ANEUPLOIDIE Variazioni del numero di particolari cromosomi allinterno

ANEUPLOIDIE: Variazioni del numero di particolari cromosomi all’interno di un assetto

Non disgiunzione meiotica: Non disgiunzione meiotica completa: n n n+1 Aneuploidia Poliploidia n-1 n+1 n-1 n n

Diagnosi prenatale

Sindrome di KLINEFELTER: 47, XXY

Sindrome di TURNER: 45, X 0

CORPO DI BARR Cellule umane femminili normali XX, con corpi di Barr (frecce) Cellule umane maschili normali XY, senza corpi di Barr

Sex Determination in Humans • Chromosomal sex is determined at fertilization • Sexual differences begin in the 7 th week • Sex is influenced by genetic and environmental factors • Females (generally XX) do not have a Y chromosome • Males (generally XY) have a Y chromosome

Fig. 7. 10

Sex Differentiation • In early embryo there are two internal duct systems – Wolffian (male) – Müllerian (female) • At 7 weeks, developmental pathways activate different sets of genes • Cause undifferentiated gonads to develop as testes or ovaries • Determine the gonadal sex of embryo

Genes on the Y Chromosome • Cause the indifferent gonad to develop as a testis • Sex determining region is the SRY gene • Other genes on the autosomes play an important role • Once testes develop they secrete two hormones – Testosterone – Müllerian Inhibiting Hormone (MIH)

Females Develop in the Absence of Y • Embryonic gonads develop into an ovaries • Testosterone not produced – Wolffian system degenerates • MIH is not produced – Müllerian duct system develops to form oviduct, uterus and parts of the vagina • Sexual phenotype develops – Hormones are important

I. SRY codes for Testis-Determining Factor • Was the object of an intense search. • SRY gene on the Y chromosome was identified as the gene that codes for TDF: – SRY is translocated to X in rare XX males – SRY is absent from Y in rare XY females • The “home run” experiment by Koopman et al. used transgenic mice.

The Transgenic Sry Experiment: How It Was Done • Reference: Nature 351: 117 (1991) • Nuclei of fertilized XX eggs were injected with Sry gene, then the eggs were transplanted to surrogate mothers. • Sry gene then randomly incorporated into a chromosome and was inherited in subsequent cell divisions. • Animals karyotyped after development to adult.

Genotypically Female Mice Transgenic for SRY are Phenotypically Male XY male XX male

Dosage Compensation • Equalizes the amount of X chromosome products in both sexes • In XX females an inactivated X chromosome forms a Barr body in each cell • XY males do not contain Barr bodies

Lyon Hypothesis • One X chromosome is genetically active in the body cells; the second is inactive and tightly coiled • Either the maternal or paternal chromosome can be inactivated • Inactivation is permanent (reset in germ cells) • Inactivation of second X equalizes the activity of X linked genes in males and females • ROSENSTIEL AWARD - Mary Lyon (+ others) 2007

X Chromosome Inactivation • X chromosome inactivation – In cells of female mammals, either the maternal or paternal X chromosome is randomly condensed (Barr body) and is inactive – Occurs in an early embryonic stage, so that all descendents of that particular cell have the same inactive X chromosome, resulting in “mosaic” gene expression – The situation of only females cats with a calico coat is a result of Barr bodies

Lyon-Hypothesis: X-inactivation A precursor cell to all coat color cells Random inactivation early in dev. **Also in calico cats

Mosaicism Reveals the Random Inactivation of one X chromosome Anhidrotic ectodermal dysplasia in a heterozygous woman Regions where sweat glands are absent.

X Chromosome Inactivation (a) Note red Barr bodies in these 4 XX cells. (b) Two XY cell nuclei. (c) Dark patches are due to active pigment mutation of X chromosomes in skin cells.