affect the
phenotype.
C) 45,X - Turner Syndrome
1) The only monosomy that is viable through gestation, but 90% of conceptuses
are not carried to term.
2) Single X chromosome is maternal in origin in 70–80%; thus, the paternallytransmitted sex chromosome is lacking
3) Associated with the Turner phenotype of webbed neck, shield chest,
coarctation of the aorta, short stature and renal malformations.
4) Associated with gonadal dysgenesis, a process of partial or complete
regression. This highlights the need for two structurally intact X chromosomes
that are active in the oocytes of the developing fetus to prevent ovarian
regression. Note that some individuals with 45,X/46,XX mosaicism do not
have gonadal dysgenesis.
5) Isodicentric chromosome of the long arm of X Is also associated with gonadal
dysgenesis and Turner phenotype, suggesting that critical anti-Turner genes
are located on the short arm of the X chromosome.
VIII) Overexpression of X-linked genes. Duplications of regions of the X chromosome indicate
the locations of dosage-sensitive genes.
A) dup(X)(p21)
1) Duplication of the short arm of the X chromosome leads to gonadal
dysgenesis in 46,XY individuals. This duplication suppresses the testisdetermining effects of the Y chromosome.
B) ring (X) with deletion of Xce
1) This chromosome is not subject to inactivation.
2) Abnormal phenotypes that include mental retardation and other features not
observed in 47,XXX or 47,XXY (Supernumerary X chromosomes are
inactivated.)
IX) Y-linked phenotypes have been inferred on the basis of male-to-male transmission, and have
been identified in individuals with deletions or translocations of the Y chromosome.
A) Testis determination.
1) The testis determination factor (TDF) has been mapped to the short arm of the
Y chromosome. Its position has been refined by analyzing the Y chromosome
of 46,XX males and 46,XY females with gonadal dysgenesis.
2) TDF is the same as SRY ("sex-determining region Y"). Mutations are
associated with gonadal dysgenesis. It is likely that SRY is a transcription
factor that is critical for a cascade of gene expression.
B) Spermatogenesis: interstitial deletions of Yq (deletion of AZFa,b,c genes) are
associated with:
1) Oligospermia, in which there is a decreased production of sperm
2) Azospermia, in which the production of sperm becomes arrested at an
immature stage of development.
C) Prevention of the Turner phenotype 1) Deletion of the short arm of the Y chromosome proximal to SRY is associated
with TS.
2) 45,X males with large Y-autosomal translocations do not have TS.
D) Gonadoblastoma (pericentric Y) - individuals with gonadal dysgenesis and
normal or structurally aberrant Y chromosomes develop tumors in their
dysgenetic gonads.