X-inactivation: Lyon hypothesis: placental mammals randomly inactivate all but 1 X at the 200-400 cell embryo stage (blastocyst).

The inactivated X's become Barr bodies: late-replicating condensed chromatin sitting on the nuclear membrane (heterochromatin). Seen in XXY, XXX, etc.

Mosaics: example calico cats. Each cell inactivates one X at random. Descendant cells keep same X inactive. Mosaics: example calico cats.

Mechanism of inactivation: Xic (X inactivation center) first seen as a spot where the inactive X first folds after mitosis in Xq13. Xce (X-controlling element) affects the choice of what chromosome remains active. Its molecular action is still unknown.

XIST is a gene in the XIC region which is expressed only from the INACTIVE X. It has 8 exons, but it codes for structural RNA (not mRNA). TSIX overlaps XIST, but on the antisense strand. It is expressed in ES cells and in early embryos and it is thought to control XIST at the onset of X inactivation.

Barr bodies are inactive X chromosomes "painted" with XIST RNA. XIST encodes a large molecule of RNA Barr bodies are inactive X chromosomes "painted" with XIST RNA.

Some genes on X are not inactivated. Genes in pseudo-autosomal regions PAR1 and PAR2. Also, approx. 20% of other genes escape inactivation, ie, for them a 2:1 ratio does not pose a problem. XIST, active only on the Inactive X.

Sex Chromosome Aneuploidies nondisjunctions

Aneuploidie dei cromosomi sessuali: YO : letale nelle prime fasi dello sviluppo embrionale XO : sindrome di Turner (femmina, sterile) XY: maschio XX: femmina XYY: maschio normale (altezza >180cm) XXX: femmina normale, salvo alcuni casi XXY, XXXY o XXXXY: sindrome di Klinefelter (maschio, sterile)

Most fetuses with abnormal chromosome complements spontaneously abort, accounting for 20% to 50% of all miscarriages. The most common cause of miscarriage is X0.

X chromosome polyploidy 47, XXY (Klinefelter’s syndrome) extra X chromosomes predispose to azoo and female phenotype development (micropenis, etc.), mental retardation, disproportionate growth of the legs, and other somatic anomalies, with estimated incidence of 1:500 in newborns.

HUMAN TRISOMY Except for the sex chromosomes, only three trisomies are compatible with life.

PATAU syndrome = trisomy 13 - facial defects, polydactyly, heart defects, die within a few months of birth EDWARDS syndrome = trisomy 18 - small + muliple defects, usually die in first year of life DOWN syndrome = trisomy 21

Turner’s Syndrome XO 1/2500 live births Female, but sterile, often no breast development, short stature, some distinctive physical features ("webbed neck"). Generally normal intelligence.

Y chromosome polyploidy: Estimated incidence is 1:750 newborns, may be fertile with frequent miscarriage of their wives, perinatal death and chromosomal anomalies of their children.

There are men who appear to be normal men, but have an XX chromosomal combination (about 1 out of every 20,000 males), and women who appear to be normal women but have the XY combination.

Four brothers with testicular feminization syndrome Four brothers with testicular feminization syndrome. All four subjects in this photograph have 44 autosomes plus an X and a Y, but they have inherited the recessive sex-linked allele conferring insensitivity to androgens (male hormones).